Androgen Receptor Signaling Inhibitors (ARSIs), such as enzalutamide and abiraterone, have significantly improved patient outcomes. However, their long-term efficacy is often limited by the development of treatment resistance. Cancer cells cleverly adapt, frequently through mechanisms involving AR itself – such as mutations, amplification, or splice variants – which ultimately retain the tumor’s dependency on AR signaling, rendering existing therapies ineffective.

To address this critical challenge, a new generation of therapeutics is emerging. GDC-2992 (also known as RO7656594)represents a promising candidate in this class. As detailed in recent preclinical findings, GDC-2992 is a potent, orally bioavailable, heterobifunctional molecule designed to combat AR-driven prostate cancer, particularly in the context of resistance.

GDC-2992 employs a sophisticated mechanism distinct from traditional ARSIs. It acts like molecular matchmakers:
One end of GDC-2992 binds specifically to the Androgen Receptor (AR).
The other end simultaneously binds to cereblon (CRBN), a component of the E3 ubiquitin ligase complex – the cell’s natural machinery for tagging proteins for disposal.
By bringing AR and CRBN together, GDC-2992 triggers the ubiquitination (tagging) of AR, marking it for destruction by the proteasome.
This targeted degradation effectively removes the AR protein from the cancer cell, shutting down its signaling pathway. Crucially, preclinical studies demonstrate that GDC-2992 is effective against both wild-type AR and various AR mutants known to confer resistance to standard-of-care ARSIs. Furthermore, unlike some ARSIs that can paradoxically exhibit partial agonist activity under certain conditions (especially with mutated AR), GDC-2992 has shown no evidence of agonism against the AR variants tested.
GDC-2992 also acts as a direct, competitive antagonist at the AR, similar to how traditional ARSIs work,providing an additional layer of inhibition.

The potential of GDC-2992 is supported by robust preclinical data.
In Vitro: Effectively inhibits AR signaling and degrades AR protein (both wild-type and resistant mutants) in prostate cancer cell lines. Maintains anti-cancer activity even when degradation is partially inhibited.
In Vivo: In animal models of prostate cancer, GDC-2992 demonstrated a dose-responsive decrease in circulating Prostate-Specific Antigen (PSA) – a key biomarker for prostate cancer – and significantly inhibited tumor growth.
Based on this compelling preclinical evidence, GDC-2992 has advanced into clinical trials. An ongoing Phase I dose-escalation and expansion study (NCT05800665) is currently recruiting patients with advanced or metastatic prostate cancer who have previously received AR-targeted therapy and experienced disease progression.

Source.

Clinical Trial.