Phase II study of the efficacy of abirateron acetate with dutasteride for castration-resistant prostate cancer.

112 Background: Abiraterone (Abi) has been becoming a pivotal drug not only for metastatic castration resistant prostate cancer (mCRPC), but also for metastatic hormone sensitive prostate cancer (mHSPC). Abi is metabolized to delta-4 Abi (D4A), the strongest antitumor metabolite, by 3βHSD, and D4A is metabolized to 3-keto-5-α Abi, which acts as agonist to AR, by 5 α reductase. Reduction of 3-keto-5-α Abi by 5 α reductase inhibitor may increase the antitumor activity of Abi. Purpose of this study is to evaluate the efficacy and safety of the combination therapy of Abi and dutasteride (Duta), a 5 α reductase inhibitor, for the patients with CRPC. Methods: This is a non-randomized single-arm prospective phase II study. Patients with CRPC without any prior AR-targeting agent or docetaxel were recruited in this study with estimated enrollment of 20. Patients were treated with Abi (1,000 mg daily) and prednisone (5 mg daily) for 4 weeks, followed by the add-on of Duta (0.5 mg daily) for 12weeks. If PSA decline continued, combination treatment was allowed until progression. Abi and its metabolites including D4A and 3-keto-5-α Abi were measured by ESI-TOF-MS at baseline, 4, 6, 8, 12, 16, and 20 weeks, and the sample was collected at 2-4 hours after Abi administration. Primary endpoint was PSA decline >50%, and secondary endpoints were Time-to-treatment failure (TTF), and safety. Results: Totally 17 cases with CRPC (mean age: 78.4, initial PSA:92.6ng/ml, median Gleason score: 9) were recruited, and 14 were eligible for starting the combination therapy. Efficacy could be evaluated in 11 cases except 3 on-protocol treatment. Mean PSA decline of Abi/Duta combination therapy was significantly higher than that of monotherapy (p = 0.0143, 73 vs. 35 %). PSA decline>50% was noted in 36.4% for monotherapy, and 72.7% for combination therapy, respectively. Surprisingly, PSA decline>50% was significantly associated with lower Abi, D4A, and 3-keto 5 α Abi at 2 and 4 weeks after combination. Median TTF and progression (radiographic and/or PSA) was noted in 10.4 months (0.9-32), and 5 (45,4%), respectively with a median follow-up of 13.8 months. Progression was significantly associated with lower D4A, and 3-keto 5 a Abi at 4 and 8 weeks after combination therapy. Concerning safety, Grade 2 vertigo occurred in a case during Abi monotherapy period, while no adverse effect was found in combination therapy. Conclusions: Abi/Duta combination therapy seems to be theoretical to decrease AR-agonistic metabolite (3-keto 5 α Abi), and feasible for patients with first-line treatment of CRPC with lesser toxicity. Clinical trial information: UMIN000027795.