Treating metastatic prostate cancer now and in the future

The public focus on prostate cancer has largely shifted from metastatic disease to low-risk, localized disease with controversy surrounding the routine use of prostate-specific antigen (PSA) for screening. Although the prostate cancer screening debate has highlighted important issues for men’s health and cancer screening efforts, the fact remains that prostate cancer is not only the most common malignancy among men in the U.S., but is expected to cause 29,480 deaths in 2014.1 Thus, many cases of prostate cancer progress, and the management of more advanced and metastatic disease is of continued importance.

Previous advances in prostate treatment

The use of methods to manipulate the hormonal axis in the treatment of prostate cancer dates back more than 70 years ago, when researchers found that metastatic disease responded to surgical castration, thereby demonstrating that the prostate is dependent on androgens.2 Androgen deprivation therapy (ADT) has been the primary form of treatment in men with metastatic prostate cancer and has been accomplished by either orchiectomy or by reducing testosterone synthesis through central blockage of luteinizing hormone release from the pituitary gland using luteinizing hormone releasing hormone (LHRH) agonists or antagonists. In addition, medications that block the androgen receptors, so-called  antiandrogens, were discovered in the 1960s and have been used in conjunction with medications that lower the levels of testosterone.

Significant advances in the treatment of men with metastatic prostate cancer have occurred in the last decade through drug development and clinical trials (see table). Despite the use of ADT, disease progression and emergence of castration-resistant prostate cancer (CRPC) can occur over time. Options for CRPC had been limited and were generally palliative, until docetaxel, a microtubule inhibitor, was approved in 2004 for men with metastatic CRPC based on two trials demonstrating a survival benefit.3,4 Since then, multiple phase III trials have been conducted, adding a variety of agents to docetaxel with disappointing results (for example, bevacizumab in cancer and leukemia group [CALGB] 90401).5

Critical trials in metastatic castration-resistant prostate cancer


Clinical setting

Mechanism of action




Survival (months)

FDA approval

Docetaxel2 +/– symptoms Microtubule inhibitor Mitoxantrone



19.2 v 16.3*


Docetaxel+ estramustine3 +/– symptoms Microtubule inhibitor Mitoxantrone



17.5 v 15.6


Sipuleucel T5 – or minimal symptoms Immunotherapy Placebo



25.8 v 21.7


Cabazitaxel6 Post-docetaxel Microtubule inhibitor Mitoxantrone



15.1 v 12.7


Abiraterone7 Post-docetaxel CYP17A1 inhibitor (adrenal androgens) Placebo



14.8 v 10.9


Abiraterone8 Pre-docetaxel most asymptomatic CYP17A1 inhibitor (adrenal androgens) Placebo


0.75 rPFS

35.3 v 30.1 (ns)


Enzalutamide9 Asymptomatic post-docetaxel  Antiandrogen Placebo



18.4 v 13.6


Radium-22315 Bone but no visceral metastases Alpha emitter Placebo



14.9 v 11.3


Enzalutamide9 Asymptomatic pre-chemotherapy  Antiandrogen Placebo



32.4 v 30.2


HR=hazard ratio of death; rPFS=radiographic progression-free survival; ns=not statistically significant; NR=not reported
*Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: Updated survival in the TAX 327 study. J Clin Oncol. 2008;26(2):242-245.

In 2010, the U.S. Food and Drug Administration approved two additional agents. The first was sipuleucel-T, an autologous active cellular immunotherapy, which reduced the risk of death by 22 percent in men with asymptomatic or minimally symptomatic metastatic CRPC.6 The second was cabazitaxel, a docetaxel derivative, which demonstrated a survival benefit in men who had progression after prior docetaxel.7

In 2011, abiraterone was approved in the post-chemotherapy setting.8 This drug, an inhibitor of the enzyme CYP17A1, further reduces testosterone levels by affecting synthesis of the precursors dehydroepiandrosterone and androstenedione within all tissues, particularly the adrenal glands, which continue to produce low levels of testosterone despite orchiectomy or LHRH inhibition. A subsequent trial has demonstrated improved radiographic progression-free survival and a trend toward improved overall survival, even in patients who had not received prior chemotherapy.9

As mentioned earlier, blockage of the androgen receptor has been possible for many decades, but used alone, it was not highly effective for CRPC. Enzalutamide was discovered and found to be a more potent antiandrogen by having a higher affinity for the androgen reception, preventing receptor translocation to the nucleus, and preventing receptor binding to DNA and co-activator proteins. Phase III trials have demonstrated the efficacy of enzalutamide in men with metastatic CRPC both before and after chemotherapy.10,11

New Alliance trial

Given the availability of multiple new agents for metastatic CRPC and the different mechanisms of action, current studies are exploring the optimal timing, sequence, and combination of these drugs. The Alliance A031201 is a prospective randomized trial comparing enzalutamide alone versus enzalutamide and abiraterone in men with metastatic CRPC who have not received docetaxel chemotherapy. The primary endpoint is overall survival, with secondary endpoints including PSA response, radiographic progression-free survival, and toxicity of combined therapy; target accrual is 1,224 men.

Consideration of bone health is particularly important in men with metastatic CRPC, given the propensity of metastases to the bone as well as the adverse long-term impact of ADT on bone mineral density. ADT-induced osteoporosis increases the risk of fracture more than five-fold per year, which is associated with significant risk of morbidity and mortality. The use of the bisphosphonate zoledronic acid decreases the risk of skeletal-related events (SREs) and is indicated in men with CRPC and bone metastases, as well as in men with osteoporosis receiving ADT.12 It has been hypothesized that the administration of zoledronic acid earlier in the course of disease, used to modulate the bone microenvironment, may be advantageous. CALGB 90202 addressed this question by giving zoledronic acid to men with castration sensitive prostate cancer and bone metastases. The randomized, placebo-controlled trial accrued 645 patients and did not observe a difference in time to first SRE nor overall survival.13 The recently reported Zometa European Study also did not report an advantage of earlier administration of zoledronic acid in men with high-risk localized prostate cancer, with the rate of developing bone metastases at 4.8 years of 14.7 percent and 13.2 percent in the treatment and control groups, respectively.14

In another advancement in treatment options, denosumab—a human monoclonal antibody that binds and inhibits RANK ligand—has proven superior to zoledronic acid with respect to prevention of SREs. In addition, compared with placebo, denosumab delayed the time to first bone metastasis but did not improve overall survival in men with non-metastatic CRPC.15 The most recently approved drug for CRPC with bone-only metastasis is radium-223. The alpha-particle emitting drug improved overall survival, as well as time to first SRE, time to increase in alkaline phosphatase, and time to increased PSA.16

The past decade has seen a paradigm shift in the treatment of men with advanced prostate cancer. The numerous available, approved agents are the result of improved understanding of disease biology, investment in basic research and identification of rational therapeutic targets, collaboration with industry, and design and completion of well-designed clinical trials. It is anticipated that continued efforts in these areas will translate into novel agents and optimization of drug sequencing and combination, leading to improvements in the modest absolute survival currently observed.


  1. American Cancer Society. Prostate cancer: What are the key statistics about prostate cancer? Available at: Accessed July 15, 2014.
  2. Huggins C, Hodges CV. Studies on prostate cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1(4):293-297.
  3. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512.
  4. Petrylak DP, Tangen CM, Hussain MHA, et al. Docetazel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15):1513-1520.
  5. Antonarakis ES, Eisenberger MA. Phase III trials with docetaxel-based combinations for metastatic castration-resistant prostate cancer: Time to learn from past experiences. J Clin Oncol. 2013;31(14):1709-1712.
  6. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422.
  7. de Bono JA, Oudard S, Ozguroglu M, et al.  Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet. 2010;376(9747):1147-1154.
  8. Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: Final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13(10):983-992.
  9. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-148.
  10. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-1197.
  11. Beer TM, Armstrong AJ, Sternberg, CN, et al. Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study. Genitourinary Cancers Symposium. Abstract LBA1. Presented January 30, 2014.
  12. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94(19):1458-1468.
  13. Smith MR, Halabi S, Ryan CJ, et al. Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: Results from CALGB 90202 (Alliance). J Clin Oncol. 2014;32(11):1143-1150.
  14. Wirth M, Tammela T, Cicalese V, et al. Prevention of bone metastases in patient with high-risk nonmetastatic prostate cancer treated with zoledronic acid: Efficacy and safety results of the Zometa European study (ZEUS). Eur Urol. Epub ahead of print, February 20, 2014.
  15. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: A randomised, double-blind study. Lancet. 2011;377(9768):813-822.
  16. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

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