Pantoprazole affecting docetaxel resistance pathways via autophagy (PANDORA): A phase II trial in men with metastatic castrate resistant prostate cancer (mCRPC)

Abstract

Background: Enhancing the effectiveness of docetaxel for men with mCRPC is an unmet clinical need. Preclinical studies in our laboratory demonstrated that high dose pantoprazole can prevent or delay resistance to docetaxel via the inhibition of autophagy in several solid tumor xenografts. Methods: Men with chemotherapy-naïve mCRPC with a PSA >10ng/ml and adequate organ function were eligible for enrolment. The study regimen included intravenous pantoprazole (240mg) and docetaxel (75mg/m2) every 21 days, with continuous prednisone 5mg twice daily. The primary endpoint was a confirmed >50% decline of PSA. Progression free (PFS) and overall survival (OS) were assessed by the Kaplan-Meier method. This trial used a Simon's 2-stage design. Results: Between November 2012 and March 2015, 21 men with a median age of 70 years (range 58-81 years) were treated (median 6 cycles, range 2 to 11). Participants ( pts) had received prior systemic therapies (median 4, range 1 to 8) and 14 had received abiraterone and/or enzalutamide. The PSA response rate was 52% (11/21) which did not meet the prespecified criterion (≥13/21 responders) to proceed to stage 2 of the study. At interim analysis with a median follow-up of 12 months, 13 (62%) pts were deceased (10 CRPC, 2 unknown, 1 radiation complication). Of the pts with RECIST measurable disease, the radiographic partial response rate was 31% (4/13). The estimated median PFS was 5.3 months (95%CI: 2.6-12.9) and median OS was 15.7 months (95% CI: 9.3-19.6). There were no toxic deaths and most adverse events were attributed to docetaxel (hematological: 14% febrile neutropenia, 14% G4 neutropenia, 19% G3/4 anemia; non-hematological: 24% G3 fatigue and 5% G3 anorexia). Conclusions: The combination of docetaxel and pantoprazole was tolerable, but the resultant clinical activity was not sufficient to meet the ambitious predefined target to warrant further testing. Planned correlative studies to evaluate tumor samples for autophagy are in progress, and are expected to provide insights into autophagy in the context of docetaxel resistance.