Abiraterone Acetate and Ketoconazole in Prostate Cancer Patients

Chicago—A study of patients with progressive metastatic castration-resistant prostate cancer (mCRPC) who had previously used ketoconazole and then took abiraterone acetate showed that the 2 drugs could be used as sequential therapy. The researchers concluded that ketoconazole did not result in permanent adrenal dysfunction, and it did not affect the safety of abiraterone acetate. Charles J. Ryan, MD, the study’s lead author, presented the results at the ASCO meeting during a clinical science symposium titled Translational Science Advancing AR Targeting in Prostate Cancer. Dr. Ryan is an oncologist in the genitourinary medical oncology program at the University of California–San Francisco’s Helen Diller Family Comprehensive Cancer Center. The study was titled Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer and Prior Therapy with Ketoconazole: A Prostate Cancer Clinical Trials Consortium Study. In April, the US Food and Drug Administration approved abiraterone acetate to use with prednisone to treat patients with mCRPC that has progressed despite receiving prior docetaxel-containing chemotherapy. During the randomized phase 3 trials that led to abiraterone acetate’s approval, patients who had used ketoconazole were excluded because of concerns about confounding efficacy, adrenal dysfunction, and toxicity. Abiraterone acetate and ketoconazole both inhibit CYP17, the rate-limiting enzyme in androgen synthesis, although abiraterone acetate is a more potent CYP17 inhibitor. In this trial, Dr. Ryan said the researchers were interested in examining the efficacy of abiraterone acetate in patients whose disease progressed while taking ketoconazole. They also wanted to study the potential sequential use of abiraterone acetate and ketoconazole and characterize the relationship between androgen levels and response to therapy. Patients were included in the study if they had progressive mCRPC, used ketoconazole for >28 days, experienced disease progression or grade 3 or 4 toxicities while using ketoconazole, and demonstrated normal baseline organ function and ACTH stimulation test. They were excluded if they had received prior chemotherapy. The trial enrolled 16 patients and was then halted to add another site to participate in the first phase of the study through the US Department of Defense/Prostate Cancer Foundation prostate cancer clinical trials consortium. The average age of the patients was 72.5 years, with a range of 52 to 93 years, and they had a median prostate-specific antigen (PSA) of 62.5 ng/dL. The median duration of prior ketoconazole use was 58 weeks, and the mediation duration since the patients used ketoconazole was 17 weeks. Of the 16 patients, 14 completed 12 weeks of therapy. At the time of the presentation in June, Dr. Ryan said 4 patients remained on the treatment, 3 developed PSA working group progression, 3 developed Response Evaluation Criteria In Solid Tumors (RECIST)-defined progression, 4 developed RECIST and PSA working group progression, and 2 withdrew consent from the protocol. Of the 14 patients, 3 had a PSA decline of ≥50% and 6 had a PSA decline of ≥30%. There was no statistically significant difference in adverse events compared with previously published data from abiraterone acetate trials. The authors also performed an exploratory analysis of patients with detectable dehydroepiandrosterone (DHEA) at baseline compared with those who had no detectable DHEA at baseline. They found that all of the patients who had no detectable DHEA at baseline failed to demonstrate a response to abiraterone acetate after 12 weeks of treatment. Dr. Ryan said potential markers of response to abiraterone acetate include adrenal androgen levels. For instance, he said that patients with no detectable serum androgens may not benefit from abiraterone acetate therapy, although that conclusion must be validated in larger studies in patients with and without prior ketoconazole therapy. In addition, he said that, consistent with previous studies, this study showed abiraterone acetate rendered most patients’ androgrens undetectable.