Metastatic castration-resistant prostate cancer

Chemotherapy for Prostate Cancer: Why Bother?

by Brad Guess, PA-C | Executive Director, PCRI | Edited from PCRI Insights May, 2006 vol. 9 no.2

Introduction

I recently had the opportunity to sit in on a prostate cancer (PC) journal club meeting attended by PC experts from a multitude of medical specialties. The focus of this meeting was the use of chemotherapy in PC, specifically docetaxel(Taxotere®), a drug recently approved by the Food and Drug Administration (FDA) for metastatic hormone-refractory prostate cancer. One participant at the meeting, an eleven year advanced PC survivor, patient advocate and lay expert, raised an important and challenging question about the results of the two large phase III clinical trials that led the FDA to approve the drug.

“I speak to guys with advanced disease every day,” he said.“They read these studies, and they say to me, ‘You’ve gotta be kidding me; if I do chemotherapy I’m going to live 2 to 2 1/2 months longer. Why bother?’” In this article, I will attempt to answer this question, as well as discuss the use of docetaxel in earlier stages of PC, and introduce some novel drugs in clinical development for advanced PC, many of which are being combined with chemotherapy.

The First Chemotherapy Drug to Increase Survival in Metastatic Hormone-Refractory Prostate Cancer

Prior to the approval of docetaxel in May 2004, the only other FDA-approved chemotherapy for advanced PC was mitoxantrone. Even though mitoxantrone showed no evidence of a survival benefit in two large randomized phase III clinical trials (in 1996 and 1999), the FDA approved it because it demonstrated that approximately one-third of symptomatic patients experienced improvement in pain.1,2

Then in October 2004, the New England Journal of Medicine reported on two studies using docetaxel in advanced PC. The first was TAX 327, which randomized 1006 men to docetaxel plus prednisone or mitoxantrone plus prednisone. After completion of the study, the median survival of all patients treated with docetaxel was 18.2 months compared with 16.4 months for those treated with mitoxantrone.3 The second study was SWOG 9916, which randomized 770 men to docetaxel and estramustine compared with mitoxantrone and prednisone. In this study, overall survival favored docetaxel (18.9 months compared with 16 months for mitoxantrone).4

Why Bother?

Mark Twain’s (sometimes attributed to Disraeli) famous quip about the practice of lying, identified three types, each worse than the one before – lies, damned lies, and statistics. “Survival analysis” with the production of “survival curves” (see Figure 1) is the most common statistical method used to determine the effectiveness of a new drug in cancer patients, for the purposes of FDA approval.

This type of analysis compares the “median survival” of one group of patients treated with a new drug or treatment to the median survival of those patients who were treated with a conventional drug (or placebo if no conventional drug exists). Median survival (see Figure 2) is the time at which half of the patients have died, or to say more optimistically, the time at which the percentage surviving is 50%.
In the two previously mentioned docetaxel studies, it was an increase in the median survival of men treated with docetaxel compared to the conventional drug mitoxantrone that led to FDA approval. Considering that docetaxel compared to mitoxantrone (a treatment which offered no improvement in survival) increased median survival by only 2 to 2 1/2 months, it is no surprise that many medical practitioners and informed patients ask the question “Why bother for 2 to 2 1/2 more months?” However, this conclusion should be avoided, since survival analysis is very easily misinterpreted, often in the direction of underestimating hope.

Survival Analysis

Several points should be made about the survival analysis in these studies. First, both studies crossed over (to docetaxel) men who initially received mitoxantrone and did not respond. In other words, some men who were treated with mitoxantrone eventually received docetaxel (the better treatment), but only after a considerable delay. This cross over skewed the differences in survival between the two treatment groups by improving the survival of some of the mitoxantrone treated men.

Second, survival analysis that is done by comparing median survival of two groups obscures an improvement in survival when less than half the men treated have their lives prolonged. This is because such analysis includes all patients, not only those who respond, but also those that do not respond. Additionally, the survival of any one individual may be much longer (in some cases several years) than that of the median of the study population.

The third point to consider is that median survival analysis says little about patients on the right side of the survival curve (the men who respond to treatment, despite a poor prognosis). In a study of the data of 217,573 patients with breast, colorectal, lung, and prostate cancer, Kato et al analyzed conditional median survival.5 Conditional median survival can be defined as a survival rate conditioned on having survived x years (for example, a 5-year rate for individuals having already survived 2.5-years). To say it another way, the prognosis of people with common cancers who had metastatic disease at the time of their initial diagnosis changed as a result of their continued survival.

The existence of a small group of survivors far past the “median” point, even in cancers with a dire prognosis such as advanced PC, should provide real hope even when the prognosis is bleak.

Lastly, and on a more practical note, when men who are not a part of a clinical trial are treated with chemotherapy and are not responding, their treatment is quickly changed, and they go on to other potentially beneficial treatments, which may also have the potential to extend life. These facts are not taken into consideration in survival analyses. (For a much more comprehensive and articulate handling of the statistics of survival and other related topics, see Steve Dunn’s excellent Web site www.cancerguide.org.)

A Closer Look at the Benefits of Docetaxel for Men with Advanced Prostate Cancer

In addition to survival, two other important benefits (which should not be overlooked) were seen in men treated with docetaxel. The first benefit was that pain was reduced more frequently among men receiving docetaxel compared to those treated with mitoxantrone. Anyone who has experienced or taken care of a man with bone pain from advanced PC understands the significance of this benefit. The second benefit seen with the use of docetaxel compared to mitoxantrone in men with advanced PC, was an improvement in quality of life. The greatest benefit in the docetaxel group with regard to quality of life was in the area of weight loss, appetite, pain, physical comfort, and bowel and genitourinary function. It is well known that if untreated, advancing PC will ruin the quality of life of a man, often for many months or even years, before he succumbs.

What About Chemotherapy in Earlier Stages of PC?

With the benefit of a docetaxel-based therapy in advanced PC now well established, its potential role in earlier-stage PC becomes a much more important question. There are several groups of earlier-stage PC patients to be considered. The first group is men who have been newly diagnosed with “high-risk” PC. Generally speaking, high-risk PC is defined as having a PSA > 20 or a Gleason score of 8 or higher or a Clinical Stage of T3 or higher determined by a digital rectal exam (tumor is already extending outside of the prostate gland). Men with high-risk PC have a high chance (usually > 50%) of disease recurrence even after definitive local therapy such as surgery, radiation or cryotherapy. The primary reason for this is the presence of microscopic disease outside the prostate and beyond the reach of the local prostate treatment. Clinicians and patients are now better able to identify those men at high risk through the use of nomograms (see Dr.Glenn Tisman’s article “Using Nomograms to Predict PC Treatment Outcomes” in PCRI Insights Nov 2005 Vol. 8, No. 4).

The use of chemotherapy in high-risk patients takes place in a “neoadjuvant” or “adjuvant” setting. (Neoadjuvant chemotherapy is the use of chemotherapy prior to any other treatment such as surgery or radiation. Adjuvant chemotherapy takes place at the same time as one or multiple other therapies.) Recently, pre-clinical data evaluating the optimal timing and combination of chemotherapy and hormone blockade supports the use of simultaneous therapy.6

Numerous small phase II trials using neoadjuvant and adjuvant chemotherapy in men with high-risk PC have been performed, with encouraging results.7 A small but interesting trial, and one which makes an argument for early chemotherapy in high-risk men, was performed by Wang et al.8 They randomly assigned 96 men with high-risk PC or advanced metastatic PC to mitoxantrone plus combined hormone blockade (CHB) versus CHB alone. In the 38 patients without metastatic disease treated with mitoxantrone and CHB, the median survival was significantly better (80 months compared to 36 months for patients treated with CHB alone). In contrast, no survival advantage was seen with the combination of mitoxantrone and CHB in men with metastatic disease. Several large randomized phase III clinical trials are ongoing or are planned and should give us better answers to the question of whether adding chemotherapy to the treatment of men with high-risk PC is effective.

The second study in which men are being treated with early chemotherapy focuses on men with a rising PSA after local therapy (commonly called a “PSA relapse”), especially men with a fast PSA doubling time (< 6 months), and risk of shortened survival.9 Hussain et al studied 39 men (7 with clinical metastasis and 32 without) with a rising PSA of > 4 ng/mL after surgery or radiation, treated with docetaxel followed by CHB for 12-20 months. The most interesting finding in the study was that five of the men treated with the combination maintained a low and stable PSA at 0.1ng/mL for a median of 18.9 months after therapy. Three of these five men had soft tissue metastasis at entry but remained in a complete remission.

A third group consists of men with hormone-refractory prostate cancer (HRPC). HRPC is commonly defined as a rising PSA despite castrate (= 20 ng/dL) levels of testosterone, but no visible cancer outside the prostate, such as in the bones or lymph nodes. Men who develop HRPC have a high likelihood of developing visible metastatic disease (in approximately nine months, according to one analysis11), especially if they do not achieve a PSA nadir of less than 0.05 ng/mL anytime after the initiation of CHB.12 The argument that chemotherapy should be utilized as soon as HRPC is diagnosed is suggested by experience and proven benefits reported in other solid tumors such as breast and colorectal cancer, where adjuvant chemotherapy is considered standard.13

Combining Chemotherapy with Novel Agents in Advanced Prostate Cancer

An important consideration when deciding on treatment for metastatic HRPC is the heterogeneity of the disease. Heterogeneity in advanced PC simply means that there are several or multiple forms or clones of PC cells existing within one patient. Therefore, the combination of chemotherapy with a novel or innovative agent takes advantage of our evolving understanding of advanced PC biology.

Table 1 contains a list of novel agents being studied individually or in combination with docetaxel in advanced PC. One of the more exciting of these novel agents for advanced PC is bevacizumab (Avastin®) which has already been approved by the FDA for kidney cancer. Bevacizumab is an antivascular endothelial growth factor (VEGF) antibody, and works by inhibiting the blood supply to tumors (antiangiogensis). In a phase II study of 79 men with advanced PC, the combination of docetaxel, estramustine and bevacizumab resulted in a PSA decline in 81% of patients, a median time to disease progression of 9.7 months, and an overall median survival of 21 months.14

Another antiangiogenic agent, thalidomide, has been evaluated in phase II studies both alone and in combination with docetaxel in men with advanced PC.15 When thalidomide was combined with docetaxel, the response rates were better than with docetaxel alone, and survival was improved. Recently, the use of the triple combination of docetaxel, thalidomide and bevacizumab in advanced PC was reported.16 Early results of this phase II trial of 60 patients show PSA response rates of 86% and significant improvement in measurable disease in many of the patients.

Another novel agent, DN-101, a high dose form of calcitriol, which is a biologically active form of vitamin D, has shown encouraging results when combined with docetaxel in advanced PC. Beer et al recently reported early results from the AIPC Study of Calcitriol Enhancing Taxotere (ASCENT).17 These results suggest an improved survival advantage with the combination versus docetaxel alone; however analysis is ongoing and larger studies are planned for the future. Interestingly, the addition of DN-101 appears to protect against side effects of chemotherapy, such as a loss of energy, gastrointestinal and thromboembolic events. (A full discussion of the side effects of chemotherapy will be presented in an article in an upcoming issue of Insights.)

Radiopharmaceutical agents, namely strontium-89 and samarium-159 have been shown to relieve bone pain in men with metastatic PC.18,19 (This was described in Oliver Sartor’s article, “Newer Concepts in the Treatment of HRPC with Bone Metastases” in PCRI Insights May 2005 Vol. 8, No. 2.) It is thought that by releasing short-range radiation, these agents may kill PC cells in bone, leading to relief of pain. Data from a small phase I study combining samarium and docetaxel has shown impressive results with a decrease in PSA of > 80% in 4 of 6 patients.20 Further studies are ongoing.

Conclusion

With the benefit of docetaxel-based therapy in advanced PC now well established, more men are likely to be offered chemotherapy in advanced disease. The conclusion that the only benefit one can expect is 2 to 2 1/2 months increased median survival is deceptive. This small time period is a watered-down average that includes all the men who did not respond as well as men who were treated with mitoxantrone but subsequently were treated with docetaxel. Other benefits received by chemotherapy in this group of men, such as a reduction in pain and general overall improved quality of life, also need to be pointed out. In all likelihood the use of neoadjuvant or adjuvant chemotherapy in high-risk, PSA relapse and HRPC patients is going to be utilized with increased frequency. Lastly, the combination of docetaxel with novel cancer agents is a logical extension, and exciting responses are occurring that in the past would have never been thought possible.

1. Tannock IF, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone- resistant prostate cancer: A Canadian randomized trial with palliative endpoint. J Clin Oncol 14:1756-1764, 1996.

2. Kantoff PW, et al: Hydrocortisone with or without mitoxantrone in hormone-refractory prostate cancer: results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol 17:2506-2513,1999.

3. Tannock IF, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351;1502-1512,2004.

4. Petrylak DP, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513-1520,2004.

6. Eigl B,et al: Timing is everything:Pre-clinical evidence supporting simultaneous rather than sequential chemo-hormonal therapy for prostate cancer. Clin Cancer Res 11:4905- 4911,2005.

7. Gleave M, et al: High-Risk localized prostate cancer: A case for early chemotherapy. J Clin Oncol 23(32):8186-8191, 2005.

8. Wang J, et al: Adjuvant mitoxantrone chemotherapy in advanced prostate cancer. BJU Int 86:675-680, 2000.

9. D’Amico AV, et al: Prostate specific antigen failure and mortality. Prostate Cancer Sym (suppl; abstr 204:195) 2006.

10. Hussain A, et al: Docetaxel followed by hormone therapy in men experiencing increasing prostate-specific antigen after primary local treatment for prostate cancer. J Clin Oncol 23(12): 2789-2796, 2005.

11. Bianco FJ, et al: Duration of response to androgen deprivation therapy and survival after subsequent biochemical relapse in men initially treated with radical prostatectomy. J Clin Oncol 22: 394s, (suppl; abstr 4552), 2005.

12. Scholz, et al: Ultra-sensitive PSA nadir on testosterone-inactivating pharmaceutical accurately predicts early prostate cancer progression. Prostate Cancer Sym (suppl; abst 40:113), 2006.

14. Picus J, et al: The use of bevacizumab with docetaxel and estramustine in hormone refractory prostate cancer: Initial results of CALGB 90006. Proc Am Soc Clin Oncol (suppl; abst 1578) 2003.

15. Salimichokami M, et al: Combining angiogenesis with cytotoxic chemotherapy enhances PSA response in hormone refractory prostate cancer: a randomized study of weekly docetaxel alone or in combination with thalidomide. Proc Am Soc Clin Oncol (suppl; abst 1725) 2003.

16. Ning, YM, et al: A phase II trial of docetaxel, thalidomide, bevacizumab, and prednisone in patients with metastatic androgen-independent prostate cancer. Prostate Cancer Sym (suppl; abst 224: 205) 2006.

17. Beer TM, et al: “ASCENT: A double-blinded randomized study of DN-101 plus docetaxel vs. placebo plus docetaxel in androgen independent prostate cancer (AIPC)”. ECCO (abst 811), 2005.

18. Oosterhof GO, et al:Strontium-89 versus palliative local field radiotherapy in patients with hormonal escaped prostate cancer: A phase III study. Eur Urol 44: 519-526, 2003.

19. Sartor O, et al: Samarium-153 for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology 63:940-945, 2004.

20. Widmark A, et al: Optimizing the time of co-administration of docetaxel and samarium-153 for advanced androgen independent carcinoma of the prostate . Proc Am Soc Clin Oncol 22: 433, 2003.

September 8, 2014

Introduction

To help doctors give their patients the best possible care, the American Society of Clinical Oncology (ASCO), along with Cancer Care Ontario, has developed recommendations on systemic, or full-body, treatments for men with metastatic castration-resistant prostate cancer. This guide for patients and caregivers is based on ASCO recommendations.

Key Messages:

  • Metastatic castration-resistant prostate cancer is when the cancer has spread to parts of the body other than the prostate, and it is able to grow and spread even though drugs or other treatments to lower the amount of male sex hormones are being used to manage the cancer.
  • When deciding on treatments for metastatic castration-resistant prostate cancer, it is important to weigh the possible benefits with the risks and costs.
  • There are several different treatment options available for this type of prostate cancer.
  • In addition to treatment for the cancer, relieving symptoms and side effects is an important part of cancer care and treatment.

Background

Prostate cancer growth is often driven by male sex hormones called androgens, which include testosterone. Because of this, a common treatment option for prostate cancer is to lower the levels of androgens in a man’s body. Androgen levels can be lowered by surgically removing the testicles or with drugs that stop the testicles from making androgens or block how they affect the body. This type of treatment is called hormone therapy or androgen-deprivation therapy.

If the cancer spreads to other parts of the body beyond the prostate in a process called metastasis, hormone therapy is usually continued. Eventually, many men with metastatic prostate cancer develop castration-resistant disease. This means that the cancer is able to grow and continue to spread despite using hormone therapy. For men with this type of disease, additional treatment is needed to help control the growth of the cancer. These treatments may include chemotherapy, targeted therapy, and other types of treatments.

Recommendations for men with metastatic castration-resistant prostate cancer

ASCO recommends that men with metastatic castration-resistant prostate cancer continue hormone therapy to keep androgen levels in the body low, regardless of the other treatments used. Relieving side effects, also called symptom management or palliative care, is also an important part of cancer care and treatment.

The following treatments may be given in addition to continuing hormone therapy:

  • Abiraterone (Zytiga) and prednisone (multiple brand names)
  • Enzalutamide (Xtandi)
  • Radium-223 (Xofigo) for men with cancer that has spread to the bone
  • Docetaxel (Docefrez, Taxotere) and prednisone
  • Sipuleucel-T (Provenge) for men who have few or no symptoms from the cancer
  • Cabazitaxel (Jevtana) and prednisone for men with prostate cancer that has worsened while receiving docetaxel

The following treatments could be options, as well. However, the research has not yet shown that they lengthen men’s lives:

  • Mitoxantrone (Novantrone) plus prednisone
  • Bicalutamide (Casodex), flutamide (Eulexin), nilutamide (Nilandron), which are all types of anti-androgens
  • Ketoconazole (Nizoral, Xolegel)
  • Low-dose corticosteroids

The following treatments are not recommended:

  • Bevacizumab (Avastin)
  • Estramustine (Emcyt)
  • Sunitinib (Sutent)

What This Means for Patients

A diagnosis of metastatic castration-resistant prostate cancer often means that treatments to slow, stop, or eliminate the cancer are no longer working by themselves. This diagnosis is stressful, and it may be difficult to discuss with your health care team. There are several promising treatments available, each of which affects a man’s life differently. Because of the variety of treatment options, men should talk with their doctor about the different treatment options for castration-resistant prostate cancer, including the overall goals of treatment, possible benefits, the risks, and the costs. Before considering additional treatments, it is important to have open and honest conversations with your doctor and health care team to express your feelings, preferences, and concerns.

Questions to Ask the Doctor

Consider asking the following questions of your doctor:

  • What type of prostate cancer do I have? What does this mean?
  • What is my prognosis (chance of recovery)?
  • What clinical trials are open to me?
  • What treatment plan do you recommend? Why?
  • What is the goal of each treatment? Is it to eliminate the cancer, help me feel better, or both?
  • How well is this treatment likely to work? What are the risks?
  • How will we know the treatment is working?
  • How will my quality of life change over time?
  • What are the next steps if the cancer worsens or comes back?
  • What treatments are available to manage the symptoms of the cancer?
  • If I’m worried about managing the costs related to my cancer care, who can help me with these concerns?
  • Where can I find support for me and my family?
  • Whom should I call with questions or concerns?

Read the entire clinical practice guideline published at a separate ASCO website.

Guide to Prostate Cancer

Hormone Therapy for Advanced Prostate Cancer

Advanced Cancer Care Planning

Navigating Challenges Video Series: Talking with Your Cancer Care Team, Making Decisions about Your Cancer Treatment, Managing the Cost of Your Cancer Care, and Finding Emotional Support after a Cancer Diagnosis

‘More Is Not Better’ in Metastatic Castration-Resistant Prostate Cancer

CHICAGO—Combination therapy with enzalutamide, abiraterone, and prednisone did not prolong overall survival in men with metastatic castration-resistant prostate cancer (CRPC) compared with enzalutamide alone.

The results of the Alliance A031201 study (abstract 5008) were presented by Michael J. Morris, MD, of Memorial Sloan Kettering Cancer Center in New York, at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 31–June 4 in Chicago.

When androgen receptor agonists are used for the treatment of metastatic CRPC, compensatory mechanisms can limit the anti-androgen activity. Therefore, the Alliance A031201 investigators hypothesized that combining the anti-androgen enzalutamide with the androgen biosynthesis inhibitor abiraterone to prevent androgen compensation would prolong survival. The primary endpoint was overall survival (OS).

“Secondarily, this was the third of a preplanned series of prospective studies to qualify radiographic progression–free survival (rPFS) as a regulatory outcome measure sufficient for new drug approval and, therefore, we examined the relationship of rPFS and OS,” said Morris.

The phase III trial included patients with progressive metastatic CRPC who had not received prior treatment with taxanes or enzalutamide, abiraterone, and prednisone; however, chemotherapy was allowed for nonmetastatic prostate cancer that had progressed. In total, 1,311 patients were randomized to receive enzalutamide (n = 657) or enzalutamide plus abiraterone and prednisone (n = 654). Randomization was stratified by prior chemotherapy and Halabi prognostic three risk groups, factors which were adjusted for in the primary analysis.

“There’s simply not that much more anticancer activity in one arm vs another,” said Morris.

The investigators continued to image the patients post-treatment if the patients ended treatment for nonradiographic progression–related reasons, providing on-treatment and off-treatment rPFS. Overall, rPFS was not different between the on- and off-treatment groups; however, to qualify rPFS as a regulatory biomarker for drug approval, the correlation between on-treatment rPFS and OS (Kendall’s tau), which represents a per-patient level analysis, was strong, at 0.70 (95% CI, 0.67–0.72), meaning that “the faster a patient progresses, the shorter his life,” noted Morris.

Progression or death occurred in 48% of patients taking enzalutamide/abiraterone/prednisone and 57% of patients taking enzalutamide alone. The primary reason for discontinuing treatment was radiographic progression (enzalutamide, 42% vs combination, 33%).

Grade 3–5 adverse events occurred in 55.6% and 68.8% of patients taking enzalutamide and enzalutamide/abiraterone/prednisone, respectively. Treatment discontinuation (12% vs 5%) and patient withdrawal rates (13% vs 5%) were higher in the combination group due to adverse events.

“The Alliance study shows that more is not better in first-line metastatic therapy,” said Michael Carducci, MD, of the Sidney Kimmel Cancer Center at Johns Hopkins, who was the discussant for the study.

Introduction

Prostate cancer is one of the most commonly diagnosed cancer in men in the United States with an estimated 164,690 new cases and 29,430 deaths in 2018.1 Most prostate cancer patients are diagnosed at a localized stage and are treated with definite radiotherapy, radical prostatectomy (RP), or active surveillance.2–4 About 40–50% of patients, who initially present with the localized disease eventually progress.5,6 Biochemical recurrence (BCR) is a clinical stage of prostate cancer in which patients present with a rising prostate-specific antigen (PSA) level, after initial definite local therapy and no evidence of metastasis on conventional imaging like radionuclide bone imaging, computed tomography (CT) scan or magnetic resonance imaging (MRI). Systemic treatment with androgen deprivation therapy (ADT) has an important role in the management of patients with BCR who are not candidate of salvage prostatectomy, salvage radiation therapy or who have BCR recurrence after salvage treatment. Early initiation of ADT in BCR reduces PSA level and delays time to metastatic disease.7 However, randomized controlled trials are lacking to demonstrate the impact of early ADT on overall survival (OS), prostate cancer-specific survival, and quality of life (QoL) in patients with BCR. Many patients who receive ADT for BCR eventually progress. The median duration of response to ADT in patients with non-metastatic prostate cancer is 19 months, after which many men progress to non-metastatic castrate-resistant prostate cancer (nmCRPC).8 The disease state in which patients have PSA recurrence only while on ADT without evidence of metastasis on conventional imaging including radionuclide bone imaging, CT scan, or MRI is defined as nmCRPC.9

This review discusses the role of AR in prostate cancer, mechanism of resistance to ADT, nmCRPC stage, the clinical development of apalutamide, pivotal trials evaluating apalutamide, enzalutamide, and darolutamide in nmCPRC, and the active clinical trials evaluating the role of apalutamide in different stages of prostate cancer.

Role of the androgen receptor (AR) and ADT in prostate cancer

The AR mediates the action of androgens by acting as a transcription factor.10 The AR consists of N-terminal domain, central DNA binding domain, and C terminal ligand binding domain (LBD).10 Testosterone, a weak ligand is converted by 5-alpha reductase to potent dihydrotestosterone (DHT) in prostate cells. When DHT binds to C terminal LBD of AR, conformational changes occur in AR and heat shock protein dissociates from AR.10 The androgen-AR complex forms a dimer and enters the nucleus where it binds to specific DNA sequences called androgen responsive elements and activates transcription.10,11 Charles and Huggins first recognized that prostate cancer cells thrive on androgens (testosterone and DHT) and ablation of androgens cause prostate cancer cells to undergo apoptosis and the cells who survive are arrested in the G1 phase of cell cycle.12 Since then, ADT has been the critical component of the management of prostate cancer for the last several decades which is achieved by suppression of gonadal androgens by gonadotrophin-releasing hormone (GnRH) agonist. Several mechanisms of ADT resistance have been proposed including incomplete blockade of AR, ligand activation by intra-tumoral androgen which activates AR signaling pathway despite castrate level of testosterone, amplification of AR gene, AR mutation, ligand-independent activation of ARr by oncogenes such as ERBB2 or HRAS which can cause increased mitogen-activated protein kinase signaling, and activation of other survival pathways including PI3K pathway.13–17

Non-metastatic castrate resistant prostate cancer

The incidence of nmCRPC in the United States is about 50,000–60,000 cases per year.18 Prostate Cancer Working Group 3 defines nmCRPC as rising PSA level with 25% increase above the nadir level (considering a starting value of ≥1ng/mL) with minimum rise of 2 ng/mL, no evidence of local recurrence or distant metastases on conventional imaging including radionuclide bone imaging, CT scan or MRI, and serum testosterone level <50 ng/mL (castrate level). The value of rising PSA should be confirmed on the second measurement, 3 weeks apart.9 The average metastasis-free survival (MFS) in patients with nmCRPC is about 25–30 months.19 Approximately, one-third of patients with nmCRPC develop bone metastasis in 2 years.19,20 PSA doubling time (PSA-DT) (estimated time required for the PSA level to double) <10 months is associated with a significant risk of progression to metastasis in patients with nmCRPC.21 nmCRPC is a challenging disease for the development of therapeutic strategies due to the lack of radiologic evidence of metastatic disease and the absence of clinical symptoms. Until recently, the standard of care for nmCRPC was continuation of GnRH agonist, addition of first-generation AR antagonist (nilutamide, flutamide or bicalutamide) to GnRH agonist, increasing the dose of bicalutamide, switching to other AR antagonist, AR antagonist withdrawal, or other hormonal therapies with no significant impact on OS.22–28

A known limitation of conducting studies in localized prostate cancer is the long-term follow-up required to assess the impact of the therapeutic intervention on OS which in some cases exceeds a decade. This paradigm changed about 2 years ago when Intermediate Clinical Endpoints in Cancer of the Prostate study (ICECap), a meta-nalysis of 28 randomized trials with localized prostate cancer, found a strong correlation between change in MFS and change in OS (Kendall’s t correlation, 0.91). MFS (as per ICECaP study) is the time measured from the date of random assignment to the date of the first evidence of metastases confirmed by imaging or histologic evidence – or death from any cause.29 Consequently, MFS was recognized as a surrogate marker for OS in patients with prostate cancer based on ICECaP study.29 This endpoint was considered for all confirmatory Phase III studies in nmCRPC setting and will be discussed later. In 2011, the FDA recognized MFS as a reasonable clinical endpoint as the development of the metastatic disease is a clinically relevant event that can be associated with pain and need for additional interventions.30,31

Pharmacologic properties of apalutamide

Apalutamide (ARN-509) is a synthetic beryl thiohydantoin that retains full AR antagonist activity in the setting of increased AR expression.32 Apalutamide is a novel, second-generation AR antagonist which demonstrated seven to ten fold greater affinity to AR than bicalutamide in vivo and animal models.33 Apalutamide inhibits nuclear translocation of AR and inhibits binding of AR to androgen response like elements in the context of AR expression.33 Apalutamide did not exhibit agonist activity in prostate cancer cell lines which were made to overexpress AR as in metastatic castration-resistant prostate cancer. Apalutamide caused ≥50% tumor regression in eight of ten castrate immunodeficient mice harboring LNCaP/AR xenograft tumors, whereas bicalutamide caused ≥50% tumor regression in only one of ten mice.33 Clerg et al compared the dosage of enzalutamide and apalutamide in the murine xenograft model of human CRPC and showed that maximal therapeutic response of apalutamide was achieved at 30 mg/kg/day, whereas the same response required 100 mg/kg/d of enzalutamide and higher steady-state plasma concentration.33 Enzalutamide and apalutamide have low affinity for the GABA receptor in the brain. However, the steady-state level of apalutamide was four fold lower than enzalutamide, suggesting lower seizurogenic potential and less CNS adverse effects as compared to enzalutamide.33

Clinical development of apalutamide: Phase I, II, and III data

The first in human, Phase I trial of apalutamide enrolled 30 patients with progressive metastatic castrate-resistant prostate cancer (mCRPC). The primary objective of this trial was to assess the pharmacokinetics (PK), safety, tolerability, and to define the recommended Phase II dose (RP2D).34 A total of 30 patients with a median age of 68 years (45–81), baseline median PSA of 42 ng/mL (2.3–326.6) were included. The patients were assigned sequentially to escalating dose levels of apalutamide following a traditional 3+3 design, in a 28-day cycle. The starting dose of apalutamide was 30 mg once daily. The most common adverse effects of any cause were fatigue (47%), back pain (30%), diarrhea (30%), arthralgia (24%), nausea (26%), and dyspnea (29%), all of them were grade 1–2. Only three patients (9%) had grade 3 adverse effects including abdominal pain, nausea, and arthralgia. At 12 weeks, 14 (46.7%) of 30 patients had a ≥50% decline in PSA as compared with baseline. The median PSA change from baseline at 12 weeks was −43.2% (range, −98.6% to 120.6%), and the maximum median decline on the study was −62.7% (range, −99.8% to 16.7%). Five (50%) of the ten patients who had baseline measurable soft tissue disease showed stable disease >6 months. One patient (10%) experienced disease progression and four patients (40%) had an indeterminate response. Apalutamide was rapidly absorbed, with peak plasma concentrations in 2–3 hrs after administration. Peak concentrations of apalutamide and AUCs were dose proportional. The RP2D dose of apalutamide was 240 mg daily.34 Based on these data, a Phase II multicenter, multicohort study was initiated with three distinct sets of patients 1) high-risk nmCRPC, 2) chemotherapy-naive and abiraterone acetate/prednisone-naive mCRPC, and 3) progressive mCRPC after abiraterone acetate plus prednisone.35,36 In the high-risk nmCRPC cohort (PSA≥8 ng/mL, PSA-DT≤10 months or both), 51 patients were enrolled. Apalutamide was given at the dose of 240 mg orally daily. The primary endpoint was post treatment percentage change in PSA relative to baseline at 12 weeks (or earlier for those who discontinued therapy) and maximal change at any time on the study. The secondary endpoints were time to PSA progression (TTPP) and MFS. The median age of the enrolled patients was 71 years (51–88), 57% of patients had Gleason score ≤7, 35% had Gleason score 8–10, baseline PSA level was 10.7 ng/mL (0.5–201.7), and 45% of patients had PSA-DT was ≤10 months. At 12 weeks, 89% had a PSA decline of ≥50%. The median TTPP was 24 months (95% CI, 16.3 months – not reached); median MFS was not reached (95% CI 33.4 months – not reached). Apalutamide was discontinued in 22% of patients due to disease progression and in 18% of patients due to adverse effects. The most common adverse effect was fatigue (61%); however, only 4% of patients experienced grade 3 fatigue.36 The positive results in the high-risk nmCRPC cohort led to the international Phase III, double-blind, placebo-controlled trial (SPARTAN) which evaluated apalutamide in patients with high-risk nmCRPC with PSA-DT of ≤10 months.37 The primary endpoint was MFS. Secondary endpoints were time to metastasis, progression-free survival (PFS), time to symptomatic progression, OS, and time to the initiation of cytotoxic chemotherapy. Exploratory endpoints included TTPP (defined as time from randomization to PSA progression according to Prostate Cancer Working Group 2 criteria),38 PSA response rate, patient-reported outcomes, and second PFS. The second PFS was defined as the time from randomization to investigator-assessed disease progression (PSA progression, detection of metastatic disease on imaging, symptomatic progression, or any combination thereof) during the first subsequent treatment for metastatic castration-resistant disease or death from any cause.

A total of 1207 patients were randomized in 2:1 fashion to receive apalutamide 240 mg daily (807 in the apalutamide arm) or placebo (401 in the placebo arm) and ADT was continued in both arms during the study. The patients were stratified by PSA-DT (<6 months or ≥6 months), use of bone-sparing agents and classification of nodal status as N0 or N1. The median age of the patients was 74 years (range, 48–97), 71.3% had a PSA-DT ≤6 months, 10.0% used a bone-sparing agent, and 83.6% had N0 nodal status. Most of the patients (73.1%) had previously used a first-generation AR antagonist. At the planned primary analysis, apalutamide demonstrated significant improvement in MFS compared with placebo (40.5 vs 16.2 months; HR for death or metastasis: 0.28, 95% CI 0.23–0.35; p<0.001). Similarly, median PFS was 40.5 months in the apalutamide arm vs 14.7 months in the placebo arm (HR: 0.29; 95% CI 0.24–0.36; p<0.001). Of the other exploratory endpoints, apalutamide was associated with improved TTPP (HR: 0.06; 95% CI 0.05–0.08; p<0.0001), time to symptomatic progression (HR: 0.45; 95% CI 0.32–0.63; p<0.001), and time to initiation of cytotoxic chemotherapy (HR: 0.44; 95% CI 0.29–0.66). PSA response rate (≥50% decline) was observed in 90% of patients in the apalutamide group as compared to 2% in the placebo group. The patients in the apalutamide arm reported stable overall health-related QoL as did the patients in the placebo arm. The second PFS was significantly longer in the apalutamide arm than the placebo arm (HR: 0.49; 95% CI 0.36–0.66). Of note, the OS data were not mature at the time of publication but apalutamide showed a trend toward improved OS with HR of 0.70. Notably, an exploratory landmark analysis in the SPARTAN trial suggested an association between MFS and OS in high-risk nmCRPC who develop metastases at 6, 9, and 12 months (Spearman’s correlation coefficient: 0.62; p<0.0001).39

The most common adverse effects of any grade in the apalutamide group versus the placebo group were fatigue (31.3% vs 21.4%), hypertension (39.1% vs 31.6%), rash (29% vs 5.8%), diarrhea (21.3% vs 15.6%), and falls (17.3% vs 9.8%). Significant (grade 3 or 4) adverse events were observed in 45.1% of patients in the apalutamide group compared with 34.2% in the placebo group. Due to adverse effects, 10.6% of patients discontinued apalutamide as compared to 7% in the placebo group.39 The treatment-related mortality rate in the apalutamide group was 1.2% as compared to 0.3% in the placebo group. Based on the improvement in MFS, FDA approved apalutamide on 14 February 2018 for the treatment of patients with nmCRPC.40

Genomic data and apalutamide resistance

Despite the activity of apalutamide in CRPC, resistance to apalutamide eventually develops and associated with specific mutations in the AR gene. The most studied example includes F877L mutation, a missense mutation at AR LBD. F877L mutation was found to be associated with a lack of antitumor activity in castrated immunodeficient mice injected with LNCaP cell lines expressing F877 L mutation.41 In a Phase I study of apalutamide, 3 (10.3%) of the 29 enrolled patients showed F877L mutation in circulating tumor DNA samples after treatment with apalutamide with no evidence of F877 L mutation in pretreatment samples suggesting acquired treatment resistance to apalutamide.41 A different Phase II study by Rathkopf et al showed that only 2 (2.2%) of 93 patients analyzed had the F877L mutation at baseline suggesting that other mechanisms may play a role in resistance to apalutamide including AR splice variant within the N-terminal domain, increase steroidogenesis, development of androgen-independent tumor and/or activation of the PI3K signaling pathway.42–44 Further studies are needed to detect de-novo and acquired mutations in patients exposed to apalutamide which would help to optimally use apalutamide in sequence or in combination with other AR signaling targeting agents.

Treatment options for patients with nmCRPC

In addition to apalutamide, two other novel AR-targeted therapies – enzalutamide and darolutamide were evaluated in nmCRPC and are briefly discussed here.

Enzalutamide is a second-generation AR antagonist which inhibits binding of androgen to AR, inhibits AR translocation to the nucleus, impairs DNA binding to androgen response elements, and recruitment of coactivators.45 Enzalutamide has five to eight fold affinity than bicalutamide for AR and unlike bicalutamide, it does not appear to switch from antagonist to agonist.46 Two large multicenter Phase III trials (PREVAIL and AFFIRM) established the safety and efficacy of enzalutamide in patients with metastatic prostate cancer while PROSPER study evaluated the efficacy of enzalutamide in nmCRPC setting.47–49 PROSPER involved 1401 nmCRPC patients with PSA-DT of ≤10 months and randomized them to receive enzalutamide 160 mg daily or placebo, ADT was continued in both arms.49 The median MFS was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group (HR for metastasis or death, 0.29; 95% CI 0.24 −0.35; p<0.001). In the interim analyses of secondary or exploratory endpoints, TTPP, PSA response rate, time to the first use of subsequent antineoplastic therapy was longer in the enzalutamide group than in the placebo group. The median OS was not reached in either group. The most common adverse effects of any grade in the enzalutamide group as compared to placebo were fatigue (36% vs 15%), hot flashes (13% vs 8%), nausea (11% vs 9%), hypertension (15% vs 7%), fall (12% vs 5%), dizziness (10% vs 4%), major adverse cardiovascular events (5% vs 3%), and mental impairment disorders (5% vs 2%), respectively. Enzalutamide had a higher adverse effect-related mortality rate as compared to placebo (3% vs 1%). The rate of discontinuation for adverse eventswas 10% with enzalutamide versus 6% with placebo.49

Darolutamide is a non-steroidal second-generation AR antagonist which inhibits androgen-induced translocation of AR to the nucleus, thus decreasing activation of genes required for prostate cancer cell growth. Darolutamide and its metabolites have exhibited tighter binding to AR than enzalutamide and apalutamide.50 Darolutamide has shown to retain full AR antagonist activity in the presence of AR mutations which can cause a switch of AR antagonist to agonist; F877 L mutation can cause enzalutamide and apalutamide to become an agonist, W742L and T878A mutations can cause bicalutamide to act as an agonist.50,51 Darolutamide showed lower affinity of γ-aminobutyric acid type A receptors in the brain and lower blood-brain penetration than enzalutamide and apalutamide in pre-clinical models.52 Darolutamide showed antitumor activity and safety in Phase I and II studies in patients with metastatic prostate cancer which led to the evaluation of darolutamide in Phase III (ARAMIS) trial in patients with nmCRPC.53,54 ARAMIS enrolled 1509 patients with nmCRPC and PSA-DT of ≤10 months and randomized them to received darolutamide plus ADT or placebo plus ADT. The primary endpoint was MFS. Secondary endpoints were OS, time to pain progression (assessed by Brief Pain Inventory Short Form), time to first symptomatic skeletal event, and time to first cytotoxic chemotherapy. Exploratory endpoints included PFS (defined as the time from randomization to evidence of any radiographic disease progression, including local relapse or new pathologic lymph nodes, or death from any cause, whichever occurred first), time to first prostate cancer-related invasive procedure, time to initiation of subsequent antineoplastic therapy, PSA progression and response, deterioration in ECOG performance status, and QoL. QoL was assessed by the European Organization for Research and Treatment of Cancer QoL Prostate Cancer module (EORTC-QLQ-PR25) at baseline and every 16 weeks until the end of treatment. Darolutamide plus ADT was associated with improved MFS as compared to placebo plus ADT (40.4 vs 18.4 months; HR: 0.41, 95% CI 0.34–0.50; p < 0.001). At the time of interim analyses, darolutamide showed improvement in secondary and exploratory endpoints as compared to placebo.55 The OS data were not mature at the time of publication of results.55 The most common adverse effects of any grade in the darolutamide group as compared to the placebo group were fatigue (12.1% vs 0.9%), back pain (8.8% vs 9%), arthralgia (8.1% vs 9.2%), and hypertension (6.6% vs 5.2%) respectively. The rate of side effects of any grade was 83.2% in patients treated with darolutamide and 76.9% in those who received a placebo. Grade 3 or 4 adverse effects of any cause were 24.7% in the darolutamide group versus 19.5% in the placebo group. Notably, darolutamide was not associated with a higher incidence of falls (4.2% vs 4.7%), seizure (0.2% vs 0.2%), or fractures (4.2% vs 3.6%) as compared to the placebo group. There was one treatment-related death in the darolutamide group (0.4%) vs 3 deaths (0.2%) in the placebo group. The rate of treatment discontinuation due to adverse effects was 8.9% in the darolutamide group as compared to 8.7% in the placebo group.55

Role of apalutamide beyond nmCRPC

Several trials are currently underway to evaluate the role of apalutamide in early and advanced stages of prostate cancer. During ASCO 2019 meeting, the results of the TITAN trial were presented. TITAN was a Phase III trial which assessed the efficacy of apalutamide plus ADT versus placebo plus ADT in patients with metastatic hormone-sensitive prostate cancer. The patients who previously received docetaxel for advanced prostate cancer (11%) were also enrolled. The primary endpoints were radiologic progression-free survival (rPFS) and OS. At the time of first interim analysis, apalutamide plus ADT was associated with improved rPFS as compared to placebo plus ADT (HR: 0.48; 95% CI 0.39–0.60; p<0.001).57 OS survival data were not mature at the time of the first interim analysis. Grade 3–4 adverse effects were 42.2% in the apalutamide plus ADT arm vs 40.8% in the placebo plus ADT arm.57

ACIS is a Phase III, randomized, placebo-controlled, double-blind study which is evaluating apalutamide in combination with abiraterone and prednisone (AAP) versus AAP alone as first-line treatment in patients with mCRPC, with rPFS as the primary endpoint.58 Secondary endpoints are OS, time to long-term opioid use, time to initiation of cytotoxic chemotherapy, time to pain progression, and time to skeletal-related events.58 Another smaller Phase II study is investigating the same combination in two cohorts of Caucasian and African American men (PANTHER study, NCT03098836).59 LACOG 0415 is a Phase II, randomized, a three-arm study evaluating the role of abiraterone acetate plus ADT versus apalutamide versus abiraterone and apalutamide in patients with advanced prostate cancer with non-castrate testosterone. The primary endpoint of the study is undetectable PSA levels (below 0.2 ng/mL) at week 25, aiming for 65% of undetectable PSA at week 25. Secondary endpoints are PSA progression and PSA response (50% and 80%) at week 25, rPFS, safety, health QoL, and correlation of serum androgen levels with response.60 PILLAR, a Phase II study is comparing apalutamide with stereotactic body radiation therapy (SBRT) versus apalutamide alone in patients with mCRPC. The patients will receive apalutamide for 52 weeks in both arms. The primary endpoint is to determine if the proportion of patients with an undetectable serum PSA at 6 months following cessation of apalutamide is higher with the addition of SBRT to prostate-specific membrane antigen -avid oligometastatic sites of disease compared to the group of patients receiving apalutamide monotherapy.61 A three-arm Phase II study is evaluating apalutamide in combination with abiraterone acetate and prednisone (AAP) in patients with mCRPC either with ipilimumab or carboplatin and cabazitaxel. In this open-label study, the patients will be randomized in 1:1:1 fashion into three treatment arms: control arm consisting of apalutamide and AAP, experimental arm consisting of apalutamide, AAP and ipilimumab, and other experimental arm consisting of apalutamide, AAP, carboplatin, and cabazitaxel. The primary outcome of the study is OS in each arm.62

ATLAS, a Phase III, randomized double-blind placebo-controlled trial is evaluating the role of apalutamide in combination with GnRH agonist compared with GnRH agonist alone in patients with high risk, localized or locally advanced prostate cancer who are receiving radiation therapy as initial definite therapy.63 The primary endpoint is MFS.

A Phase III is evaluating the role of apalutamide in men with biochemically recurrent prostate cancer who have PSAD-T≤9 months. In this three-arm, open-label study, the patients will be randomized in 1:1:1 fashion into one of three treatment arms: control arm consisting of degarelix monotherapy, experimental arm consisting of apalutamide in combination with degarelix, and another experimental arm consisting of apalutamide, AAP and degarelix.64 The patients will be treated for a maximum duration of 52 weeks. The primary endpoint of the study is PSA PFS in the intent-to-treat patient population. Secondary endpoints include PSA PFS in testosterone-evaluable population, 36-month PSA PFS rate in both intent-to-treat and testosterone-evaluable populations, time to testosterone recovery, time to castration resistance, MFS, QoL, and safety. A Phase II trial is evaluating neoadjuvant apalutamide in patients with intermediate to high-risk prostate cancer followed by radical prostatectomy. The patients will receive apalutamide for 12 weeks. The primary endpoints are pathologic down staging and biochemical response (to achieve PSA level <0.03 µg/L) after neoadjuvant apalutamide followed by RP.65 A Phase II randomized, multicenter trial is evaluating active surveillance with or without apalutamide in low-risk prostate cancer. The patients will receive apalutamide for 6 months. The primary endpoint is time to initiate local treatment.66 Table 1 summarizes the ongoing Phase III trials with apalutamide in different stages of prostate cancer.

Table 1 Phase III trials of apalutamide in prostate cancer

Conclusion

The treatment landscape of prostate cancer is dramatically changing, with the incorporation of novel AR-targeted therapies early in the course of the disease. Apalutamide was the first drug that demonstrated a delay in the development of metastasis as detected on conventional imaging in patients with nmCRPC. Other mechanistically similar therapies – enzalutamide and darolutamide have also shown to delay time to metastatic disease in patients with nmCRPC.

Apalutamide and enzalutamide have received FDA approval in the nmCRPC setting. It is very clear from the previous data that patients with nmCRPC with rapidly rising PSA level (PSA-DT <10 months) are at increased risk of developing bone metastases and would benefit from novel AR-targeted therapies. The benefit of novel AR-targeted therapies in patients with longer PSA-DT has yet to determined.

It is noteworthy that none of the novel AR-targeted agent has demonstrated OS benefit in the nmCRPC setting. In our opinion, the adverse effect profile would most likely influence the selection of the individual agent in the nmCRPC setting. In addition, the emerging use of sensitive molecular imaging will probably impact the use of novel AR-targeted therapies in the nmCRPC setting. Future studies will help to determine the mechanism of resistance to apalutamide, therapeutic ways to circumvent this resistance and the role of apalutamide as monotherapy or with other therapies in different stages of prostate cancer.

Impact of Age at Diagnosis on Outcomes in Men with Castrate-Resistant Prostate Cancer (CRPC)

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J Cancer 2013; 4(4):304-314. doi:10.7150/jca.4192

Research Paper

Michael R Humphreys1, Kimberly A Fernandes2, Srikala S Sridhar3

1. Division of Medical Oncology, British Columbia Cancer Agency, Vernon, BC, Canada;
2. Department of Biostatistics, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada;
3. Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See http://ivyspring.com/terms for full terms and conditions. Citation:
Humphreys MR, Fernandes KA, Sridhar SS. Impact of Age at Diagnosis on Outcomes in Men with Castrate-Resistant Prostate Cancer (CRPC). J Cancer 2013; 4(4):304-314. doi:10.7150/jca.4192. Available from http://www.jcancer.org/v04p0304.htm

Abstract

Background: The association between age and outcomes in men with castrate resistant prostate cancer (CRPC) is not well understood.

Objective: We aimed to evaluate CRPC patients to determine if their age at initial diagnosis impacted their cancer specific outcomes.

Outcome Measurements and Statistical Analysis: Primary endpoints included impact of age at diagnosis on overall survival (OS) and on prostate cancer specific survival. Secondary endpoints were time from diagnosis to development of CRPC, time from CRPC to death, and time from diagnosis to bone metastases.

Conclusions: Age at initial diagnosis appears to impact on outcome of patients who subsequently develop CRPC with a bimodal distribution of risk, with the shortest survivals in the ≥75 and <55 groups.

Keywords: Castrate-resistant prostate cancer, overall survival, age at diagnosis, hormone-refractory.

Introduction

In 2012, an estimated 241,740 men were diagnosed with prostate cancer in the US, of which approximately 28, 170 died from the disease.1 While a diagnosis of prostate cancer in men under the age of 50 is rare, the incidence and mortality increases steadily with age. Several disease-specific factors (e.g. stage, tumor grade, prostate-specific antigen (PSA) level) and patient-specific factors (e.g. co-morbidity, primary treatment modality, and functional status) have been identified as important predictors of survival.2-6 However, the influence of age on outcomes in prostate cancer remains controversial.2,6-9

In a review of 34 studies involving patients with localized prostate cancer, six studies found that young age at diagnosis carried a poor prognosis; five studies showed young age portended a good prognosis, and the remaining 23 studies found no association.9 A more contemporary study analyzing 4003 patients on androgen deprivation therapy (ADT) enrolled in the Cancer of the Prostate Strategic Urological Research Endeavor (CaPSURE) study from 1995-2007 found men < 65 at diagnosis were at a significantly higher risk of developing metastasis (HR=2.11).10 Supporting this observation was a Surveillance, Epidemiology, and End Results (SEER) database study showing that patients diagnosed at a younger age had worse survival, especially when accompanied by advanced histological grade and stage.11 In contrast, a second SEER based study did not show an impact of age on survival; however, this study also failed to stratify patients into multiple age categories.12

For CRPC patients, Gleason score, PSA, PSA doubling time, hemoglobin (Hgb), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), performance status (PS), pain at baseline, chemotherapy type, ethnicity, presence of visceral disease and advanced age have all been identified as factors that impact OS.13-15 Only one study, by Halabi et al, has directly assessed the impact of age on outcome in CRPC.14 This study, which utilized pooled data from 8 CALGB trials, found that men aged 80-89 were at increased risk for death, compared to their younger counterparts. Interestingly, they also reported that younger men (age 50-59) were at a 25% increased risk of clinical progression and 26% increased risk of prostate cancer death compared to those aged 70-79 but this did not translate into a decreased OS (p=0.172).14

Understanding the relationship between age and outcomes may not only have prognostic implications, but in the era of molecular targeted therapy and personalized medicine may also have important therapeutic implications. In our study, we evaluated 333 consecutive CRPC patients to determine if age at initial diagnosis of prostate cancer impacted on OS.

Patients and Methods

Following ethics approval, a retrospective chart review was performed on 3295 consecutive prostate cancer patients referred to the PMH between January 1, 1995 and December 31, 2005. PMH registry database and chart review identified 333 patients that fulfilled inclusion criteria. Vital statistics were obtained by linking to the Cancer Care Ontario database (accessed July 31, 2012).

Eligible patients had histologically confirmed adenocarcinoma of the prostate with disease progression after androgen ablation as indicated by two consecutive PSA rises or with measurable disease progression as defined by RECIST criteria.16 Summary statistics for demographic and clinical factors were generated for each case at diagnosis and during treatments. The Charlson Comorbidity Index (CCI) was used as an assessment of comorbidities at the time of diagnosis.17,18

The primary endpoints were the impact of age at diagnosis on OS and on prostate cancer specific survival. Secondary endpoints included impact of age on a) time from diagnosis to development of CRPC b) time from CRPC to death and c) time from diagnosis to bone metastases. A prespecified subset analysis evaluated the impact of age on OS, progression free survival (PFS) and PSA-PFS in patients receiving chemotherapy. PFS was defined as a composite of PSA progression, bone progression, nodal or visceral progression, and death, while PSA-PFS was defined by PCWG2 criteria.19

OS curves were created by the Kaplan-Meier approach. Univariate and multivariate Cox PH regression analyses were conducted. All covariates were entered into the multivariate model. All statistical analyses were performed using SAS version 9.1 and R version 2.7.1. All statistical tests were two-sided and p-values ≤ 0.05 were considered statistically significant. Multiple imputation methodology was performed when indicated for incomplete data sets. Patients lost to follow-up were censored at last known contact. In order to account for an uneven distribution of patients across the 4 age groups we performed our sample size calculation post-hoc based on the smallest group. The total sample size required to detect the increased risk of death of 32% on multivariate analysis (HR=1.32) identified in this study, at a power of 80% with a 2-sided p=0.05 was 293 patients.

Baseline Characteristics

Amongst the 333 eligible CRPC patients, average age at diagnosis was 65; most patients had Gleason scores of 8-10; median PSA was 146, LDH 223, ALP 144 and Hgb 120. A greater proportion of patients in Groups A and D presented with Stage 4 disease. Group D patients had more comorbidities and were less likely to have undergone definitive local therapy. However, they achieved a quicker PSA nadir on ADT at an average of only 9.2 months (mos). Prior to initiation of chemotherapy, Group D patients had poorer PS and were less likely to receive chemotherapy than younger patients (Table 1).

Table 1

Baseline characteristics of study population (n=333).

Abbreviations: PSA, prostate specific antigen; Dx, diagnosis; RT, radiotherapy; CCI, Charleston comorbidity index, CRPC, castration resistant prostate cancer; ADT, androgen deprivation therapy; ECOG, Eastern Cooperative Oncology Group; LDH, lactose dehydrogenase; ALP, alkaline phosphatase; Hgb, hemoglobin (†, meets p<0.05 statistical significance per Fisher’s Exact Test or Chi-squared test).

Time from Initial Diagnosis to Death

After a median follow-up of 6.6 yrs, 255 of 333 patients (77%) had died. Median survival in Group A was 5.5 yrs; Group B was 6.7 yrs; Group C was 7.8 yrs; and Group D was 4.3 yrs with the differences between the groups being statistically significant (log-rank p<0.0001, Table 2a, Fig 1). For the entire cohort, overall 5-yr survival rate from diagnosis was 62%, but 10-yr survival rate was only 28%. As shown in Table 2b, on univariate analysis there was a statistically significant increased risk of death associated with age ≥75, HR of 2.58 (p=0.0002). Patients <55 also showed a trend towards an increased risk of death with a HR of 1.49 (p=0.13). On multivariate analysis, age ≥75 was associated with the largest HR for death (2.84, p<0.0001), followed by stage 4 disease (HR=2.83, p<0.0001), and Gleason ≥8 (HR=2.57, p=0.008; Table 2b).To account for non-prostate cancer deaths, which could be a source of bias, the above analyses were repeated for disease specific survival. The results remained similar to the OS analysis with HR of 1.7 (p=0.04) for Group D and 1.5 (p=0.09) for Group A on univariate analysis. On multivariate analysis the HR was preserved in the older cohort but the statistical significance was lost (HR=1.6; p=0.16). Multivariate analysis suggested that stage at diagnosis was the primary driver (HR=2.2, p=0.004) for increased risk of death. As noted above, patients at both extremes of age had an increased proportion of advanced stage disease at diagnosis.

When time from diagnosis to the development of bone metastasis and duration of hormone sensitivity were included in the analysis of OS, both were independently predictive of OS from diagnosis (HR=0.71 per 1 yr increase, p<0.001, and HR=0.80 per 1 yr increase, p<0.001, respectively). The time from diagnosis to death was not significantly influenced by CCI. Non-docetaxel based chemotherapy was associated with a worse prognosis compared to no therapy (HR=2.01, p=0.002). Time from initial diagnosis to death was divided into two clinically relevant time frames: a) time from initial diagnosis to CRPC and b) time from CRPC to death, and analyzed independently.

a)Time from Diagnosis to CRPC

b)Time from CRPC to death

At the time of data-lock, 77% (230/300) deaths were observed. The median time from CRPC to death was 2.9 yrs. There was no statistically significant difference in OS between the age stratified cohorts (Fig 3). The key factors that were independently predictive of adverse survival from CRPC to death were presence of visceral metastasis, absolute PSA nadir on ADT (>4 vs ≤4ng/ml), time to PSA nadir on ADT (<6 vs ≥ 6 mos), and duration of hormone sensitivity determined by time from starting a gonadotropin releasing hormone (GnRH) agonist to CRPC (<12 vs ≥12 mos, Table 4). Anti-androgen withdrawal response occurred in 26% of patients and did not impact OS. There was no discernible difference between patients receiving docetaxel compared to no chemotherapy, but CRPC patients receiving non-docetaxel chemotherapy exhibited a reduced survival (HR=2.00, p<0.0001). Variables measured at diagnosis did not influence survival from CRPC. We also found that age <55 at the time of CRPC diagnosis was associated with a trend to increased risk of death on univariate analysis (HR=1.78, p=0.13) but not on multivariate analysis (HR=1.19, p=0.62, Fig 4).

Table 2a

Overall Survival (From Initial Diagnosis to Death).

Table 2b

Univariable and Multivariable Cox-PH Regression Analysis of Overall Survival.

Table 3

Median Time from Diagnosis to Development of CRPC.

Table 4

Univariable and Multivariable Cox-PH Regression Analysis of the Time from CRPC to Death.

Figure 1

Percent survival over time, stratified by age at initial diagnosis (n=333).

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Figure 2

Percent not progressing from diagnosis to CRPC over time, stratified by age at initial diagnosis. (n=314).

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Figure 3

Percent not progressing from CRPC to death over time, stratified by age at initial diagnosis (%).

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Figure 4

Percent not progressing from CRPC to death over time, stratified by age at CRPC diagnosis (%).

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Figure 5

Bone metastasis-free survival from diagnosis over time, stratified by age at initial diagnosis (n=333).

(Click on the image to enlarge.)

Time from Initial Diagnosis to Bone Metastasis

Patients in Group A, showed a median time from initial diagnosis to bone metastasis of only 1.2 yrs (95% CI 0.03-2.75) compared to 4.1 yrs (2.89-5.50) for Group C (Table 1). Figure 5 demonstrates that patients in Groups A and D both had an increased risk of developing bone metastases, and the curves continue to diverge for approximately ten years. Group A patients on univariate analysis had a HR of 1.55, bordering on statistically significance (p=0.067) and on multivariate analysis had a HR of 1.49 (p=0.13).

Table 5

OS Multivariate Cox PH Regression of Significant Covariates in CRPC Patients Receiving Chemotherapy from Start of Chemotherapy.

Abbreviations: OS, overall survival; CRPC, castration resistant prostate cancer; PSA, prostate specific antigen; ECOG, Eastern Cooperative Oncology Group; ALP, alkaline phosphatase; Hgb, hemoglobin.

Chemotherapy Overall Survival Subset Analysis

A subset analysis of 246 chemotherapy treated patients, with average follow-up of 1.1 yrs, observed 193 deaths. The median survival was 55 weeks (wks) with no differences on the basis of age stratification. Median PFS was 24.4 wks and median PSA-PFS was 26 wks, respectively, with no statistical difference between age groups. On multivariate analysis of significant covariates, PSA doubling time of less than 1 month, ECOG PS ≥3, and baseline Hgb less than 100 g/L were consistent predictors of shorter OS, PFS, and PSA-PFS. Elevated LDH was an important predictor of OS but not PFS or PSA-PFS. Treatment with docetaxel chemotherapy was statistically protective versus non-docetaxel based regimens for both OS and PFS on multivariate analysis (HR=0.47, p=0.0001, and HR=0.64, p=0.02, respectively, Table 5).

Discussion

In this study of 333 CRPC patients, treated over a 10 yr period, advanced age (≥75) at the time of initial prostate cancer diagnosis is associated with a statistically significant shorter OS, from the time of initial diagnosis to death. Interestingly, we also show a trend towards worse survival in patients who were ≤55 at the time of initial diagnosis. This is similar to the SEER study showing a bimodal distribution of risk, based on age at diagnosis especially in patients with advanced stage or histology.14

Patients ≥75 had a decreased OS (and prostate cancer specific OS) likely due to a shorter duration from diagnosis to CRPC. Our data suggests this is related to both advanced stage at diagnosis and a statistically significant shorter duration of hormone sensitivity. This latter finding is consistent with results presented by Hussain et al where a shorter duration of response to hormonal therapy correlated with a decreased OS.20 One reason for the reduced duration of hormone sensitivity may be lower pretreatment testosterone levels in the elderly population; though not directly measured in our study this has been linked to worse survival. 21

Patients who were <55 at the time of diagnosis showed an unexpected trend towards worse survival (5.5 yrs versus 7.8 yrs) despite having fewer comorbidities and a better performance status. This group developed bone metastases earlier, a result that bordered on being statistically significant. At presentation a greater proportion of these patients had low PSA levels (<10ng/ml), stage 4 disease, and visceral metastases. Further studies are needed to understand if there are unique host or tumor factors that lead to this presentation in younger patients or if these tumors are more poorly differentiated and non-PSA producing. A positive family history was also found in the majority of these patients, raising the question of whether there is a link between early onset prostate cancer, family history and genetics. Indeed such a link has been described. In one study up to 43% of patients under 55 had a genetic predisposition.22,23 While several mechanisms have been described, recent attention has focused on genes, such as the BRCA gene, which when mutated has been shown to confer an increased risk of recurrence following local therapy and increased prostate cancer-specific death (HR 5.16).24-26 Understanding mutations like BRCA may have important screening, diagnostic and therapeutic implications.

In terms of survival from CRPC to death, neither age at diagnosis, nor age at onset of CRPC impacted survival. This is consistent with an analysis of the TAX 327 study where age was not a statistically significant prognostic factor.27 Our results perhaps differ slightly from those presented by Halabi et al, which showed CRPC patients over 80 had worse outcomes than other age groups, but the age categories in these two studies were overlapping (≥75 and ≥ 80), there were relatively few patients in the advanced age groups in both studies, and the Halabi study predated the use of docetaxel chemotherapy.14 The key factors that were independently predictive of survival from CRPC to death were absolute PSA nadir on ADT (<4 vs ≥4ng/ml), time to PSA nadir on ADT (<6 mo vs ≥ 6mos), duration of hormone sensitivity (<12 vs ≥12 mos), presence of bone metastases, and presence of visceral metastases (Table 4).

In patients receiving chemotherapy, consistent with other studies, a significantly reduced risk of death was seen for those who received docetaxel-based therapy.28,29 We did not find that the mortality associated with chemotherapy was age-related, suggesting patients were appropriately selected and confirmed earlier observations that there is no strict age criteria that should preclude appropriate treatment.17 This is an important finding since even in our study we show that patients who were ≥75, were less likely to receive chemotherapy than younger patients. Given both the palliative and survival benefits of chemotherapy, its use should therefore not be dictated by age alone.

Conclusions

In this study we evaluated CRPC patients over a 10 yr period and showed that age at initial diagnosis of prostate cancer did influence outcomes with a bimodal survival curve. Poorer outcomes were most evident in the elderly (>75) age group with an overall survival of only 4.3 yrs. In this group, the duration of hormone sensitivity was shorter, possibly owing to the reduced testosterone levels at baseline. Based on these results, it may be reasonable to prepare the very elderly patients that hormonal therapy may only have short term benefits and that chemotherapy may be needed to optimize disease control. A similar approach may also be warranted in younger patients where again outcomes appeared worse. One strategy to improve outcomes overall may be with the use of novel more effective hormonal treatments, such as abiraterone acetate (a CYP17 inhibitor) or enzalutamide (a new generation androgen receptor antagonist) earlier in the course of the disease to delay the development of CRPC; or alternatively introducing chemotherapy earlier in the course of treatment, especially in the younger and fitter patients. These are approaches currently under evaluation in clinical trials. Although age at initial diagnosis requires validation, it could be an important stratification factor for patients on clinical trials. As we look to the future, a more comprehensive understanding of prostate cancer from both a prognostic and molecular perspective may open further diagnostic and therapeutic avenues, allowing tailoring of therapy and ultimately lead to better outcomes in the future.

Acknowledgements

The authors would like to thank Cancer Care Ontario (CCO) for linking study patients with the CCO vital statistics registry, and Princess Margaret Hospital / University Health Network for providing biostatistics support and funding this study. The authors would also like to specifically thank Alisha Albert-Green, Manjula Maganti, and Melania Pintilie for their statistical support and expertise.

Competing Interests

The authors have declared that no competing interest exists.

1. Siegel R, Naishadham D, Jemel A. et al. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10-29

2. Kattan M, Cuzick J, Fisher G. et al. A nomogram incorporating PSA level to predict cancer-specific survival for men with clinically localized prostate cancer managed without curative intent. Cancer. 2007;110:69-74

4. Klotz K. Nomogram for predicting survival in men with clinically localized prostate cancer who do not undergo definitive therapy. Nat Clin Pract Urol. 2008;5(7):362-363

5. Tewari A, Gamito E, Crawford J. et al. Biochemical recurrence and survival prediction models for the management of clinically localized prostate cancer. Clin Prostate Canc. 2004;2(4):220-227

6. Zagars G, von Eschenbach A, Ayala A. Prognostic factors in prostate cancer. Analysis of 874 patients treated with radiation therapy. Cancer. 1993;72:1709-1725

7. Sandhu D, Munson K, Benghiat A. et al. Natural history and prognosis of prostate carcdinoma in adolescents and men under 35 years of age. Br J Urol. 1992;69:525-529

8. Aprikian A, Zhang Z, Fair W. Prostate adenocarcinoma in men younger than 50 years. Cancer. 1992;74(6):1768-1777

9. Parker C, Gospodarowicz M, Warde P. Does age influence the behavior of localized prostate cancer?. BJU Int. 2001;87:629-637

10. Abouassaly R, Paciorek A, Ryan C. et al. Predictors of clinical metastasis in prostate cancer patients receiving androgen deprivation therapy. Cancer. 2009;115:4470-4476

11. Merrill RM, Bird JS. Effect of young age on prostate cancer survival: a population-based assessment (United States). Cancer Causes Control. 2002;13:435-443

12. Tward JD, Lee CM, Pappas LM. et al. Survival of men with clinically localized prostate cancer treated with prostatectomy, brachytherapy, or no definitive treatment: impact of age at diagnosis. Cancer. 2006;107:2392-2400

13. Halabi S, Small E, Kantoff P. et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol. 2003;21:1232-1237

14. Halabi S, Vogelzang N, Ou S. et al. Clinical outcomes by age in men with hormone refractory prostate cancer: a pooled analysis of 8 cancer and leukemia group B (CALGB) studies. J of Urol. 2006;176:81-86

15. Armstrong AJ, Garett-Mayer ES, Yang YO. et al. A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: A TAX327 study analysis. Clin Cancer Res. 2007;13(21):6396-6403

16. Therasse P, Arbuck S, Eisenhauer E. et al. New guidelines to evaluated the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205-216

17. Hall W, Jani A, Ryu J. et al. The impact of age and comorbidity on survival outcomes and treatment patterns in prostate cancer. Prostate Cancer and Prostatic Diseases. 2005;8:22-30

18. Charlson M, Pompei P, Ales K. et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis. 1987;40:373-383

19. Scher HI, Halabi S, Tannock I. et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the prostate cancer clinical trials working group. J Clin Oncol. 2008;26:1148-1159

22. Steinberg G, Carter B, Beaty T. et al. Family history and the risk of prostate cancer. Prostate. 1990;17:337-347

23. Carter B, Beaty T, Steinberg G. et al. Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci. 1992;89:3367-3371

24. Forrest M, Edwards S, Houlston R. et al. Association between hormonal genetic polymorphisms and early-onset prostate cancer. Prostate Cancer and Prostatic Diseases. 2005;8:95-102

26. Gallagher DJ, Gaudet MM Pal P. et al. Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res. 2010;16(7):2115-2121

27. Armstrong AJ, Garret-Mayer ES, Yang YO. et al. A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis. Clin Cancer Res. 2007;13:6396-6403

28. Tannock IF, DeWit R, Berry W. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512

29. Petrylak D, Tangen C, Hussain M. et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-1520

Author contact

Received 2013-1-29
Accepted 2013-3-1
Published 2013-3-21

Surgery for the treatment of urological complications

Obstructive uropathy is the key urological complication of advancing prostate cancer, and is associated with poor prognosis.22 The primary tumour can cause both bladder outflow obstruction, from direct urethral pressure, and ureteric obstruction, from tumour infiltration of the trigone and periureteric tissue. It may also cause bothersome haematuria. In addition, lymph node metastases can cause supra-vesical ureteric obstruction.

Bladder outflow obstruction not only causes obstructive uropathy, but also produces symptoms that have a considerable impact on quality of life. Both can be easily palliated with urethral catheterization. More definitive treatment may be achieved surgically or with radiotherapy. Transurethral resection of the prostate (TURP) is the preferred treatment option and can be performed in this group of patients with significant improvement in urinary symptoms and low morbidity, although rates of urinary retention and incontinence are higher than in patients undergoing TURP for benign prostatic obstruction.23 Radiotherapy is infrequently used to improve this type of obstructive uropathy, although it can improve obstructive symptoms in up to 80% of patients.24 Radiotherapy is, however, particularly good at treating haematuria, which is less well controlled by TURP.

Supra-vesical obstruction is usually unilateral at first, and may not require treatment if asymptomatic with adequate overall renal function. However, bilateral ureteric obstruction causes life-threatening, progressive renal failure, which requires urgent attention. Effective palliation of renal failure is usually achieved by percutaneous nephrostomy, ureteric stent or a combination of both, which are procedures with low morbidity that can improve quality of life.25 Expandable metallic ureteric stents, extra-anatomic stents and surgical diversion are alternative methods of invasive treatment. Radiotherapy can also reduce the obstruction; however, it is neither as immediate nor effective.26 Such palliation of renal failure raises an ethical dilemma in the hormone-relapsed patient. These patients generally have a short life expectancy and their prognosis should be considered before initiating treatment, so that life is not perpetuated to allow the development of other problems, without improving the quality of useful life.

Prednisolone and other steroids

Patients who have received medical or surgical castration will still receive androgen stimulation of their prostate tumour cells as a result of androgens produced by the adrenal glands. Treatment with steroids such as hydrocortisone reduces adrenal androgen production in a subset of patients and there is an additional benefit from low-dose corticosteroid therapy in terms of improved anabolism and reduced fatigue.27, 28 Anti-androgen therapy will inhibit the stimulation of the prostate cancer cells by competing with residual testosterone for binding to the receptor. However, whereas a randomized trial found the time to progression and survival periods for prednisone and flutamide to be equivalent, the steroid therapy significantly improved the overall quality of life and in particular, pain, fatigue, role functioning, appetite loss and gastrointestinal distress.29

Radiotherapy

Bone pain in patients with locally advanced or metastatic prostate cancer is invariably indicative of bone metastases and is one of the most common signs of progression or recurrence. In patients in whom metastases are limited to a few sites, single-fraction external-beam radiotherapy is an option for palliative pain control.30, 31 Approximately 76% of patients will have effective pain relief from this approach with a median duration of around 6 months. In addition to the low cost of localized radiotherapy, the approach also has the advantage that subsequent isolated metastases may also be treated in the same way and, if necessary, the development of pain over a larger area can be treated by wide-field or hemi-body radiotherapy. Although this latter approach is often accompanied by the typical side effects of radiotherapy including nausea, vomiting and diarrhoea, which may require hospitalization, this is usually avoidable with suitable anti-emetic prophylaxis, and it remains a good treatment option for the frail and elderly in whom treatment options are limited.

Radionuclides

Palliation of bone pain arising from widespread bony metastases may be effected by the intravenous administration of radionuclides that target bone metabolism, for example strontium-89, samarium-153 and phosphorous-32. Of these, strontium-89 is the most utilized providing pain relief in up to 80% of patients, and complete freedom from pain in approximately 10%, for periods that can exceed 3 months.32, 33 The combination of strontium-89 injection and external-beam radiotherapy improved pain relief, delayed progression and enhanced some quality of life measures compared with external-beam therapy alone.34 However, a phase III study has suggested that in some patients, systemic strontium-89 may be inferior to local field radiotherapy in terms of survival (11 vs 7.2 months, P=0.0457).35 The selection of patients has a significant impact on outcome and response, and duration of response to radionuclide therapy in terms of bone pain palliation is reduced in those with widespread metastatic disease or a short life expectancy.36, 37 Consequently, the use of radionuclides appears to be optimal at an early stage in disease management. However, their efficacy is reduced or lost with repeated use, and overtreatment can also lead to irreversible pancytopenia, which can compromise any subsequent use of chemotherapy.

Bisphosphonates

The use of bisphosphonates in oncology has increased over the last decade, although their use remains the subject of controversy in prostate cancer. The bisphosphonates inhibit bone catabolism by reducing the numbers of functioning osteoclasts and have been an established treatment for osteoporosis and similar conditions for many years, and more recently have been used to manage bone metastases in breast cancer.38 In addition, some bisphosphonates, for example zoledronic acid but interestingly not clodronate, arrest cell proliferation, induce apoptosis and inhibit the growth factor stimulation of cultured prostate cancer cells.39

In the early 1990s, pamidronate as a single i.v. infusion was shown to reduce bone pain in 30% of patients for between 2 and 3 weeks with no tolerability issues.40 A later report presented pooled results from two studies (INT-05 and CGP 032) in which 378 patients received placebo or pamidronate as randomized therapy for up to 27 weeks.41 The investigators found no significant difference between pamidronate and placebo in terms of pain measurements, analgesic use, skeletal-related events or mobility. Recently a large randomized, placebo controlled study (MRC PR05) reported that clodronate improved the pain-free survival period and overall survival periods for patients with metastatic prostate cancer compared with placebo, although the benefits did not achieve statistical significance (i.e. P>0.05).42 Further, although patients in the clodronate group were significantly less likely to experience a deterioration in their performance status (HR 0.71, 95% confidence interval 0.56–0.92, P=0.008), they reported more gastrointestinal side effects, increased lactose dehydrogenase and required more trial dose modifications. In the sister trial (MRC PR04), clodronate was added to standard therapy (radiotherapy, hormone therapy or both in >90% of patients) for locally advanced, non-metastatic prostate cancer with the objectives of determining its effect on the onset of symptomatic bone metastases or disease-specific death, overall survival and toxicity.43 Over 500 men were randomized to receive placebo or clodronate for 5 years duration and the results from 7 years of follow-up found no evidence for prevention of bone metastases or prostate cancer death (hazard ratio 1.29, 95% confidence interval 0.92–1.82, P=0.13) and no difference in overall survival (hazard ratio 1.03, 95% confidence interval 0.76–1.39, P=0.86).

The more potent bisphosphonate zoledronate has been investigated in HRPC. Zoledronate, given at a dose of 4 mg as a 5-min infusion every 3 weeks, significantly reduced the proportion of skeletal-related events by around 11% compared with placebo (P=0.021) and increased the median time to the first of such events (P=0.011). However, there was no difference between the two groups for disease progression, performance status or quality of life. A third arm in this trial received zoledronate at an initial dose of 8 mg, but this was associated with progressive renal dysfunction, which necessitated dose reduction, and the results from this patient group were difficult to interpret and not significantly different from placebo. A 9-month extension to this study in 133 patients found that 4 mg zoledronate reduced the risk of a skeletal-related event by 53% compared with placebo (hazard ratio 0.467; 95% confidence interval 0.243–0.897, P=0.022).44, 45

In summary, the role of bisphosphonates in the adjuvant setting is uncertain although there is some evidence to support their inclusion in pain management programmes. Two current randomized trials are addressing the use of zoledronate in prostate cancer in the UK: Stampede and Trapeze (see below).

Treatment of spinal cord compression

Dexamethasone should be given as immediate therapy to alleviate oedema. Although surgery or radiotherapy may be effective for the relief of pain and neurological complications, a surgical approach is only really a viable option for spinal cord compression in patients with otherwise good performance status and well-controlled symptoms. Preliminary data indicate that by combining radiotherapy with decompressive surgical resection, patients retain the ability to walk for a significantly longer period compared with radiotherapy alone (126 vs 35 days, P=0.006) and are also more likely to maintain continence.46 This is therefore the preferred approach if at all possible if precompression performance status was good. Prompt diagnosis and referral to a centre specializing in spinal surgery are essential if patients are to have any chance of neurological recovery.

Summary of bone metastases management

The successful management of bone metastases is a major consideration for patients with HRPC and has the potential to make a significant impact on quality of life. The early use of palliative radiotherapy, radiotherapeutics and bisphosphonates can control pain, may delay or even possibly prevent the development of significant skeletal complications and are well tolerated with few toxicity issues. Early detection and aggressive surgery with concomitant radiotherapy in cases of spinal cord compression may preserve good neurological function, and maintain an acceptable quality of life.46 However, in late-stage disease, radiotherapy and analgesia are currently the only real options for gross spinal complications.

Chemotherapy

Mitozantrone

Given that chemotherapy is not normally used in non-metastatic or early prostate cancer, one might expect to see substantial responses to the first exposure of cytotoxic drugs in hormone-refractory patients. Historically, this has not been the case, and despite recent developments many urologists still consider HRPC to be a chemo-insensitive condition. Over the last two decades, estramustine, vinblastine, etoposide, doxorubicin and mitozantrone have all been investigated for the treatment of HRPC. The absence of a consensus on definitive end points has hampered comparative assessments of these agents and mitozantrone plus prednisone, is approved (in the USA but not in Europe) on the basis of a significant improvement in palliative end points compared with prednisone alone.11, 47 Mitozantrone+prednisone improved palliation (defined as a two-point decrease in a six-point pain scale without an increase in analgesic score) in 29% of patients compared with 12% in the prednisone-only arm (P=0.01), and the duration of palliation was also significantly longer (43 vs 18 weeks, P<0.0001). There was no difference in survival between the two groups, although the trial was not powered on this basis. In addition, patients in the prednisone-only group who did not show a palliative response could cross over to the combination after 6 weeks.

A retrospective follow-up study in 161 of the original patients found that 34% of the patients in the mitozantrone plus prednisone group achieved a PSA response (defined as a decline of ⩽50% relative to baseline) compared with 11% in the prednisone-only group (P=0.0001).48 Further analyses indicated that a PSA response was associated with an increased likelihood of a palliative response (P=0.001) and, in conjunction with better performance score and a high haemoglobin level, was an indicator for increased survival (P<0.001). A separate, later study compared mitozantrone with and without hydrocortisone and found similar results; the combination provided a small but significant increase in time to progression compared with steroid monotherapy (3.7 vs 2.3 months, respectively, P=0.02) but no difference in overall median survival (12.3 vs 12.6 months, respectively, P=0.77).49 Finally, a further study found similar extensions to the progression-free period with the combination, as well as an increase in the number of patients with a PSA response, but confirmed no survival difference between mitozantrone plus prednisone and prednisone alone.50

A follow-up study to the initial investigation by Tannock et al.51 examined the cost implications of introducing mitozantrone for HRPC management. A detailed examination was performed of the costs incurred for 114 patients from three of the largest centres between randomization and death and included hospital admissions, outpatient visits, investigations, all therapies and palliative care. The mean total cost for a patient who received mitozantrone with prednisolone from randomization to death was 27 300 Canadian dollars, which was effectively the same as the 29 000 Canadian dollars spent on a patient in the prednisolone-only group. The major proportion of cost in both arms was in-patient admissions (53 vs 66% for the chemotherapy and steroid-only groups, respectively). This dominant role of in-patient costs is evident when the costs for an individual patient are plotted against time (Figure 2). This study indicates that by reducing pain and improving function, fewer admissions were required for pain control or failure to cope at home, and that this more than offset the cost of chemotherapy. Similar deferred costs have been noted in other active treatments for HRPC, for example strontium-89, where the initial costs were recovered by savings in other aspects of patient care.53

Figure 2

Cumulative costs from the mitoxantrone economic study for an individual patient from study randomization to death.52 The steep parts of the curve coincide with periods of in-patient care.

Docetaxel

The taxanes are a relatively new class of drugs that prevent completion of the cell cycle at the G2/M checkpoint by stabilizing the microtubule structures of the nucleus. Preclinical studies indicated that the anti-tumour activity of docetaxel was superior to that of mitozantrone in prostate cancer xenograft models.54 Docetaxel or paclitaxel in combination with estramustine demonstrated a response rate of 50% in phase II studies and was moderately well tolerated.52 In large, direct randomized comparative phase III trials, some docetaxel combinations have demonstrated increased PSA responses, progression-free survival, overall survival, improved palliation and better quality of life compared with the clearly active, standard mitozantrone combination (Table 1). Varying the dose and administration of docetaxel affected the relative efficacy, with, for example, the 75 and 60 mg/m2 three-weekly regimens providing a clear increase in survival, relative to mitozantrone, whereas the 30 mg/m2 weekly schedule did not (Figure 3). Adverse event and serious adverse event reporting increased in the docetaxel arms of both studies,55, 56 although the degree of significance was not consistent between studies. Low numbers of treatment-related deaths occurred in both the docetaxel arms and mitozantrone control arms with no clear or consistent differences. Generally, the docetaxel regimens were reasonably well tolerated and the adverse event profiles were similar to those seen with other cytotoxic regimens and included grade 3 or 4 neutropenia, fatigue, alopecia, diarrhoea and stomatitis. Although such conditions are of obvious concern, they can be managed and docetaxel therefore offers the patient with HRPC tangible benefits in terms of increased quality of life and overall survival over that provided by the current standard therapy.

Table 1 Phase III randomized study data comparing docetaxel chemotherapy with mitozantrone in hormone-refractory prostate cancer Figure 3

Effect of docetaxel on overall survival in HRPC.

Future directions

In demonstrating an increase in survival and quality of life, docetaxel has demonstrated an improvement in the treatment of what was previously thought of as a chemo-insensitive disease. The challenge for the immediate future will be to consolidate these findings and maximize the potential for existing drugs in this setting. This may be achieved by manipulating the regimens already in use, exploring the efficacy of new combinations and by investigating earlier or aggressive treatment in suitable patients. For example, a modified vinca alkaloid, vinorelbine, appears to be as effective as mitozantrone in combination with steroid therapy.57 Another new possibility is the oral platinum analogue satraplatin, which has shown encouraging activity in HRPC and is undergoing phase III evaluation in the second-line chemotherapy setting vs best supportive care.58, 59 This trial is set to be closed in early 2006. If positive, it will further extend the indications for chemotherapy in prostate cancer and open the way to further combination therapy trials.

The new generation of targeted anticancer drugs such as those directed against the epidermal growth factor receptors (e.g. gefitinib, cetuximab and trastuzumab) are well tolerated and have improved the treatment of certain solid human tumours like lung, breast, colorectal and head and neck. However, their use in HRPC has yet to progress past phase II and this is unlikely given that the available data suggest that the epidermal growth factor receptor family is not a viable target for the treatment of HRPC.60 Other therapies with activity against specific targets in HRPC are being developed. For example, atrasentan is a small molecule inhibitor of the endothelin-A receptor. Blocking the binding of the natural ligand endothlin-1 prevents autocrine stimulation and inhibits several cellular processes including hormone production, mitogenesis and cell migration.61 The endothelin autocrine loop is upregulated in HRPC, possibly as a result of androgen ablation, and clinical studies show promising results with significant effects not only on the tumour cells, but also on bone metastases.62 Atrasentan is well tolerated and no dose limiting toxicities were seen in phase I studies. However, in common with other targeted therapies, and unlike cytotoxic therapies such as docetaxel, phase II data for atrasentan are consistent with cytostasis, leading to delays in progression rather than a reduction in tumour burden.63 For the time being, the role of these agents remains in doubt as the results of phase III trials mature. Nonetheless, the eventual introduction of the new targeted therapies that are now in clinical development will be an important step in the management of HRPC. Although the activity of targeted therapies as monotherapy may be limited, their good tolerability means that they can be combined with established combinations with minimal impact in terms of safety. Clearly, the options for chemotherapy in the treatment of HRPC are set to increase over the coming years.

Finally, there is a growing literature on the use of cell-based or immunotherapeutic approaches to prostate cancer. In particular, a phase III trial of a dendritic cell therapy called Provenge is underway in the USA and definitive results are eagerly awaited for this study.

Current State of Castration-Resistant Prostate Cancer

Prostate cancer (PrCa) is the most common cancer found among men in the United States, and is the second-leading cause of death for these individuals. Although most patients with prostate cancer experience disease control after primary therapy, approximately 20% to 40% of these patients will eventually encounter recurrent disease. While androgen deprivation therapy may achieve temporary tumor control or regression in the majority of patients with advanced disease, virtually all patients with metastatic disease will experience progressive PrCa. Consequently, their disease may no longer respond to primary androgen blockade and may then spread to distant sites, most commonly to the bones and/or regional lymph nodes. This state of disease, termed castration-resistant prostate cancer (CRPC), is heterogeneous, has a variety of clinical symptoms which may include biochemical progression, progression in bone, or soft tissue, and may present with or without symptoms from cancer. While treatments were previously somewhat limited, there has been a substantial increase in the understanding of the biological and genetic basis for PrCa progression. The mechanisms of androgen independence in CRPC include, but are not limited to, autocrine production of androgen by the prostate cancer cell, as well as androgen receptor activity despite low testosterone levels, through a variety of different mechanisms. These findings have led to more targeted therapies for CRPC, improved clinical outcomes, and increased survival. Further understanding of the mechanisms that cause castration resistance potentially could improve therapeutic efficacy.
(Am J Manag Care. 2013;19:S358-S365)

The Progression of Prostate Cancer to Castration- Resistant Disease
Prostate cancer (PrCa) is the most common cancer found among men in the United States and is the second-leading cause of death for American males. Statistical analyses have projected an estimated 238,590 cases of PrCa among US men in 2013 alone, with approximately 29,720 expected deaths in this population during 2013. In males, the probability of developing invasive PrCa increases with each decade of life, with a risk that rises from 1 in 37 males between 40 and 59 years of age to 1 in 8 males for those who are 70 years and older. Between birth and death, the probability of developing invasive PrCa is estimated to be 1 in every 6 US men.1 Improvements in the early detection of PrCa have led to a substantial reduction in the number of patients who are diagnosed with advanced stages of the disease. Increased rates of screening for levels of prostate-specific antigen (PSA) have led to a notable decline in late-stage diagnoses of PrCa. Analyses of data from the Surveillance, Epidemiology and End Results (SEER) database between 1992 and 2008 identified a 75% reduction in late-stage disease incidence. However, regardless of these improvements in early detection, PrCa continues to be a leading cause of mortality among US males, invariably due to the emergence of hormonerefractory, androgen-independent disease.1-4
Although many patients with PrCa experience disease control after primary therapy, 1 retrospective analysis of patients who had undergone prostatectomy after an initial instance of PrCA found that 34% of patients developed metastatic disease after a median of 5.4 years of follow-up.5 For those men whose disease recurs, the majority will relapse biochemically as evidenced by elevated PSA levels, but the use and timing of androgen deprivation therapy (ADT) for biochemical relapse is controversial.6 Although higher levels of PSA at baseline in a patient is indicative of greater risk for metastatic disease or subsequent disease progression, it should be noted that PSA remains an imprecise marker of risk.7 PSA alone may not predict the onset of metastatic disease. Also, other factors, such as PSA doubling time, patient life expectancy, and comorbidities, may often prescribe when hormonal therapy is utilized.
In patients with advanced disease, androgen deprivation blockade, which may be achieved pharmacologically or surgically, leads to the regression of metastatic disease in the majority of patients.8 With androgen blockade, patients with high-risk, locally advanced, or metastatic disease may experience long-term regressions in disease activity, but advanced PrCa virtually always progresses to castration-resistant PrCA (CRPC), which is also known as androgen-independent PrCa (AIPC).9 CRPC is clinically detected by recurring symptoms, a rise in PSA levels, progression in soft tissue disease, or progression on bone scan.10 A significant PSA elevation is typically defined as 3 consecutive rises over its lowest point following treatment.9 This rise in PSA occurs in the context of the patient having castrate levels of serum testosterone (<50 ng/dL) following a withdrawal of antiandrogen therapies for at least 4 weeks, despite secondary hormonal manipulations and/or radiologic evidence for disease progression.9
The management of CRPC presents a number of difficult clinical challenges. Notably, systemic therapeutic options for this stage of PrCa have been very limited in the past. Historically, for patients with PrCa who failed hormonal therapy, traditional treatments were only approved for, and used primarily to provide, symptomatic benefits.9 These therapies included: (1) bisphophonate agents to protect the skeletal integrity in patients with bony metastases; (2) secondary hormonal manipulations, such as ketoconazole combined with hydrocortisone; (3) the addition of antiandrogen chemotherapy; and (4) beta-emitting radioactive isotopes.9 Over the past decade, however, there have been substantial improvements in the understanding of the biological and genetic bases for the progression of PrCa. This increased comprehension is partially attributable to the development of high-throughput genomic, transcriptomic, and proteomic technologies.9 The mechanisms of androgen independence in CRPC have been researched extensively, including pathways that are mediated by the androgen receptor (AR), as well as the pathways that bypass this receptor.9,11,12 In addition, the mechanisms that are common to all cancer types underlying malignant proliferation, angiogenesis, metastatic spread, and the avoidance of immune surveillance also play major roles in the progression of PrCa to castration-resistant disease. With all these potential targets, new mechanisms of action, treatment pathways, and novel therapies have been investigated to better target therapy for CRPC in efforts to potentially retard disease progression and to further improve patient outcomes.9
Mechanisms Surrounding Development of CRPC and Metastatic Disease
Androgen Receptor Signaling and CRPC
Prostate function and cellular differentiation depend upon androgen receptor signaling (ARS), a component that is also critical in the progression of PrCa.13 The AR is expressed to some degree in almost all primary PrCas, and there appears to be a relationship between the AR on a cellular level, primary prostate tumors and metastatic lesions, and the subsequent progression of disease to CRPC.14-17 Androgens mediate their effects by binding to and activating the AR in normal and in cancerous prostate cells. Leuteinizing-hormone-releasinghormone (LHRH) agonists and antagonists, as well surgical castration, deplete testosterone levels and thus abrogate signaling along the AR signaling axis.18 While ADT is highly effective, PrCa eventually becomes unresponsive to hormonal treatments, leading to CRPC. CRPC cells are capable of adapting to low circulating levels of androgens, and AR can become hypersensitive and activated by these low androgen levels, as well as through various other cellular mechanisms,8,18 which include: (1) AR amplification/overexpression; (2) gain of function AR mutations; (3) intracrine androgen production (the production of androgens by PrCa cells); (4) overexpression of AR cofactors that sensitize cells to low levels of androgens; (5) AR activation by cytokines or growth factors; and (6) altered ARs known as messenger ribonucleic acid (mRNA) splice variants that have androgenic activity in the presence of little to no androgen stimulation.13,14,19-24 Measurement of PSA is the most commonly used evaluation to detect progression of disease, and rising levels of PSA may indicate dysfunctional AR activity in CRPC. However, given the heterogeneity of the disease, patients can progress in bone and in soft tissue disease without a significant rise in PSA.7,8,14
AR Amplification/Overexpression
AR amplification/overexpression is considered one of the major causes of disease progression to CRPC, and this overexpression may be attributed to factors such as gene amplification, transcriptional upregulation, translational upregulation, and decreased degradation.25 Increased expression of AR is required for the transformation of some PrCa cell lines from a hormone-sensitive phenotype to one that is refractory to hormone-deprivation therapy.9,26 AR overexpression occurs in most cases of CRPC, mostly due to transcriptional upregulation.25 A study published in 1995 that examined 23 samples of PrCa lesions found that AR gene amplification was detected in 30% of samples of recurrent tumors, whereas none of the primary tumors demonstrated AR gene amplification. Gene amplification leads to increased AR protein expression, which sensitizes PrCa cells to respond to low levels of androgen ligand.13,27
AR Mutations and Splice Variants
Mutations in the AR gene have been detected with higher frequency in patients with castration-resistant, distant, metastatic tumors compared with patients who have lower-grade primary tumors or those who have been treated solely with castration. Multiple mutations with different consequences on AR activity have been identified. Most identified mutations are associated with increased functional activity of the AR, leading to a receptor that is more sensitive to low levels of androgen or can be activated by other steroids, such as adrenal androgens, estrogens, and progestins, as well as antiandrogens that are designed to treat PrCa. Constitutive activation (gene expression) without ligand binding may also be observed.13,25,28 In addition to AR mutations, the discovery of AR splice variants has become a significant point of interest in CRPC therapy. These variants tend to exhibit transcriptional activity without the presence of androgens, and may contribute to the progression of CPRC in the presence of a ligand (ie, androgens) for activation.25

AR Coregulators
Alterations of the balance between AR and its coregulators may also play a role in the progression to castrationresistant disease.29 Coactivators of AR have been shown to be overexpressed or overactivated in the development of progressive PrCa, with the deregulation of AR activators tending to increase with tumor progression, which is correlated with the aggressiveness of disease, poorer prognoses, and the development of CPRC.22,25,30 Many kinase pathways may enhance the activity of AR through the phosphorylation of coactivators.29 Oxidative stress can regulate AR signaling by affecting the levels of expression of AR coregulators, which then induces AR target gene transcription.24
AR Activation by Growth Factors/Cytokines
Many patients with PrCa who do not have AR mutations nor amplification retain active AR signaling even when levels of androgen are reduced with antiandrogen therapy.13,25 Proliferation of PrCa can also be regulated via indirect pathways, involving paracrine mediators that are produced by stromal cells, which include insulin-like growth factor (IGF), transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), and epidermal growth factor (EGF).13,25,31,32 These growth factors have been demonstrated to stimulate the expression of androgen-responsive genes, regardless of androgen levels.13,23 In addition, serum elevation of several cytokines has been found in patients with PrCa, and may be associated with more severe, malignant disease. For example, elevations in plasma interleukin-6 (IL-6) and its soluble receptor have been associated with progressive disease and poorer prognoses in patients with PrCa.13,33,34 In addition, the tumor suppressor gene (phosphatase and tensin homolog deleted on chromosome 10 )/AKT pathway plays a role with the AR in tumor development and progession. Decreased PTEN expression also correlates with progression of disease.35 Growth factors and cytokines act together with AR signaling through their downstream intracellular signal-transduction pathways.25
De Novo Intraprostatic Androgen Synthesis

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