Two studies presented at the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting suggested that abiraterone acetate (AA; Zytiga), an androgen biosynthesis inhibitor,1 has the potential to be used earlier in the course of prostate cancer than its current US Food and Drug Administration (FDA) indication (ie, after failure of chemotherapy in men with metastatic castration-resistant prostate cancer [CRPC]). A second interim analysis of a phase 3 trial had positive outcomes with AA in men with metastatic CRPC who had not yet received chemotherapy,1 and a preliminary phase 2 study suggested AA may have a role in the neoadjuvant setting before radical prostatectomy is performed in men with early-stage localized high-risk prostate cancer.2 In addition, secondary results from the AFFIRM trial confirmed the superiority of enzalutamide to placebo in men with CRPC following treatment with docetaxel.3
Abiraterone in Chemotherapy-Naive Metastatic CRPC1
Results of the second interim analysis of COU-AA-302 showed that AA plus prednisone significantly improved radiographic progression-free survival (rPFS), with a strong trend toward increased overall survival (OS) compared with placebo plus prednisone in men with metastatic CRPC who had not received chemotherapy. This study evaluated earlier use of AA than the current FDA indication for use following failure of chemotherapy in CRPC.
“This is the first randomized trial to demonstrate both an overall survival and progression-free survival benefit in chemotherapy-naive patients with metastatic CRPC and show that inhibition of persistent extragonadal androgen synthesis significantly delays initiation of cytotoxic chemotherapy,” stated lead author Charles J. Ryan, MD, of the University of California San Francisco.
The study enrolled 1088 patients at 151 centers in 12 countries. Patients were randomized 1:1 to AA (1 g) plus prednisone (5 mg BID) versus placebo plus prednisone. The Independent Data Monitoring Committee unblinded the study early, when all primary and secondary outcomes were seen to favor AA, and patients were allowed to cross over from placebo to the AA arm.
At a median follow-up of 22.3 months, median rPFS was not yet reached in the AA arm versus 8.3 months in the placebo arm (P <.0001). Median OS was not yet reached in the AA arm and was 27.2 months in the placebo arm (P = .0097).
The interim analysis also confirmed the acceptable tolerability and safety profile of AA in this setting.
Neoadjuvant Abiraterone Acetate2
Another study of even earlier use of AA suggests that the drug will find a role prior to the development of metastatic prostate cancer. Preadjuvant treatment with 6 months of AA given concurrently with leuprolide acetate (LHRHa), a hormonal therapy, and prednisone prior to radical prostatectomy successfully eradicated prostate cancer cells in about 30% of men with high-risk early prostate cancer in a randomized phase 2 trial.
“These results are particularly amazing in this incredibly high-risk group of patients, and suggest that this combination therapy could improve outcomes for a substantial number of men with early high-risk prostate cancer,” stated lead author Mary-Ellen Taplin, MD, of Harvard Medical School and the Dana-Farber Cancer Institute in Boston, Massachusetts. This is a preliminary study, and larger, longer trials will be needed to establish a role for AA plus hormone therapy in the neoadjuvant setting.
The phase 2 trial included 58 men who were defined as high risk because they had at least 1 of the following features: ≥3 positive biopsies; Gleason score ≥7 (71% of men had scores of 8-10); prostate-specific antigen (PSA) >20 ng/mL (19%); T3, T4 bulky disease (24%); or PSA velocity >2 ng/mL/year (16%). Men with extranodal disease were allowed to enroll.
The men were randomized to receive 3 months of treatment with LHRHa alone or 3 months of LHRHa plus AA plus low-dose prednisone. Prednisone 5 mg/day was given with AA to prevent side effects associated with this drug. After 3 months, a prostate biopsy was performed to measure serum testosterone and dihydrotestosterone levels, after which the men received 12 more weeks of LHRHa/AA/prednisone.
At 3 months, 10% of the men who were treated with LHRHa/AA/prednisone had pathologic complete response (pCR), compared with 4% of those treated with LHRHa alone; near pCR was observed in 24% and 11%, respectively.
Enzalutamide in Metastatic CRPC3
Enzalutamide, an androgen receptor signaling inhibitor, was superior to placebo for both the primary and secondary end points in the phase 3 AFFIRM trial in men with progressive CRPC. Primary end point results for OS reported earlier showed that enzalutamide significantly improved OS by 4.8 months compared with the placebo group; the risk of death was reduced by 37% in men randomized to enzalutamide (P <.0001).4,5
“These are the best survival rates we have seen in the post-chemotherapy setting,” said Johann S. de Bono, MD, ChB, of the Institute for Cancer Research and the Royal Marsden NHS Foundation Trust, United Kingdom.
At the ASCO Annual Meeting, de Bono presented new data on secondary outcomes in AFFIRM. Enzalutamide was superior to placebo for the following measures: PSA response, soft tissue objective response, and quality-of-life response as assessed by FACT-P, as well as such indicators of disease progression as rPFS and time to first skeletal-related event.
AFFIRM randomized 800 patients to enzalutamide and 399 to placebo. Median age was 69 years. At baseline, both groups were well matched for demographic and disease characteristics. Almost 50% of the group assigned to enzalutamide had received prior hormone therapy compared with 53% of placebo patients; median number of prior chemotherapy regimens was similar between groups.
PSA response to enzalutamide was high; 54% of patients in the enzalutamide group had >50% declines in PSA level.
Following a prespecified interim analysis, the Independent Data Monitoring Committee recommended that the AFFIRM trial be halted and unblinded, and eligible patients in the placebo arm were allowed to cross over to enzalutamide.
Enzalutamide was well tolerated. A greater percentage of patients in the treated group reported fatigue, and 5 patients had seizures versus none with placebo.
On August 31, 2012, enzalutamide (Xtandi; Medivation) was approved by the FDA for the treatment of patients with metastatic CRPC who have previously received docetaxel.
- Ryan CJ, Smith MR, de Bono JS, et al; on behalf of the COU-AA-302 Investigators. Interim analysis (IA) results of COU-AA-302, a randomized, phase 3 study of abiraterone acetate (AA) in chemotherapy-naïve patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 2012; Chicago, IL. Abstract LBA4518.
- 2. 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. Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 2012; Chicago, IL. Abstract 4521.
- 3. de Bono JS, Fizazi K, Saad F, et al; for the AFFIRM Investigators. Primary, secondary, and quality-of-life endpoint results from the phase III AFFIRM study of MDV3100, an androgen receptor signaling inhibitor. Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 2012; Chicago, IL. Abstract 4519.
- 4. Scher HI, Fizazi K, Saad F, et al; for the AFFIRM Investigators. Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI), on overall survival in patients with prostate cancer postdocetaxel: results from the phase III AFFIRM study. J Clin Oncol. 2012;30 (suppl 5):Abstract LBA1.
- 5. Scher HI, Fizazi K, Saad F, et al; the AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy [published online ahead of print August 15, 2012]. N Engl J Med.