Phase I study of apalutamide (ARN) plus abiraterone acetate (AA), docetaxel (D) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC)

Abstract

Background: 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 ARpathway 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. Trial design: 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-naive 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 preand post-therapy to explore resistance mechanisms.