Abiraterone received FDA approval in April 2011 for the treatment of men with metastatic castrate-resistant prostate cancer (mCRPC) whose disease has progressed after chemotherapy. In December 2012, the agency expanded that approval to include men with mCRPC who had not received docetaxel. The expanded approval was based on data from a third prespecified interim analysis of the randomized controlled Cougar-302 trial of 1,082 patients, which has now been reported at this year's Genitourinary Cancers Symposium.
Use of abiraterone plus prednisone was found to nearly double the duration of radiographic progression-free survival compared with use of placebo plus prednisone in men who had not received chemotherapy (16.5 vs. 8.3 months), with a hazard ratio of 0.53 (Abstract 5).
As in the previous interim analysis, although there was a trend toward improvement in overall survival with the combination at 35.3 months compared with 30.1 months for placebo, the difference did not reach the necessary boundary for statistical significance in the interim analysis.
At the time of the interim analysis, in May 2012, 77 percent of patients in the abiraterone arm had discontinued therapy, as had 89 percent in the placebo arm. The primary reason for discontinuation was disease progression, at 57 and 68 percent in the abiraterone and placebo arms, respectively.
Additionally, seven percent of patients in the abiraterone arm discontinued treatment due to adverse events, as did 10 percent of patients in the control arm.
“One of the key features of this study was the focus on clinical benefit, not just radiographic disease,” said the researcher who presented the data, Dana E. Rathkopf, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center and co-principal investigator for the Department of Defense Prostate Cancer Clinical Trials Consortium (PCCTC) Site Award, an initiative designed to increase patient access to clinical trials across the country. “Therefore patients were allowed to stay on therapy beyond radiographic progression until a time point of unequivocal clinical progression.”
At the time of discontinuation, 23 percent of patients in the abiraterone arm had radiographic-only progression, as did 32 percent of the patients in the placebo arm. Twenty-two percent and 26 percent of patients in the two arms had unequivocal clinical progression, which was defined as one or more of the following events: pain requiring opiates, chemotherapy, palliative radiation therapy, decline in ECOG performance status, or surgical intervention. Additionally, 10 percent of patients in the combination arm and 12 percent in the control arm had both radiographic and clinical progression.
The most common adverse event in each arm was fatigue, all grades of which affected 40 percent of patients in the abiraterone arm and 35 percent in the control arm. Two percent of patients in each arm experienced Grade 3/4 fatigue, seven percent of patients in the combination arm and one percent of patients in the control arm had Grade 3/4 cardiac disorders, and six and one percent of patients, respectively, developed Grade 3/4 ALT increases. A few patients in each arm developed Grade 3/4 fluid retention (1% in the combination arm vs. 2% in the control arm), hypokalemia (3% vs. 2%), hypertension (4% and 3%), and hyperglycemia (3% vs. 2%).
“Importantly there were no new safety signals that emerged with the longer duration of abiraterone or prednisone beyond two years,” Rathkopf concluded.
Overall Survival Difference May Be Difficult to Detect
The majority of patients in both arms of the study received subsequent therapy after discontinuing the study drug—65 percent in the abiraterone arm and 72 percent in the placebo arm. Docetaxel was the most common post-trial agent and was used by 57 and 63 percent of patients in the two arms, respectively.
Patients also used cabazitaxel, ketoconazole, sipuleucel T, and, somewhat surprisingly, abiraterone (9% and 16%). Rathkopf noted that the post-trial abiraterone use occurred prior to unblinding and was not per-protocol.
Given the number of agents now available to patients with metastatic castrate-resistant prostate cancer, investigators may not be able to show a statistically significant benefit in overall survival with abiraterone, noted the Discussant for the study, William Oh, MD, Chief of the Division of Hematology and Medical Oncology and the Ezra M. Greenspan, MD, Professor in Clinical Cancer Therapeutics at Mount Sinai School of Medicine and Associate Director for Clinical Research at the Tisch Cancer Institute in New York City.
“We may never get the answer to whether pre-chemotherapy abiraterone will improve overall survival, and that to me is okay as long as we still have evidence that it is of meaningful value for patients,” he said. He noted that secondary endpoints, including time to opiate use, time to chemotherapy initiation, and time to performance status deterioration all favored abiraterone over placebo, as did exploratory quality-of-life analyses.
Early Use May Be Best Option
Because abiraterone is approved now for patients before and after chemotherapy, a key question is which setting provides the most benefit with the drug.
To begin to answer that question, Oh compared data from the Cougar-301 post-chemotherapy trial with the newly reported interim data from the pre-chemotherapy study. The absolute benefit in progression-free survival with abiraterone in the pre-chemotherapy study was eight months and two months in the post-chemotherapy setting. The hazard ratio also favored the pre-chemotherapy setting, at 0.53 versus 0.66 in the post-chemotherapy setting. By contrast, the apparent gain in overall survival was similar in the two trials, around five months, a measure which is confounded by the use of all the other treatments, he said.
“So my conclusion is that the maximal benefit for abiraterone is likely to be seen when used prior to chemotherapy. I think this is rational, and certainly our patients appreciate using this type of agent.”
During her talk, Rathkopf had described an individual patient who was hesitant to go on docetaxel treatment because neuropathy would interfere with his gardening and writing. She was able to offer him entry onto the abiraterone study and he benefited from the drug, while continuing to pursue his passions.
Oh said, “I really liked that story because it hits close to home for all of us, that we are trying to choose therapies that will most meaningfully help our patients, not just let them live longer.”
The pre-chemotherapy findings are very important, noted Anthony D'Amico, MD, PhD, Chair of the Division of Genitourinary Radiation Oncology at Dana-Farber Cancer Institute and Professor of Radiation Oncology at Harvard Medical School. He said that although not a medical oncologist himself, he expects the data will lead to a change in practice, shifting the use of abiraterone from the post-chemotherapy setting to pre-chemotherapy use.
The study was supported by Janssen Research & Development. Several co-authors on the study reported working as a consultant, advisor, or employee of the company. Oh has served as an advisor to Janssen Research & Development as well. D'Amico did not report any relevant financial conflicts.
The meeting is co-sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.