Aggressive androgen-deprivation therapy with abiraterone acetate shows promise as neoadjuvant and adjuvant therapy for patients with localized high-risk prostate cancer, results of a randomized Phase II study suggest (Abstract 4521).
About one-third of 30 such patients who underwent 24 weeks of treatment with a combination of abiraterone and leuprolide acetate prior to prostatectomy had a pathologic complete response (pCR) or near pCR, defined as 5 mm or less of residual tumor, reported Mary-Ellen Taplin, MD, Associate Professor of Medicine at Harvard Medical School and the Dana-Farber Cancer Institute.
The findings on abiraterone, which helps stop cancer cells from making both testosterone and dihydrotestosterone (DHT), were highlighted at a news media teleconference held in advance of the ASCO Annual Meeting, where she was scheduled to present the results to colleagues.
Abiraterone was approved last year for the treatment of men with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel. That made the drug, made by Janssen Biotech under the brand name Zytiga, the first once-daily, oral therapy for metastatic prostate cancer.
The new study “is one of the first, if not the first, to show a drug can make [localized] prostate cancer disappear in a significant number of patients,” commented the moderator of the teleconference Nicholas J. Vogelzang, MD, Chair of ASCO's Cancer Communications Committee and Medical Director of the Developmental Therapeutics Committee of U.S. Oncology in Las Vegas.
Still, it has not yet been shown that abiraterone improves clinical outcomes in such patients, Taplin noted.
Most patients with localized prostate cancer can be cured with surgery or radiation therapy, but outcomes among men with high-risk localized prostate cancer are “very poor,” she explained. The disease is infrequently cured with prostatectomy, and to date, neoadjuvant androgen-deprivation therapy (ADT) has not shown clinical benefit.
Localized high-risk disease is generally defined as prostate cancer in men with PSA levels of 20 ng/mL or above, high-grade disease with a Gleason score of 8 to 10, high PSA velocity, and bulky Stage T3 or T4 tumors on prostate exam. Nodal involvement is not excluded.
The 58 men enrolled in the current study were “very high risk,” Taplin reported, with 41 of them (71%) having Gleason scores of 8 to 10. All had three or more positive biopsies, and a Gleason score of 7 or higher, Stage T3 disease, a PSA level of at least 20 ng/mL, or a PSA velocity above 2 ng/mL per year.
A total of 28 men were randomized to 12 weeks of leuprolide followed by leuprolide plus abiraterone for another 12 weeks, and 30 men were randomized to abiraterone plus leuprolide for 24 weeks. All the men also received prednisone (5 mg daily).
After 24 weeks, a radical prostatectomy was performed and pathologic complete response (pCR) and near-pCR rates and safety were determined.
Among the 29 men who completed 24 weeks of abiraterone therapy, the pCR and near-pCR rates were 10% and 24%, respectively. In the 27 men who completed 12 weeks of abiraterone therapy, the pCR and near-pCR rates were 4% and 11%, respectively.
“To put this into context, the historical pCR with any type of hormone therapy [for localized high-risk prostate cancer] is 5% or less. So these are very impressive results,” Taplin said.
There was a non-significant trend for improved pathologic outcomes with longer abiraterone therapy (34% for 24 weeks vs. 15% for 12 weeks).
Therapy was well tolerated by both groups, she said. Grade 3 adverse events included elevated liver enzymes in five (9%) patients and hypokalemia in three (5%) patients. No Grade 4 mineralocorticoid-related adverse effects were observed.
As it does in advanced disease, prednisone prevented symptoms of increased adrenocorticotrophic hormone (ACTH) levels associated with abiraterone, she noted.
Prospective Trial Needed
“The long-term clinical benefit of intensive androgen-deprivation therapy with abiraterone, either before or after prostatectomy, awaits validation in larger, prospective, randomized clinical trials. But for this proportion of patients with high-risk disease to have very little to no detectable cancer in the prostate after six months of therapy is dramatic,” she said.
ASCO 2012–2013 President Sandra M. Swain, MD, Medical Director of the Washington Cancer Institute at Medstar Washington Hospital Center, Professor of Medicine at Georgetown University, and a member of Lombardi Comprehensive Cancer Center, noted that studies in breast cancer suggest that pathologic complete responses are associated with clinical benefit.
“There are two large studies [in breast cancer] that looked at patients who had a pCR, and their overall outcomes and survival were better.” In fact, oncologists are working with the FDA to develop guidelines for use of pCR rates as a surrogate endpoint for clinical benefit in clinical trials, she added.
Taplin stressed, however, that physicians should not prescribe abiraterone off-label to patients with localized high-risk prostate cancer until randomized trials are completed.
The study was supported by grants from Janssen Biotech.