KPG-121 is a novel cereblon modulator that binds more strongly to the CRL4-Cereblon (CRBN)complex than lenalidomide, enhancing its immunomodulatory, anti-proliferative, and anti-angiogenic properties. In preclinical work, it showed promising synergy with abiraterone, enzalutamide, apalutamide, and darolutamide. The drug was evaluated in a multi-center, open-label, Phase 1 study in which patients with metastatic castration-resistant prostate cancer (mCRPC) who were already on stable abiraterone or enzalutamide received once-daily oral KPG-121 at doses of 1.5 mg, 2.5 mg, 5 mg, or 10 mg in 28-day cycles.

Sixteen patients took part, and safety was a primary focus: 75% experienced treatment-related adverse events, including notable rates of neutropenia, lowered white blood cell counts, and platelet reductions. Five individuals discontinued therapy due to adverse events, with one COVID-19–related fatality determined to be unrelated to the study treatment. Despite these events, early efficacy signals emerged: among eight patients with RECIST-evaluable disease, 37.5% achieved partial responses and another 37.5% maintained stable disease, producing an overall disease control rate of 75%. Pharmacokinetic assessments suggested a predictable rise in drug exposure with higher doses, with the half-life ranging from just under three hours to slightly above that threshold. Lower doses, particularly in the 1.5 mg and 2.5 mg range, generally showed manageable tolerability and preliminary clinical benefit.

KPG-121 may therefore hold promise for men with mCRPC, especially given the drug’s potential to combine well with standard hormone therapies. Further trials will be necessary to confirm its efficacy and tolerability, and to determine the best way to integrate KPG-121 into existing treatment regimens for advanced prostate cancer.

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