Phase 1-2 study of progesterone receptor (PR) inhibition with extended-release (ER) onapristone (ONA) alone or in combination with abiraterone (AA) in patients (pts) with castration-resistant prostate cancer (CRPC) incorporating plasma DNA analysis to define androgen receptor (AR) status.

Abstract

5071 Background: An urgent need exists for new therapies after progression (PD) onAA and enzalutamide (ENZ). Increased PR expression or progesterone-activating AR mutations have been associated with resistance to AR targeting. We aimed to test ONA, a type I PR antagonist with clinical activity in PRpos cancers, in AA/enz-resistant CRPC. In a prospectively defined exploratory analysis, we aimed to report outcome by plasma AR status ( pAR). Methods: This was a multi-institution, open label phase I/II clinical trial in pts progressing after ENZ/AA. Pts were first treated with single agent (SA) ONA using a randomised dose escalation design. ONA at 2 doses was then combined with AA (1000mg od with pred 5mg bid) in pts progressing on AA. The primary end-points were safety, pharmacokinetics (PK) and anti-tumor activity split by p AR. Archival and metastatic biopsies were collected when possible and tested for PR status. p AR was studied using previous methods (Romanel STM 2015). Results: 21 pts received SA ONA (5 = 10mg/ 5 = 20mg/ 4 = 30mg/ 4 = 40mg /3 = 50mg BID) and 15 pts received ONA-AA combination (5 = 30mg ONA BID, 10 = 50mg ONA BID). There were not DLTs or significant LFT abnormalities and no G3/4 adverse events (AE), no treatment discontinuations due to AEs and no SAEs considered related to ONA. PK in SA ONA observed active plasma concentrations and no interaction with AA. Of 32 evaluated pts 15 had a 2105T > A (p.L702H) or 2632A > G (p.T878A) AR mutation detected in plasma pre-treatment and 1 had AR copy number gain. PSA declines were not observed with SA ONA but in 2 pts with combination (-30%, -7%) who were AR normal. The rPFS on SA ONA was 2.8 months for AR normal and 2.6 for AR aberrant (Hazard ratio (HR) 1.41; 95% CI, 0.62-3.72; P 0.48) and on combination was 4.4 months for AR normal (8/15) and 2.2 for AR aberrant (7/15) (HR 6.08; 95%CI, 6.32-221.9; P < 0.001). Conclusions: ONA is safe in CRPC as SA and in combination with AA. There was no difference in rPFS by p AR status for SA ONA but on the combination with AA, pts who were plasma AR normal had a significantly longer rPFS. Clinical trial information: NCT02049190.