Onvansertib (DB15110): A Comprehensive Profile of a Third-Generation PLK1 Inhibitor for Oncologic Indications

Executive Summary

Onvansertib is an investigational, orally bioavailable, small-molecule drug representing a third generation of Polo-like Kinase 1 (PLK1) inhibitors. Developed by Cardiff Oncology, it is engineered for high selectivity, a characteristic that addresses the toxicity issues that hampered the clinical development of its predecessors. The primary mechanism of action involves the potent and specific inhibition of PLK1, a serine/threonine kinase that is a master regulator of mitosis and is frequently overexpressed in a wide array of human cancers. By inhibiting PLK1, Onvansertib induces mitotic arrest and subsequent apoptosis in cancer cells, while its role in disrupting the DNA damage response pathway creates a strong rationale for its use in combination with standard-of-care cytotoxic therapies.

The clinical development program for Onvansertib is anchored by compelling data in its lead indication: first-line treatment of RAS-mutated metastatic colorectal cancer (mCRC), a large patient population with a significant unmet medical need. In the randomized Phase 2 CRDF-004 trial, Onvansertib combined with standard chemotherapy and bevacizumab demonstrated a clinically and statistically significant improvement in objective response rate (ORR) compared to the standard-of-care arm, with a confirmed ORR of 49% in the 30mg dose arm versus 30% in the control arm. This efficacy signal is supported by favorable trends in secondary endpoints, including progression-free survival (PFS) and depth of response.