Advances in the Treatment of Patients with Castration-Resistant Prostate Cancer

Wayne Kuznar

May 2014, Vol 5, No 4 - Prostate Cancer


Hollywood, FL—The treatment options for patients with castration-resistant prostate cancer (CRPC) have increased over the past few years. Understanding the clinical disease states is essential when choosing therapy for this patient population, according to Celestia S. Higano, MD, Professor of Medicine and Urology, University of Washington, Seattle, who described the recent additions to the therapeutic armamentarium at the 2014 National Comprehensive Cancer Network Conference.

In terms of treatment, patients with CRPC can be divided into 2 groups—those with metastatic disease and those without metastatic disease. Dr Higano focused on the current therapeutic options for patients with metastatic CRPC, which can be further categorized into asymptomatic or symptomatic disease and pre- or postchemotherapy.

Immunotherapy
Sipuleucel-T (Provenge) is the only immunotherapy agent approved by the US Food and Drug Administration for the treatment of patients with metastatic CRPC and is indicated for use in asymptomatic or minimally symptomatic patients. Its approval was based on a significant survival advantage compared with placebo in the phase 3 trial known as IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment), said Dr Higano.

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,” Dr Higano said. “I do believe the data.”

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

Prostate-specific antigen (PSA) levels do not decline with the use of sipuleucel-T, and it has no effect on progression-free survival (PFS), even though all 3 trials demonstrated significant survival benefit, she said. Sipuleucel-T is very well tolerated, with mild toxicities.

The 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,” Dr Higano said. Ideally, it should occur before the initiation of several second-line hormonal manipulations, before corticosteroid use, with chemotherapy and/or with abiraterone, at a time when the immune system is more robust and patients are less likely to have symptoms, rapid progression, or liver metastases.

When prescribing sipuleucel-T, educate patients and their families not to expect a decline in PSA, and the lack of ability to predict benefit in individual patients, Dr Higano said. Patients should be evaluated monthly for symptomatic progression. Imaging should be obtained at baseline and again at 3 months to monitor disease.

Hormonal Therapy
The 2 newest hormonal options are abiraterone (Zytiga) or enzalutamide (Xtandi). Abiraterone is an oral CYP-17 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 those who take drugs that lower the threshold for seizures. Both hormonal agents result in a decline in PSA levels.

In the pre- and postdocetaxel setting, abiraterone and enzalutamide show improvements in median overall survival compared with placebo, and a delay in radiographic PFS, said Dr Higano.

Radium-223
Radium Ra 223 dichloride (Radium-223; Xofigo) is an alpha particle–emitting radioisotope that is indicated for patients with prostate cancer who have symptoms in the postdocetaxel setting (or who are unfit for docetaxel), a population that derived significant survival benefit and a delay to a first skeletal event with radium-223 in the ALSYMPCA phase 3 study.

Dosing in ALSYMPCA was monthly for 6 months. Radium-223 is also a calcium mimetic that targets new bone growth in and around metastases; thus, skeletal-related events may become a new end point in future trials of this agent, Dr Higano said.

Although radium-223 must be administered by a specialist in nuclear medicine, there are no restrictions on patient contact with other people.

Chemotherapy
Docetaxel (Doxil) and cabazitaxel (Jevtana) are the only chemotherapy options to demonstrate a survival benefit in the setting of metastatic CRPC, according to Dr Higano. 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 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.

Dr 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 a lack of pain progression does not mean a lack of clinical benefit.