May 2014, Vol 3, No 3

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Therapy for Castration-Resistant Prostate Cancer: Use Disease State as the Guide

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Understanding the clinical disease states is essential when choosing therapy for patients with castration-resistant prostate cancer (CRPC), said Celestia S. Higano, MD.

Patients with castration-resistant disease can be divided into those with metastatic disease and those with nonmetastatic disease. The focus of her presentation was on therapeutic options for metastatic CRPC, which can be further categorized into asymptomatic or symptomatic disease and prechemotherapy or postchemotherapy. There are many approved treatment options from which to choose in the metastatic setting, including chemotherapy (docetaxel, cabazitaxel), immunotherapy (sipuleucel-T), hormonal therapy (abiraterone, enzalutamide), and a radioisotope (radium-223).

Sipuleucel-T, the only immunotherapy agent approved by the FDA for the treatment of prostate cancer, is indicated for the treatment of metastatic CRPC that is asymptomatic or minimally symptomatic. Its approval was based on a significant survival advantage compared with placebo in the phase 3 trial known as IMPACT, said Higano, professor of medicine and urology, University of Washington, Seattle, WA.

The median survival benefit with sipuleucel-T in IMPACT was 4.1 months, similar to the benefit achieved in 2 smaller phase 3 trials conducted in identical patient populations using the same trial design. “It’s consistent across all 3 trials,” she said. “I do believe the data.”

The placebo and sipuleucel-T survival curves in IMPACT overlapped for the first 6 months, which is likely “due to the fact that immunotherapy does not kick in right away like we see with chemotherapy or even hormonal therapy,” she said. “It takes time to actually make a difference.”

The prostate-specific antigen (PSA) level does not decline with treatment with sipuleucel-T, she said, and it has no effect on progression-free survival (PFS), even though all 3 trials demonstrated significant survival benefit. Sipuleucel-T is very well tolerated; toxicities are mild and include infusion-related fever and/or chills. In the studies, there was a trend toward a delay in time to disease-related pain and a statistically significant delay in time to first opioid use.

A current challenge is to determine when to prescribe sipuleucel-T. “My own belief is that it should happen early in the course of metastatic castration resistance,” she said. Ideally, it should occur before initiation of numerous second-line hormonal manipulations and before corticosteroid use with chemotherapy and/or abiraterone – at a time when patients are less likely to have symptoms or rapid progression and are less likely to have liver metastases, and when their immune system is more robust.
When prescribing sipuleucel-T, educate patients and their families not to expect a decline in PSA and of the lack of ability to predict benefit in individual patients, she said. Patients should be evaluated monthly for symptomatic progression. Imaging should be obtained at baseline and again at 3 months to monitor disease.

Other Options: Hormonal Therapy, Chemotherapy, Radium-223
The 2 newest hormonal options are abiraterone and enzalutamide. Abiraterone is an oral CYP17 inhibitor that is recommended to be taken on an empty stomach in combination with prednisone. Enzalutamide is an oral pure antiandrogen that does not require prednisone. It is contraindicated in patients with a history of seizures or in those taking drugs that lower the threshold for seizures. Both hormonal agents result in a decline in PSA levels.

In the postdocetaxel setting, both abiraterone and enzalutamide showed improvements in median overall survival compared with placebo and a delay in radiographic PFS, said Higano. Robust benefits were also observed in the predocetaxel setting, especially radiographic PFS.

Docetaxel and cabazitaxel are the only chemotherapy options to demonstrate a survival benefit in metastatic CRPC, she said. Docetaxel is a first-line chemotherapy option for patients who are symptomatic or who have rapidly progressing disease.
Cabazitaxel is a semisynthetic taxoid derivative. It has poor affinity for P-glycoprotein (the drug efflux pump) and therefore may be active in docetaxel-refractory disease. Cabazitaxel is approved for use with prednisone and is indicated for patients with metastatic CRPC previously treated with docetaxel. Higano offered practical advice for the use of cabazitaxel: reduce the initial dose to 20 mg/m2, use growth factor in all patients, and appreciate that pain progression does not mean a lack of clinical benefit.

Radium-223 is an alpha particle–emitting radioisotope indicated for patients who have symptoms in the postdocetaxel setting (or who are unfit for docetaxel), a population that derived a significant survival benefit and a delay to a first skeletal-related event with radium-223 in the ALSYMPCA phase 3 study. Dosing in ALSYMPCA was monthly for 6 months. It is a calcium mimetic that targets new bone growth in and around metastases; thus, skeletal-related events may become a new end point in trials of radium-223 in the future, she said. While radium-223 must be administered by a specialist in nuclear medicine, there are no restrictions on patient contact with other people.

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