New Agents for the Management of Castration-Resistant Prostate Cancer

Robert J Cersosimo PharmD BCOP

Disclosures

The Annals of Pharmacotherapy. 2012;46(11):1518-1528. 

In This Article

Recommendations/Summary

Until recently the only treatment that demonstrated improved survival in patients with CRPC was docetaxel-based therapy. Several pivotal Phase 3 studies have changed that, adding 3 new agents to the list of therapies demonstrated to improve survival in these patients. A key question is, where within the treatment scheme do these drugs belong? Sipuleucel-T is indicated for men with asymptomatic or minimally symptomatic metastatic CRPC. As indicated, this agent may be used before or after chemotherapy. However, most of the patients in the sipuleucel-T trials had not received prior docetaxel-based therapy. Since it may take some time for the immune response to develop, patients with stable disease and a life expectancy of several months would be better candidates for treatment than patients with progressive disease. Activity among patients with visceral disease, a negative prognostic factor, is unknown, as patients with visceral disease were excluded from the clinical trials. Additional exclusion factors include patients who are not able to adhere to 3 leukapheresis appointments as well as those for whom leukapheresis would be contraindicated, such as those with active infections or unstable cardiac or pulmonary conditions. Patients receiving concurrent immunosuppressive therapy should also be excluded. The NCCN classifies sipuleucel-T as a category 1 recommendation for management of asymptomatic or minimally symptomatic patients with prostate cancer with ECOG performance status 0–1.[6] The NCCN does not recommend sipuleucel-T for patients with hepatic metastases or a life expectancy of <6 months.

Cabazitaxel and abiraterone are both indicated for the management of CRPC patients who have received prior docetaxel-based therapy. At the present time there are no data to guide selection between these 2 drugs. The optimal sequence of these agents is unknown. There are no completed clinical trials comparing abiraterone to cabazitaxel in patients with CRPC and there are no biomarkers that predict which agent might be the better first choice after docetaxel. At present cabazitaxel may have an advantage in patients with visceral disease, as 25% of patients in the TROPIC trial had visceral disease.

A major factor that may influence choice of therapy is the adverse effect potential of each drug. Administration of abiraterone before cabazitaxel may reduce toxicity that may accompany prolonged taxane use and could possibly delay emergence of taxane-resistant disease. Patients who tolerated docetaxel well might be better candidates to receive cabazitaxel next. Conversely, patients who did not tolerate docetaxel would be better candidates for abiraterone. Abiraterone has not been studied in patients with severe hepatic dysfunction and should not be used in these patients. Cabazitaxel has been associated with significant neutropenia and may not be a good choice in a patient with a history of severe chemotherapy-associated neutropenia and should be used cautiously in the elderly. The higher incidence of cardiac deaths with cabazitaxel versus mitoxantrone suggests cautious use in patients with cardiac disease. Cabazitaxel and abiraterone have NCCN category 1 recommendations for management of metastatic castration-resistant and docetaxel-resistant prostate cancer.[6] Additional studies should help to determine the proper sequence of these agents in patients with CRPC. Questions yet to be answered include the role of administration of abiraterone before docetaxel, the activity of cabazitaxel versus docetaxel as first-line chemotherapy in CRPC, and if there is a role for concurrent administration of abiraterone and chemotherapy. At present the NCCN recognizes that some patients with metastatic CRPC may not be candidates for docetaxel therapy. Abiraterone may be appropriate for use in these patients (category 2B recommendation).[6]

The advent of 3 new agents has significantly increased the options available for management of patients with CRPC. Only time and experience will determine the optimum timing and sequence of all treatments available for this advanced disease.

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