Castration Resistant Prostate Cancer; the Rise & Fall of Systemic Chemotherapy - Highlights from Recent Phase III Studies

Omar Abdel-Rahman

Prostate cancer is the most common cancer in men with an estimated 382,000 cases occurring during 2008 in Europe. The mortality in the EU is 30,6/100,000 men/year and almost 90,000 deaths from prostate cancer occurred in Europe in 2008, making it the third most common cancer death in men (1). While in the USA, prostate cancer is the second most common cause of cancer death with an estimated 33,720 deaths expected in 2011 (2).

Castration resistant prostate cancer (CRPC) is defined as prostate cancer that recurs while a patient is receiving androgen deprivation therapy (ADT). Many treatment options have been suggested for this challenging disease; historically, mitoxantrone, in combination with prednisone, was approved for the treatment of patients with pain related to metastatic CRPC and was associated with pain-relieving effects together with higher proportion of prostate-specific antigen decrease of 50% or greater, but with no difference in overall survival (3). However, docetaxel-based regimens have then replaced mitoxantrone-based therapy as the approved standard of care after the landmark TAX 327 study resulted in a significant survival benefit for docetaxel/prednisone over mitoxantrone/prednisone (4).  

In the recent few years, a number of systemic agents began to occupy significant positions in the decision tree of castration resistant prostate cancer either in the post-docetaxel or pre-docetaxel settings based on the results of a number of landmark phase III studies; examples included sipuleucel-T dendritic cell vaccine, arbiraterone, enzalutamide (androgen receptor signaling inhibitor) and cabazitaxel.

The most recently introduced agent in this family is the alpha emitter radium-223, which is calcium mimetic that preferentially localises to areas of high-bone turnover, thereby targeting bone metastases. In the phase III, randomised, double-blind, placebo-controlled study (ALSYMPCA study), 921 patients who had previously received, were not eligible to receive, or declined docetaxel, were randomised in a 2:1 ratio to receive six injections of radium-223 or matching placebo. At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, two-sided p = 0.002). Accordingly, this study has been terminated for efficacy at the prespecified interim analysis. Interestingly enough, the number of patients who had adverse events after they received the study drug was consistently lower in the radium-223 group than in the placebo group for all adverse events including myelosuppression (5).

References:

  1. Bray F, Lortet-Tieulent J, Ferlay J et al. Prostate cancer incidence and mortality trends in 37 European countries: an overview. Eur J Cancer 2010; 46:3040–3052.
  2. Siegel R, Ward E, Brawley O et al. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011; 61(4):212-36.
  3. Tannock IF, Osoba D, Stockler MR et al Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points..J Clin Oncol 1996;14(6):1756-64. 
  4. 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):1502-12.
  5. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369:213-223.

Discussion questions:

  • How would you incorporate this new treatment into the CRPC treatments armamentarium?
  • Among the overwhelming new systemic options for CRPC, where should docetaxel-based regimens stand?

The content of this article reflects the personal opinions of the authors and is not necessarily the official position of the European Society for Medical Oncology.

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