GSK5471713: An Investigational AR Degrader Targeting Late-Stage Prostate Cancer Resistance

Note: This article treats GSK5471713 as an androgen receptor (AR) degrader based on GSK’s official clinical trial registry classification and inclusion/exclusion criteria. While confident in the AR degrader designation from the sponsor’s documentation, the specific degradation mechanism (PROTAC, SARD, or other platform) remains undisclosed in publicly available sources at the moment.

GSK5471713 is an investigational androgen receptor (AR) degrader being developed for the treatment of metastatic castration‑resistant prostate cancer (mCRPC). Publicly available information describes it as an AR‑targeted degrader therapy being tested in a Phase 1/2, first‑in‑human, open‑label, multicenter dose‑escalation and dose‑optimization trial in adult men with mCRPC who have exhausted standard hormonal options and often prior taxane chemotherapy. On this basis, and for the purposes of this article, it is reasonable to treat GSK5471713 conceptually as part of the emerging class of small‑molecule AR degraders.
The therapeutic rationale behind an AR degrader is rooted in directly eliminating the androgen receptor protein from prostate cancer cells rather than only blocking ligand binding or signaling. Conventional AR pathway inhibitors, such as enzalutamide, apalutamide, darolutamide, and abiraterone, either antagonize the receptor or suppress androgen synthesis, but the AR protein itself remains present, allowing tumor cells to adapt via AR overexpression, point mutations in the ligand‑binding domain, constitutively active splice variants, or intratumoral androgen biosynthesis. Degraders aim to overcome some of these resistance mechanisms by exploiting the cell’s own protein quality‑control machinery: once the drug binds AR and links it (directly or via recruited factors) to the ubiquitin–proteasome system, the receptor is labeled with ubiquitin chains and then destroyed by the 26S proteasome. In practice, that means repeated dosing can keep intracellular AR levels low and reduce both ligand‑dependent and, in some cases, ligand‑independent signaling, which is particularly relevant in castration‑resistant disease where AR signaling is often hypersensitized rather than absent.

From a clinical development standpoint, the ongoing Phase 1/2 study of GSK5471713 is structured to answer standard first‑in‑human questions: safety, tolerability, pharmacokinetics, and preliminary antitumor activity in a population with high unmet need. The design is non‑randomized and open‑label; all participants receive GSK5471713, with dose levels increased stepwise to define a recommended Phase 2 dose and schedule while monitoring for dose‑limiting toxicities over an initial evaluation window. Secondary or exploratory endpoints are expected to include measures such as prostate‑specific antigen (PSA) decline rates, radiographic response in measurable disease, time to progression, and pharmacodynamic markers consistent with AR pathway suppression, although detailed endpoint lists have not yet been fully disclosed.

Clinical trial.