Bavdegalutamide, a novel androgen receptor degrader, demonstrates clinical activity

In the phase 2 ARDENT trial, the first-in-class, oral, PROteolysis TArgeting Chimera (PROTAC) protein degrader bavdegalutamide induced a clinically relevant PSA decline in patients with pre-treated metastatic castration-resistant prostate cancer (mCRPC).

Bavdegalutamide (a.k.a. ARV-110) is an oral PROTAC protein degrader that selectively targets wildtype androgen receptor (AR) and clinically relevant mutants. Previous phase 1 data indicated clinical activity for bavdegalutamide in heavily pre-treated patients with mCRPC and suggested enhanced activity in patients with specific molecular profiles, like AR T878 and H875 mutations. This led to a phase 2 expansion to further characterise bavdegalutamide in biomarker-defined patient subgroups.

The phase 2 expansion trial ARDENT (NCT03888612) enrolled patients with confirmed mCRPC who experienced disease progression on or since their most recent therapy received, as well as 2 or higher rising PSA values (≥2 ng/mL). The biomarker-defined subgroups included those with AR T878A/S and/or H875Y; AR L702H or AR-V7 (co-occurring T878X/H875Y included); and wildtype AR or AR alterations other than those listed. These patients previously received 1 to 2 hormonal agents and at least 1 prior chemotherapy each for castration-sensitive disease and CRPC. There was also a clinically defined, biomarker agnostic subgroup of less pre-treated patients who received 1 prior novel hormonal agent but no prior chemotherapy. PSA response was a primary endpoint of the study. Dr Xin Gao (Massachusetts General Hospital, MA, USA) presented the results [1].

A total of 46% of participants whose tumours harboured AR T878X/H875Y mutations (n=28) experienced PSA declines of ≥50% (PSA50); 57% of these patients had PSA declines of ≥30% (PSA30); 2 of 7 RECIST-evaluable patients with tumours harbouring AR T878X/H875Y mutations had confirmed partial responses. In addition, PSA declines of ≥50% were observed in the other biomarker subgroups: 4% of participants in the AR L702H/AR-V7 subgroup, 44% in the WT/other subgroup, and 22% in the less pre-treated subgroup. Regarding safety, 83% of patients experienced treatment-related adverse events, predominantly grade 1 or 2, including nausea, fatigue, vomiting, and diarrhoea.

Based on these results, Dr Gao concluded that bavdegalutamide merits further investigation in patients with mCRPC.

1. Gao X, et al. Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC). Abstract 17, ASCO GU 2022, 17–19 February.

 

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Posted on 8 April 202217 May 2024