New Agents for the Management of Castration-Resistant Prostate Cancer

Robert J Cersosimo PharmD BCOP


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

In This Article

Hormone-responsive Disease

The PROTECT (PROvenge Treatment and Early Cancer Treatment) trial, a double-blind controlled study, examined the activity of sipuleucel-T in patients with androgen-dependent disease.[17] All patients had undergone radical prostatectomy and had a PSA increase as their only sign of recurrence. Patients received a 3-month depot injection of an LHRH agonist and, if their PSA was less than 1 ng/mL, they were randomized to receive sipuleucel-T (n = 117) or control (n = 59). Patients whose PSA was not less than 1 ng/mL were allowed a 1-month depot injection of an LHRH agonist and after that injection, if the PSA was then less than 1 ng/mL, they were eligible for randomization. The primary end point was time to biochemical failure, defined as a serum PSA of 3.0 ng/mL or more. PSA doubling time, time to distant failure, and overall survival were also assessed.

The median time to biochemical failure was 18.0 months in the sipuleucel-T group and 15.4 months in the control group (p = 0.737). Patients who received sipuleucel-T had a significantly longer PSA doubling time (155 vs 105 days; p = 0.038), a 48% increase. It was too early to report on time to distant failure or survival.[17]

Adverse Effects

Sipuleucel-T was well tolerated.[7] Most adverse effects were grade 1–2. Effects seen more commonly after sipuleucel-T compared to placebo were primarily infusion reactions and included chills (54.1%), fever (29.3%), fatigue (39.1%), nausea (28.1%), headache (16.0%), asthenia (10.9%), and flu-like illness (9.8%), as well as myalgia (9.8%), hypertension (7.4%), hyperhidrosis (5.3%), and groin pain (5%). Most effects resolved within 48 hours.

Cerebrovascular events were reported in 8/338 patients (2.4%) on sipuleucel-T versus 3/168 (1.8%) on placebo (p = 1.00) in the IMPACT trial.[7] This contrasts with the results reported in the other Phase 3 randomized trials, which report a possible increased risk of cerebrovascular events in patients who received sipuleucel-T.[14] The incidence of cerebrovascular events reported as adverse effects or causes of death was 7.5% (11/147) in the sipuleucel-T arm versus 2.6% (2/76) in the placebo arm.[14] A summary of the incidence and characteristics of cerebrovascular events from 4 randomized trials revealed the following incidences of cerebrovascular events after sipuleucel-T and placebo, respectively: cerebrovascular events (including transient ischemic attack), 4.0% versus 2.9%; ischemic stroke, 2.7% versus 2.6%; hemorrhagic stroke, 0.7% versus 0.3%; unknown stroke, 0.7% versus 0%; and transient ischemic attack, 0.8% versus 0.3%.[18] Patients who received sipuleucel-T were at a slightly higher risk for cerebrovascular events than those who received placebo (absolute risk difference 1.1%); these differences could account for the difference in cerebrovascular events between treatment and placebo groups. There was also a higher incidence of cerebrovascular event–associated deaths with sipuleucel-T (1.4%) than placebo (0.7%). In light of the uncertainties concerning the risk of cerebrovascular events with sipuleucel-T administration, the Food and Drug Administration has required the sponsor to complete a postmarketing study to evaluate the risk of cerebrovascular events in patients who receive it.[19]

Cost Considerations

A 3-treatment course of sipuleucel-T therapy has been priced at $31,000 per treatment, or $93,000 per course, making it one of the most expensive cancer treatments on the market.[20] The Centers for Medicare and Medicaid Services began an analysis of sipuleucel-T in 2010 and reported on June 30, 2011, that it determined that the evidence was adequate to conclude that sipuleucel-T improves health outcomes for Medicare beneficiaries with asymptomatic or minimally symptomatic metastatic CRPC and that it is reasonable and necessary for that indication.[21]