Androgen receptor (AR) targeted therapy is the mainstay of treatment for PC, with potent AR signaling inhibitors and CYP17 inhibitors leading to improved survival. Taxanes are the only chemotherapy class to demonstrate a survival benefit in prospective randomized studies. Docetaxel (D), inhibits AR trafficking from the cytoplasm to the nucleus via stabilizing microtubules, suggesting D may complement AR-pathway targeted therapies. Recent randomized studies showing a > 1 year median survival benefit in men treated with the combination of effective direct AR-targeted therapy combined with D, suggesting that “vertical pathway blockade” in which combinations of AR-directed therapies with complementary mechanisms of action are more effective than sequential use (Sweeney NEJM 2015, James Lancet 2016). Two phase 3 trials are testing the combination of AR signaling inhibitors and CYP17 inhibitors. The safety of combining D with AA is pts with mCRPC was demonstrated in the COU-AA-206 (Tagawa Eur Urol 2016). Combinations of therapies targeting different pathways have the potential to improve efficacy.
A multicenter phase 1 dose-escalation study will be conducted to determine the maximum tolerated dose (MTD) of ARN (novel AR signaling inhibitor) combined with AA (CYP17 inhibitor) and D (taxane) in chemotherapy-naïve mCRPC pts with ECOG performance status 0-2. Following determination of MTD, a cohort expansion at the recommended Phase 2 dose will occur. Starting doses are 120 mg/day ARN with 1000 mg/day AA, D 75 mg/m2 every 3 weeks, and prednisone 5 mg BID. Upon completion of D, pts may continue ARN and AA. The primary endpoint is the safety and tolerability of ARN when dosed with AA and D. Tumor tissue will be collected prospectively to evaluate exploratory biomarkers predictive of response and resistance. In addition, pre- and post-treatment circulating tumor cells will be interrogated for AR localization and AR splice variants. Circulating tumor DNA will also be collected pre- and post-therapy to explore resistance mechanisms.
Clinical trial identification
Legal entity responsible for the study
Weill Cornell Medical College
Janssen Scientific Affairs, LLC
A.M. Molina: Consulting for Novartis, EISAI and Exelixis. Research funding from Janssen. Y. Whang: Research funding from Janssen, Astellas, Tokai and Inovio. H. Beltran: Consultant for Janssen and Sanofi. Research funding from Janssen. D. Nanus: Genentech Roche (DSMB). S.T. Tagawa: Research funding and consulting from Janssen. Research funding and consulting from Sanofi. All other authors have declared no conflicts of interest.