In metastatic castration-resistant prostate cancer (mCRPC), resistance to existing therapies, including novel hormonal agents (NHAs), often leads to disease progression. Mutations in the ligand-binding domain (LBD) of the androgen receptor (AR) gene are associated with poor outcomes, affecting approximately 20% to 25% of mCRPC patients, with the most common mutations being L702H, H875Y, and T878A. Based on DelveInsight's assessment, out of all metastatic prostate cancer cases, around 55% are attributed to mCRPC, leading to approximately 66,000 prevalent cases in the United States.

Overcoming resistance to current treatments, such as androgen receptor pathway inhibitors (ARPIs), is crucial in this setting. ARV-766, a potent orally administered PROTAC AR degrader, targets both wild-type AR and clinically relevant AR LBD mutants, offering a promising approach. 

With around 55% of metastatic prostate cancer cases attributed to mCRPC, ARV-766 is currently undergoing evaluation in a Phase I/II study. As of April 15, 2024, safety data from 123 patients have been assessed, including 53 with AR LBD mutations. The study aims to determine dose-limiting toxicities, adverse events, and laboratory abnormalities, and evaluate the antitumor activity of ARV-766, holding potential as a significant advancement in mCRPC treatment. The results presented at ASCO 2024 were as follows:

Efficacy outcomes:

• ARV-766 showed promising clinical activity (PSA50 of 43%) in patients with tumors harboring AR LBD mutations

Safety result: 

• ARV-766 was well tolerated

• There was no dose-limiting toxicity, and a maximum tolerated dose was not reached in Phase I (part A)

• Across Phase I/II patients: 118 had ≥1 any Grade treatment-emergent adverse events (TEAE)  46 had a Grade 3/4 TEAE, 3 had a Grade 5 TEAE; 9 had TEAEs that led to dose reduction of ARV-766, 10 had TEAEs that led to discontinuations of ARV-766

KOL insights

“ARV-766 monotherapy was well tolerated; ARV-766 showed promising clinical activity in patients with tumors harboring AR ligand binding domain mutations, and based on these findings, ARV-766 warrants further development in advanced prostate cancer.” MD, professor of medicine and urology

Conclusion- 

Last month in April 2024, Arvinas entered into a transaction with Novartis, including a Global License Agreement for the Development and Commercialization of ARV-766 for the Treatment of Prostate Cancer. Findings during the conference revealed that ARV-766, an investigational PROTAC androgen receptor degrader, exhibited encouraging clinical activity alongside manageable toxicity in patients with metastatic castration-resistant prostate cancer (mCRPC). In a Phase I/II study involving pretreated mCRPC patients, ARV-766 demonstrated favorable tolerability and promising clinical efficacy, particularly in individuals with tumors harboring AR LBD mutations. These results underscore the potential of ARV-766 as a valuable addition to the armamentarium for advanced prostate cancer, warranting further development and investigation.