(UroToday.com) The 2024 GU ASCO annual meeting featured a prostate cancer session and a presentation by Dr. Arun Azad discussing preliminary data from a dose-escalation phase 1 study with HP518, an oral proteolysis targeting chimera (PROTAC) protein degrader that targets androgen receptor mutations for the treatment of mCRPC. The goal of this study was to evaluate the safety, pharmacokinetics, and anti-tumor activity of HP518, and select a recommended phase 2 dose (RP2D), conducted in a first-in-human, phase 1, open-label, multicenter, non-randomized, dose escalation study in patients with mCRPC. At GU ASCO 2024, Dr. Azad and colleagues reported results of the ongoing phase 1 study at five Australian sites.
Patients with mCRPC with disease progression on at least one novel hormonal agent and ≤ 1 line of chemotherapy received HP518 oral daily in sequential cohorts (25 mg, 50 mg, 100 mg, 200 mg, and 300 mg, 400 mg, 500 mg per day, Bayesian N-CRM design). The primary objectives were to assess HP518 safety and select the RP2D. The secondary objectives included evaluating the pharmacokinetics of HP518, PSA50 response and radiographic progression per RECIST v1.1 and PCWG3 criteria. Exploratory objectives were to evaluate androgen receptor expression in circulating tumor cells before and after 12 weeks of treatment and conduct genomic profiling using cell free DNA.
As of September 8, 2023, a total of 22 patients were enrolled, with current one-daily dosing of 500 mg HP518. Overall, HP518 was well tolerated, with cumulative 10 symptomatic adverse events (1 related/9 unrelated). No dose limiting toxicity was observed. There were 13 grade ≥3 treatment-emergent adverse events in six patients treated up to 500 mg, and there were no grade ≥4 treatment-emergent adverse events. The most common treatment-emergent adverse event in all cohorts was grade 1 or 2 vomiting and nausea, which were well managed with prophylactic anti-emetics. Preliminary pharmacokinetics results were obtained from 18 patients dosed with 25 mg to 500 mg per day. Following multiple oral doses of HP518, median peak plasma concentrations were observed at 3 -12 hours 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. Steady-state was reached between day 56 and day 84. Among 16 patients who finished the dose limiting toxicity period, a PSA50 response was seen in three patients. Two patients had a confirmed partial response per RECIST criteria, with eight patients remaining on treatment. Additionally, two patients received HP518 for ≥24 weeks including one patient with a durable PSA50 response for 52 weeks, who also showed partial response. Notably, this patient harbored an F877L, E873_F879del androgen receptor ligand-binding domain mutations.
Dr. Azad concluded his presentation discussing preliminary data from a dose-escalation phase 1 study with HP518 with the following take-home points:
- HP518, a novel androgen receptor PROTAC degrader, demonstrates in this phase 1a dose-escalation study, an acceptable safety/tolerability profile and a signal of efficacy in an unselected mCRPC patient population
- The presence of androgen receptor ligand-binding domain mutations may predict benefit from HP518, and merits further investigation in patients with mCRPC
Presented by: Arun Azad, MD, PhD, Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25th – January 27th, 2024