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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

2017; Elsevier BV; Volume: 28; Linguagem: Inglês

10.1093/annonc/mdx513.007

1569-8041

Anuradha Jayaram, Karolina Nowakowska, Joaquı́n Mateo, Tomás Martín Hernández, Sandeep Kumar, Ben Fulton, Daniel Nava Rodrigues, Ruth Riisnaes, A. Zukiwski, Stefan Proniuk, Alice Bexon, Joseph Bisaha, Diletta Bianchini, Zafeiris Zafeiriou, Remigio Lopez, Nina Tunariu, Simon Pacey, Rhys D.O. Jones, Johann S. de Bono, G. Attard,

Mass Spectrometry Techniques and Applications

Background: An urgent need exists for new therapies after progression (PD) on AA 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 ENZA/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. Plasma DNA was collected at multiple time-points (baseline, on treatment, and progression). The primary end-points were safety, pharmaco-kinetics (PK) and anti-tumor activity split by pAR. Archival and metastatic biopsies were collected when possible and tested for PR status. pAR 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, 5=50mg ONA BID). There were neither DLTs nor 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 of ONA and there was no interaction with AA. Of the 35 evaluated pts, 17 had a 2105T>A (p.L702H) or 2632A>G (p.T878A) AR mutation detected in pre-treatment plasma (of which 12 pts had both AR mutations) 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 82 days for AR normal and 79.5 for AR aberrant (Hazard ratio (HR) 1.46; 95% CI, 0.61-3.72; p 0.41) and on combination was 134.5 days for AR normal (8/14) and 68 for AR aberrant (6/14) (HR 5.32; 95%CI, 8.054 to 194.3; p < 0.001). Of the 6 pts, 5 pts had undetectable p.T878A in progression plasma samples, however this was not associated with a response. Conclusions: ONA is safe in CRPC as SA and in combination with AA. There was no difference in rPFS by plasma AR status for SA ONA but on the combination with AA, pts who were plasma AR normal had a significantly longer rPFS. 5pts had undetectable T878A at progression, but this was not associated with response. Clinical trial identification: NCT02049190 Legal entity responsible for the study: ARNO Therapuetics Funding: NA Disclosure: A. Zukiwski - stock and employee and board of director status ARNO, S. Proniuk and J. Bisaha - employee status ARNO, A. S. Bexon - Consulting status ARNO.