Biomarker assessment and pharmacology of HP518, an AR PROTAC degrader from the phase 1 dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC)

Background: HP518 is an oral PROteolysis TArgeting Chimera (PROTAC) protein degrader that degrades both wild-type AR and clinically relevant AR ligand-binding domain (LBD) mutants including L702H. To evaluate the safety, PK, and anti-tumor activity of HP518, and select a recommended phase 2 dose (RP2D), we conducted a first-in-human, Phase 1, open-label, multicenter, non-randomized, dose escalation study in pts with mCRPC. We report biomarker, pharmacology and efficacy data from this Phase 1 study. Methods: Pts with mCRPC with disease progression on at least 1 novel hormonal agent (NHA) and # 1 line of chemotherapy received HP518 QD orally in sequential cohorts (25, 50, 100, 200, and 300, 400, 500 mg per day, Bayesian N-CRM design). Primary objectives were to assess HP518 safety and select the RP2D. Secondary objectives included evaluating the PK of HP518, PSA50 response and radiographic progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and Prostate Cancer Working Group 3 (PCWG3) criteria. Exploratory objectives were to evaluate AR expression in circulating tumor cells (CTCs) at the highest dose cohort before and after 12 weeks of treatment and genomic profile using cell-free DNA (cfDNA). Results: As of 29Jan2024, a total of 22 pts were enrolled. Overall, HP518 was well tolerated, with a favorable safety profile. No DLT, and a cumulative of ten SAE (1 related/9 unrelated) were observed. There were twelve Grade $3 treatment-emergent adverse events (TEAEs) in 6 pts treated up to 500 mg; no grade $4 TEAEs. The most common TEAE in all cohorts was grade 1 or 2 vomiting and nausea. PSA50 response was seen in 3 pts. 2 pts had confirmed partial responses (PR) per RECIST criteria. 2 pts received HP518 for $24 weeks including 1 pt with a durable PSA50 and PR response for 52 weeks. Following multiple oral doses of HP518, median peak plasma concentrations were observed at 3 -12h post-dose. Over the 5-fold dose range (100 to 500 mg), the increase in Cmax and AUC0-last was approximately dose proportional on day 1. A steady state was reached after day 56. ctDNA data were available from 19 pts, of which four patients were diagnosed with AR LBD mutations. Three LBD mut non-responder pts had low drug exposures. In addition, one AR LBD mut patient had high mutational burden suggestive of AR-independent resistance. cDNA and CTC analysis showed diverse molecular changes in the AR including four pts with AR-V7 splice variant as well as non-AR resistance patterns in most patients. Conclusions: HP518, a novel AR PROTAC degrader, demonstrated encouraging efficacy in mCRPC pts, with responses seen in patients with full-length AR, AR LBD mutations, and AR amplification. These data support further investigation of HP518 in mCRPC pts. Clinical trial information: NCT05252364. Research Sponsor: Hinova Pharma.