Abiraterone acetate, an investigational oral drug, extended survival in patients with metastatic castration-resistant prostate cancer (mCRPC) by about 4 months compared with placebo in a large phase III trial reported at the 35th ESMO Congress, held October 8-12 in Milan, Italy.¹

"This should be considered a major step forward in prostate cancer therapeutics," stated lead investigator Johann de Bono, MD, of The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London. "These results are likely to be practice-changing for men with advanced prostate cancer that has progressed on docetaxel-based chemotherapy, which has been a critical unmet need."

Abiraterone is designed to treat hormone-resistant tumors by inhibiting androgen production in the testes, adrenal glands, and prostate tumors themselves. The phase III trial included 1,195 participants from 13 countries. All men had mCRPC previously treated with chemotherapy that included docetaxel.

Dr. de Bono said this oral compound, which was developed at Royal Marsden, inhibits CYP17, a key enzyme involved in the synthesis of estrogen and testosterone. Advanced prostate cancer tumors themselves produce testosterone, even in castrated men, he explained. "These cancers are not hormone-refractory as we once assumed, but are generally hormone-driven, even after castration," he said.

Trial Design and Results

Patients were randomly assigned, in a 2:1 scheme, to either abiraterone plus prednisone or placebo plus prednisone. Median overall survival was 14.8 months in the treatment arm vs 10.9 months for placebo recipients (P < .0001). The trial was unblinded early by an Independent Data Monitoring Committee after a prespecified interim analysis of the trial showed a survival benefit. "We thought it would be unethical to withhold this drug from placebo patients in the trial," he noted.

"A difference of 3.9 months may not seem like much, but only four other drugs have extended survival in prostate cancer. We plan to study this drug earlier in treatment and we hope it will extend survival," he said.

Secondary endpoints of the trial all favored treatment, including progression-free survival (PFS) according to time to prostate-specific antigen (PSA) progression, radiographic progression, and PSA response rate. Median time to progression was 10.2 vs 6.6 months for abiraterone and placebo, respectively (P < .0001). Median PFS was 5.6 vs 3.6 months (P < .0001), and PSA response was 38% vs 10%, respectively (P < .0001).

Abiraterone was well tolerated. Adverse events related to the drug were amenable to medical management and different from those associated with cytotoxic chemotherapy. Treatment-related adverse events included fluid retention (30.5% vs 22.3%, respectively) and hypokalemia (17.1% vs 8.4%), but these events were mostly grades 1 and 2 and were manageable. Liver function test abnormalities were observed in 10.4% vs 8.1%, and cardiac disorders were observed in 12.5% vs 9.4%, respectively.

Unresolved Issues

"2010 is a good year for prostate cancer. Three positive phase III trials showed a survival benefit for sipuleucel-T (Provenge), docetaxel, and cabazitaxel (Jevtana). Abiraterone results were as good," Dr. de Bono told listeners.
Unresolved issues related to abiraterone include the need to identify which subgroups of patients benefit. "Although this is a significant advance, there is still a lot of work to do to improve outcomes for patients with advanced prostate cancer," Dr. de Bono stated. ■

Reference

1. de Bono J, Logothetis CJ, Fizazi K, et al: Abiraterone acetate (AA) plus low dose prednisone (P) improves overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after docetaxel-based chemotherapy (chemo): Results of COU-AA-301, a randomized, double-blind, placebo-controlled phase III study. 35th ESMO Congress. Abstract LBA5. Presented October 11, 2010.