Use of the CYP17 inhibitor ­abiraterone acetate (Zytiga) in combination with leuprolide and prednisone prior to radical prostatectomy achieved pathologic complete response or near complete response in one-third of men with high-risk, localized prostate cancer. Abiraterone is FDA-approved for metastatic prostate cancer unresponsive to chemotherapy, and this is the first trial to study this agent upfront in the neoadjuvant setting.

“These patients were an extremely high-risk cohort, so results are particularly amazing,” said lead author Mary-Ellen Taplin, MD, of Harvard Medical School and Dana-Farber Cancer Institute, Boston, in an interview with The ASCO Post. The phase II study was presented at the 2012 ASCO Annual Meeting.¹ She cautioned that larger randomized trials are needed to validate this finding, and said that additional trials in the neoadjuvant setting are open or being planned to evaluate other prostate cancer agents now used for advanced cancer.

Study Design

Men diagnosed with high-risk prostate cancer frequently experience biochemical failure (rising prostate-specific antigen [PSA]) following primary treatment with radical prostatectomy or radiation plus hormones and require salvage therapy. The rationale for the neoadjuvant trial was to determine if giving abiraterone plus other hormonal therapy (leuprolide) prior to surgery would improve the prognosis for these patients.

“To date, no neoadjuvant or adjuvant therapy has shown a benefit for high-risk prostate cancer,” said Dr. Taplin.

The study enrolled 58 patients with high-risk disease, defined as having one or more of the following features: bulky stage T3-T4 disease on physical examination (present in 24% of participants); PSA > 20 ng/mL (19%); Gleason score 8–10 (71%); or high PSA velocity (a rise in PSA of > 2 ng/ mL between any two time points within 12 months preceding the initial diagnostic prostate biopsy [16%]). About one-third of patients also had lymph node involvement.

Patients were randomly assigned to 3 months of abiraterone, leuprolide, and low-dose prednisone (5 mg per day) or 3 months of leuprolide. Prostate biopsy was done at 3 months to assess prostate tissue androgen levels. All patients in the study received another 3 months of neoadjuvant therapy with abiraterone, leuprolide, and prednisone. After a total of 6 months of neoadjuvant therapy, radical prostatectomy was performed and surgical specimens were evaluated for pathologic response, prostate androgen levels, and androgen-receptor signaling.

Key Data

The total pathological response rate was 34% in patients treated with abiraterone for 6 months vs 15% in those who started out on leuprolide alone and then received 3 months of combination therapy. The pathological complete response rate and near complete response rate favored abiraterone, but the difference between groups was not statistically significant.

“It is rare to eliminate prostate cancer with hormone therapy,” Dr. Taplin commented. “The typical pathologic complete response with older hormone therapy is < 5%. Response rates [in this trial] are impressive given these high-risk features, with one-third of patients having positive lymph nodes,” she sated.

Treatment with abiraterone was well tolerated. Grade 3 adverse events included elevated liver enzymes in 9% and hypokalemia in 5%. Dr. ­Taplin said that low-dose prednisone was able to minimize side effects associated with abiraterone therapy, and that the dose of 5 mg given in this trial is half the usual dose used in patients with advanced disease. ■

Disclosure: Dr. Taplin reported no potential conflicts of interest.

Reference

1. Taplin M-E, Montgomery RB, Logothetis C, et al: Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized high-risk prostate cancer (LHRPC): Results of a randomized phase II study. 2012 ASCO Annual Meeting. Abstract 4521. Presented June 2, 2012.