In an interim Phase 1/2 readout in metastatic castration‑resistant prostate cancer (mCRPC), the combination of Monte Rosa’s GSPT1 degrader MRT‑2359 with enzalutamide produced a 100% PSA response rate (4/4) and a 100% disease control rate in patients harboring androgen receptor (AR) mutations, including two RECIST responses (one confirmed, one unconfirmed). Across the 14 evaluable non‑neuroendocrine patients, disease control reached 64% (9/14). Safety was largely Grade 1–2 gastrointestinal events on a 21‑days‑on, 7‑days‑off schedule at 0.5 or 0.75 mg of MRT‑2359.
The company is moving to a signal‑confirming Phase 2 study in 2026, targeting AR‑mutant and AR signaling‑dependent mCRPC and pairing MRT‑2359 with a second‑generation AR inhibitor. The planned, two‑stage trial of up to 25 patients will evaluate PSA and RECIST responses, duration of response, PFS, rPFS, and safety, with potential expansion into additional subsets if activity holds. Updated data from the ongoing study are slated for ASCO Genitourinary 2026. A small HR+ breast cancer cohort showed no compelling activity and will not be advanced.
Strategically, Monte Rosa is narrowing from a tumor‑agnostic, MYC‑driven hypothesis to a biomarker‑enriched, AR‑mutant niche that may yield a faster, more capital‑efficient path to proof. The mechanistic signal—tumor biopsy RNAseq showing modulation of MYC and E2F pathways—supports an AR‑independent contribution that could matter in ARSI‑refractory disease, where resistance is often driven by AR mutations and splice variants. That positioning differentiates MRT‑2359 from AR‑axis layering strategies that have delivered incremental benefits with added toxicity and complexity. The flip side is that today’s efficacy rests on a very small subset, identified post hoc by ctDNA, and excludes patients with neuroendocrine differentiation based on screening biopsy RNAseq—choices that heighten the need for prospective assay strategy and operationally tractable screening.
For sites and CROs, the next phase will hinge on molecular infrastructure. Prospective identification of AR‑mutant disease by ctDNA is feasible, but assay selection, mutation cutoffs, and turnaround times will dictate screen‑fail rates and cycle times. If biopsy‑based RNA signatures remain part of eligibility to exclude neuroendocrine transformation or to quantify MYC/AR pathway activity, sponsors will need to budget for invasive screening, central lab capacity, and site training, which can slow accrual in a heavily pretreated population. The 21/7 oral schedule appears manageable alongside enzalutamide and may ease visit burden, but durability and cumulative tolerability will need longer follow‑up. For regulators, PSA responses in a small, selected subset will not be determinative; robust soft‑tissue responses, rPFS, and ultimately survival signals will be necessary to justify a registrational trajectory. For competitors, the focus on AR‑mutant mCRPC collides with a rapidly shifting standard of care that now includes earlier use of radioligand therapy and PARP combinations, compressing the post‑ARSI window where novel agents must prove value.
The near‑term watch items are straightforward. The ASCO GU update should clarify durability, rPFS trends, and whether responses extend beyond the AR‑mutant subgroup into AR‑V7 or AR‑inhibitor‑naïve settings. The Phase 2 protocol will reveal the chosen AR inhibitor partner, prospective testing plan, and any companion diagnostic intent—key determinants of enrollment speed and eventual commercialization. Longer term, Monte Rosa will need to show that MYC‑driven, AR‑independent activity translates into consistent, biomarker‑anchored benefit in a randomized setting, while maintaining a clean safety profile over multiple cycles. If the signal holds and the operational model proves scalable, this could establish a practical template for molecular glue degraders in solid tumors, not just in prostate cancer.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
