New ADC Effective against Prostate Cancer

A new agent that targets prostate-specific membrane antigen (PSMA), a protein on the surface of about 90% of prostate tumors, may be an effective treatment for patients with metastatic, hormone-refractory prostate cancer. That's the conclusion of a phase I study of the drug, presented on November 8 at the 2012 Symposium on Molecular Targets and Cancer Therapeutics held in Dublin, Ireland. The symposium was sponsored by the European Organisation for Research and Treatment of Cancer, the National Cancer Institute, and the American Association for Cancer Research.

Even with the approval in the past few years of enzalutamide (Xtandi; Medivation/Astellas), abiraterone (Zytiga; Janssen), and cabazitaxel (Jevtana; Sanofi-Aventis), which have improved survival, “patients with advanced, metastatic, castration-resistant prostate cancer are not cured of their disease,” says Daniel Petrylak, MD, director of the prostate cancer program/genitourinary cancer program and codirector of the signal transduction program at Yale University Medical Center in New Haven, CT and lead author of the study. “This targeted therapeutic approach could be an effective option for patients.”

An antibody—drug conjugate (ADC), the therapy consists of a fully human monoclonal antibody developed by Progenics Pharmaceuticals (Tarrytown, NY) linked to the antimicrotubule agent monomethyl auristatin E (MMAE). The antibody binds to PSMA on the surface of malignant cells. After the cells internalize the ADC, MMAE is activated, causing cell-cycle arrest and apoptosis.

Petrylak and researchers from several other American cancer centers enrolled 50 patients with metastatic prostate cancer in their study, all of whom had experienced disease progression despite undergoing hormone-deprivation therapy and chemotherapy with docetaxel (Taxotere; Sanofi-Aventis). The patients were treated with doses of the PSMA ADC ranging from 0.4 mg/kg to 2.8 mg/kg by intravenous infusion for up to four 3-week cycles.

About half of the men who received doses of 1.8 mg/kg or higher experienced a drop in prostate-specific antigen (PSA) levels of 50% or more, a reduction in circulating tumor cells (CTC) to less than 5 cells per 7.5 mL of blood, or both. A reduction in PSA of 30% over 3 months has been linked to improved survival. Other studies have shown that prostate cancer patients with less than 5 CTCs per 7.5 mL of blood have a better prognosis than patients with 5 or more, Petrylak says.

The PSMA ADC was generally well tolerated by patients, although white blood cell levels were significantly reduced in patients who took the highest dose-2.8 mg/kg. One patient died, but the cause of death was unclear, researchers said.

Given the promising responses to higher doses of the drug, a phase II trial has begun, Petrylak adds. In addition to assessing the drug's safety, researchers will evaluate changes in PSA and CTCs, control of metastases (based on imaging), and the effect on pain in up to 75 patients taking a dose of 2.5 mg/kg.

Although multiple ADCs are in clinical trials, none has been approved for the treatment of prostate cancer, notes Petrylak.