Novel Agent Significantly Improves Survival in Men With Advanced Prostate Cancer

Roxanne Nelson

October 11, 2010

October 11, 2010 (Milan, Italy) — Greatly anticipated results from the COU-AA-301 trial have now been released — the investigational agent abiraterone acetate significantly improves survival in men with metastatic castration-resistant prostate cancer.

The results of this study are likely to alter the current standard of care for patients in this population, according to lead author Johann de Bono, MBBS, PhD, who presented the results here at the 35th European Society for Medical Oncology Congress.

Dr. de Bono

Patients who received abiraterone acetate plus prednisone had a median overall survival of 14.8 months. This was in comparison with 10.9 months for patients assigned to receive corticosteroid prednisone plus placebo.

Significant differences were also observed between the 2 treatment groups for all of the trial's secondary endpoints, including time to prostate-specific antigen (PSA) progression, radiographic progression-free survival, and PSA response rate.

"We now have evidence that this drug does improve outcome in men with advanced disease in the postchemotherapy setting," said Dr. de Bono, who is from the Institute of Cancer Research and the Royal Marsden National Health Service Foundation Trust in London, United Kingdom. "It is well tolerated, and we now hope for the patient's sake that we can make it widely available."

Dr. de Bono explained that in 2005, he started his first patient on continuous dosing with this compound. "I also have a patient that I saw in clinic 2 weeks ago — who's still on this drug 4 and a half years on — with a complete response and essentially complete resolution of his bone metastasis," he said.

Primary and Secondary Endpoint in Favor of Agent

The study raised a great deal of interest when the manufacturer announced in September that the study was going to be unblinded. On the basis of a prespecified interim analysis, which demonstrated a statistically significant improvement in overall survival and an acceptable safety profile, the Independent Data Monitoring Committee recommended unblinding the study. They also recommended allowing anyone in the placebo group to be offered treatment with abiraterone acetate.

"We have now reported both phase 1 and phase 2 studies of this drug," said Dr. de Bono. "It is an oral agent and does not have the toxicity of chemotherapy, and it is well tolerated in my experience."

The current study is a phase 3 randomized international trial, and "we have now shown a 3.9-month improved survival for the treatment arm," he pointed out. "We have also shown that all of the secondary endpoints are in favor of the treatment arm.

"While 3.9 months may not seem like much, in the history of prostate cancer, only 4 drugs have ever shown a survival benefit," Dr. de Bono noted.

Abiraterone acetate, a selective androgen biosynthesis inhibitor that acts by blocking CYP17, is an investigational agent being developed by Ortho Biotech. It acts by blocking CYP17 and potently inhibits persistent androgen synthesis from adrenal and intratumoral sources.

The authors had observed clinical responses in early phase 1-2 studies that suggested that some castration-resistant prostate cancers remain dependent on androgen receptor signaling. The COU-AA-301 study was conducted to confirm the hypothesis that overall survival in the population could be improved by targeting persistent androgen synthesis and androgen receptor signaling.

In this study, Dr. de Bono and colleagues randomly assigned 1195 patients with castration-resistant metastatic prostate cancer and who had been previously treated with docetaxel to 1 of 2 study groups — abiraterone 1000 mg plus prednisone 5 mg twice daily (n = 797) or placebo plus prednisone (n = 398) — at 147 centers in 13 countries.

The authors also hypothesized that with the number of participants enrolled in the study, treatment with arbiterone would result in a 25% improvement in survival (power = 85%; α = 0.05, 2-sided).

Table. Primary and Secondary Endpoints

Response Abiraterone Acetate Placebo Hazard Ratio (95% Confidence Interval) P Value
Median overall survival 14.8 months 10.9 months 0.65 (0.54-0.77) < .0001
Time to PSA progression 10.2 months 6.6 months 0.58 (0.46 - 0.73) < .0001
Radiographic progression-free survival 5.6 months 3.6 months   < .0001
PSA response 38% 10% N/A < .0001

Adverse events were more commonly observed in the abiraterone group. Fluid retention was more common (30.5% vs 22.3%), as was hypokalemia (17.1% vs 8.4%), but grade 3/4 hypokalemia (3.8% vs 0.8%) and grade 3/4 hypertension (1.3% vs 0.3%) were infrequent.

Liver function test abnormalities were reported in 10.4% of the patients who received the investigational agent compared with 8.1% in the placebo group. Cardiac problems were also more common in the abiraterone group compared with placebo, at 12.5% vs 9.4%.

From a clinical standpoint, there were not any specific patient subsets that appeared to derive greater benefit from the agent, Dr. de Bono explained. "Everyone benefited from this drug," he said, adding that they are currently working on teasing out subsets on the molecular level.

A Breakthrough?

"These are the most impressive results that I've seen in a long time, in this population," commented Cora Sternberg, MD, in a discussion of the paper. "The reduction in death is an important endpoint."

Several new anti-androgens are coming on the scene, she noted, and abiraterone acetate is one of them. "It may be the first one to lead the way," said Dr. Sternberg, from San Camillo Forlanini Hospital, Rome, Italy.

However, even though the results are positive, they do not go out past 1 year, she pointed out. "The final results will therefore be very important."

All secondary endpoints achieved statistical significance. "I don't disagree," she said, "But it is very hard to corroborate PSA, and it can be very difficult to measure endpoints in prostate cancer trials."

Overall, however, this is a very positive study, she emphasized. "It opens up the field, and there are other novel therapies being developed which target the androgen receptor."

Prostate cancer heterogeneity needs to be addressed to move this field forward. "But this study is the first to look at hormonal therapy postdocetaxel," Dr. Sternberg emphasized, "And I do believe we have a breakthrough for advanced prostate cancer."

Dr. de Bono is employed at the Institute of Cancer Research and has received honoraria and consulting fees from Merck, Pfizer, AstraZeneca, Johnson & Johnson, Medivation, and Genentech; K. Fizazi has received honoraria and consulting fees from Amgen, AstraZeneca, Keocyt, Sanofi Aventis, and Novartis and research funding from Cougar Biotechnology; L. Chu received research funding from Cougar Biotechnology and owns stock in Johnson & Johnson; K. N. Chi received research funding from Cougar Biotechnology; T. Kheoh, C. Haqq, and A. Molina are employees of Ortho Biotech Oncology Research and Development and own stock in Johnson & Johnson; H. I. Scher has received honoraria, consulting fees, and research funding from Cougar Biotechnology and research funding from Veridex. All other authors have disclosed no relevant financial relationships.

35th European Society for Medical Oncology Congress: Abstract LBA5. Presented October 11, 2010.