Final analysis of the large randomized Phase III placebo-controlled COU-AA-302 prostate cancer trial, published in the February issue of Lancet Oncology (2015; 2:152-160) show that use of abiraterone with prednisone increased overall survival compared with prednisone-placebo—34.7 months versus 30.3 months—in patients with castration-resistant, metastatic disease who had not previously received chemotherapy. Use of abiraterone also prolonged the median time to opiate use for prostate cancer-related pain: 33.4 months vs. 23.4 months.
These results follow the study's interim report in 2013 (Ryan et al: NEJM 2013;368:138-148) showing that median time to progression had approximately doubled with abiraterone-prednisone (16.5 vs. 8.3 months).
Median overall survival had not been reached at the time of the interim report, noted Charles J. Ryan MD, Professor of Clinical Medicine and Urology and the Thomas Perkins Distinguished Professor in Cancer Research, and Program Leader of Genitourinary Medical Oncology at UCSF Helen Diller Family Comprehensive Cancer Center.
“The survival data took a few years to fully mature, and although the survival curves separated earlier in the course of the trial, it took further maturation for the statistically significant survival separation to emerge.”
Should abiraterone now be considered a standard of care? “Absolutely,” Ryan said. “Prior to this study there was no standard of care for patients with castration-resistant prostate cancer who are asymptomatic. And there was also no standard of care for patients for whom chemotherapy was not an option. This is important because in castration-resistant prostate cancer, previous data had suggested that only about 45 percent of patients were ever receiving chemotherapy. So there was a large unmet need for a therapy that could prolong survival and delay progression of the disease with non-cytotoxic approaches.”
Rationale for Combining with Prednisone
Prednisone was combined with abiraterone in this trial, and also in the control arm, because it has shown benefits in prostate cancer, he continued.
“Prednisone has long been associated with palliative care in this disease, and 25 to 30 percent of patients experience a clinical response to prednisone. That's why the curves of the two arms failed to separate immediately in this trial and why there was some prolongation in the time until the full benefits of abiraterone in the treatment arm were seen, because of the modest effect of prednisone in the controls.”
A total of 44 percent of patients in the placebo arm went on to receive abiraterone. Ryan said that rather than confounding the results, crossover from placebo to abiraterone only strengthened the results.
“If the trial had been negative, we would have said the crossover confounded the data. But the fact that the crossover occurred and the trial was still positive for both primary endpoints strengthens the interpretation of the data.”
In 2011, the Food and Drug Administration approved abiraterone for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel. In 2012, the FDA approved an expanded indication for abiraterone in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer before chemotherapy.
In the COU-AA-302 trial, which was funded by Janssen Research & Development, a total of 1,088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology Group performance status (0 versus 1) were randomly assigned to receive either abiraterone (1,000 mg once daily) plus prednisone (5 mg twice daily) or placebo plus prednisone.
At a median follow-up of 49.2 months, the median overall survival time was significantly longer in the abiraterone group than in the placebo group, 34.7 vs. 30.3 months; and the mortality rate was also reduced—65 percent (354 of 546 patients) versus 71 percent (387 of 542 patients), respectively.
Similarly shortened, the median time to opiate use for prostate cancer-related pain was 33.4 months in the abiraterone acetate group versus 23.4 months in the placebo group.
The most common grade 3/4 adverse events reported were cardiac disorders—in eight percent of the abiraterone group versus four percent in the placebo group; increased alanine aminotransferase—six percent versus less than one percent, respectively; and hypertension—five percent versus three percent.
Inhibits CYP17, Secondary Androgen Biosynthesis
In a commentary accompanying the COU-AA-302 trial report (Lancet Oncology 2015; 2:119-121), Ravi A. Madan, MD, Clinical Director of the National Cancer Institute's Genitourinary Malignancies Branch, and William L. Dahut, MD, Clinical Director of the NCI's Center for Cancer Research, write that the trial reaffirms the importance of secondary androgen biosynthesis inhibition in patients with metastatic castration-resistant prostate cancer.
Elaborating in a telephone interview, Madan explained that abiraterone targets the CYP17 pathway, blocking the biosynthesis of androgens in the tumor microenvironment, in contrast to the situation with commonly used anti-androgens, which manipulate the endocrine system to block testicular production of testosterone.
“It's sinister that a cancer cell can produce its own fuel,” Madan said.
He added that abiraterone is one of several new drugs for metastatic castration-resistant prostate cancer, including enzalutamide, sipuleucel, cabazitaxel, a modified version of docetaxel, and the radiopharmaceutical radium-223 dichloride. There is no clear data on combinations or sequencing of these drugs, and Madan said clinicians have to weigh the side effects and potential benefit.
“With enzalutamide, for example, there is concern that patients with a history of seizures or risk of seizures may have increased seizure risk, so for that patient the clinician might consider abiraterone. On the other hand, abiraterone contains steroids which might be problematic for patients who have diabetes and so providers may choose to use enzalutamide. In addition, the enzymatic blockade with abiraterone could lead to endocrine consequences, such as fluid retention and high blood pressure.”
Emerging data suggest that by using enzalutamide and abiraterone sequentially, the benefits from the second seem to be diminished relative to the first, possibly due to development of common mechanisms of resistance, Madan said.
Clinical trials are underway to discover optimum sequencing and combinations, and a trial combining radium 223-dichloride with abiraterone is now recruiting patients (NCT02043678). In addition, Madan is involved in a trial combining enzalutamide with a therapeutic vaccine (NCT01867333).
In the commentary about the COU-AA-302 study, Madan and Dahut called the responses remarkable—and said that because patients randomly assigned to placebo plus prednisone were ultimately treated with abiraterone, the report most likely underestimated the survival advantage to abiraterone.