An overview of current and emerging therapeutic management strategies for patients with metastatic castration-resistant prostate cancer, "Beyond the Abstract," by Joelle El-Amm, MD and Jeanny Aragon-Ching, MD

BERKELEY, CA (UroToday.com) - The treatment of metastatic castrate resistant prostate cancer (mCRPC) has changed drastically over the past few years with the emergence of several new therapies. This review article summarizes the current data on the novel therapies that were recently approved by the FDA for the treatment of mCRPC and the ongoing trials with emergent therapies. Additionally, it also propose a sequencing strategy.[1]

Sipuleucel-T was approved by the FDA in April 2010 for treatment of asymptomatic or minimally symptomatic mCRPC, based on the landmark IMPACT trial which showed an overall survival ( OS) benefit in the absence of significant PSA change. It became the first vaccine to be approved for any solid tumor.[2] Cabazitaxel was approved by the FDA in June 2010 as a second-line chemotherapy agent, in combination with prednisone, after failure of docetaxel, based on the pivotal TROPIC trial which demonstrated improvement in OS, progression free survival ( PFS), and PSA response as compared to the mitoxantrone/prednisone combination.[3] Abiraterone acetate, a novel inhibitor of the cytochrome P450 17 (CYP 17), attained approval by the FDA in April 2011, in combination with prednisone, for mCRPC after docetaxel failure, based on the COU-AA-301 trial. That trial demonstrated OS, PFS, PSA response, and pain improvement compared to placebo post- docetaxel failure.[4] Denosumab is a fully human monoclonal anti-receptor activator of nuclear factor κ B ligand (RANKL) antibody that was approved by the FDA in November 2010 for the prevention of skeletal related events (SRE), in patients with mCRPC to the bones, based on a phase III trial that demonstrated decrease in the rate of SRE -- albeit with no effect on OS, PFS or PSA progression.[5] Enzalutamide is a novel androgen receptor signaling inhibitor that demonstrated significant OS benefit compared to placebo in the landmark phase III AFFIRM trial and was granted FDA approval for mCRPC post-docetaxel failure.[6] Alpharadin is a first-in-class α pharmaceutical bone metastasis-targeting agent emitting high-energy α particles of short range, which demonstrated in the landmark phase III ALSYMPCA trial OS benefit, in addition to delay of SRE, in patients with bone metastases due to mCRPC.[7] Alpharadin was approved by the FDA on May 15, 2013 for symptomatic bone metastases due to mCRPC in the absence of visceral metastases. Several other agents appear to be promising and are currently part of clinical trials in mCRPC, and these include ipilumimab, PROSTVAC-VF, Custirsen, OGX-427 , OGX-011, orteronel, galeterone, tasquinimod, and cabozantinib.

This rapid emergence of new therapies for mCRPC has led to the challenge of identifying the best sequence of their use. In the absence of direct level one evidence, we proposed dividing mCRPC into categories based on the clinical state on the disease. For asymptomatic mCRPC, current options include secondary hormonal manipulation, sipuleucel-T, and abiraterone. For rapidly progressive but asymptomatic mCRPC, options include abiraterone, docetaxel, or secondary hormone manipulations. For symptomatic mCRPC, docetaxel remains the standard first line treatment. In post-docetaxel failure, current options include abiraterone, cabazitaxel, enzalutamide, alpharadin, and mitoxantrone. The landscape for treatment of mCRPC has evolved rapidly in the last few years. With all these new therapies that are currently available, the challenge is to have guidelines to help determine the most effective therapy at the most appropriate time.

References:

  1. El-Amm J, Aragon-Ching J. The changing landscape in the treatment of metastatic castration-resistant prostate cancer. Ther Adv Med Oncol  2013 Jan;5(1):25-40
  2. Kantoff, P., Higano, C., Shore, N., Berger, E., Small, E., Penson, D. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010A; 363: 411–422
  3. de Bono, J., Oudard, S., Ozguroglu, M., Hansen, S.,Machiels, J., Kocak, I. 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: 1147–1154
  4. de Bono, J., Logothetis, C., Molina, A., Fizazi, K., North, S., Chu, L. et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995–2005
  5. Fizazi, K., Carducci, M., Smith, M., Damiao, R., Brown, J., Karsh, L. 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: 813–822
  6. Scher, H., Fizazi, K., Saad, F., Taplin, M., Sternberg, C., Miller, K. et al. Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI), on overall survival in patients with prostate cancer postdocetaxel: Results from the phase III AFFIRM study. J Clin Oncol 2012; 30(Suppl. 5): abstract LBA1
  7. Sartor, O., Heinrich, D., Helle, S., O’Sullivan, J., Fossa, S., Chodacki, A. et al. Radium-223 chloride impact on skeletal-related events in patients with castration-resistant prostate cancer (CRPC) with bone metastases: a phase III randomized trial (ALSYMPCA). J Clin Oncol 2012; 30 (Suppl. 5): abstract 9

Written by:
Joelle El-Amm, MD and Jeanny Aragon-Ching, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Division of Hematology and Oncology, Department of Medicine, George Washington University Medical Center, Washington, DC, USA

The changing landscape in the treatment of metastatic castration-resistant prostate cancer - Abstract

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