Abstract
•Cisplatin, a mainstay cancer drug, causes irreversible hearing loss in up to 60% of patients, creating a major unmet need. With ∼500,000 U.S. patients receiving platinum and other platinum-based therapies annually, preventing ototoxicity is critical.•Building on animal studies, we evaluated AZD5438, a selective CDK2 inhibitor, as a potential otoprotectant. Pharmacokinetic comparisons defined a human-equivalent tolerated dose in mice showing cross-species consistency, within which AZD5438 robustly protected against cisplatin-induced ototoxicity.•We addressed a key translational barrier—whether AZD5438 interferes with cisplatin’s efficacy—and found that otoprotective doses do not compromise its anti-tumor effect, removing a major hurdle to clinical translation.•These findings support first-in-human trials of AZD5438 as an otoprotectant and highlight its potential as a supportive cancer therapy that preserves hearing without compromising efficacy.
Cisplatin-based chemotherapy causes hearing loss in 40–60 % of all patients, yet effective preventative options remain limited. Building on prior animal studies, we demonstrate that oral administration of AZD5438, a potent and selective CDK2 inhibitor, provides dose-dependent protection against hearing loss in a clinically relevant multi-dose cisplatin mouse model. Protective doses (4.7 and 9.4 mg/kg b.i.d.) fall within the human-equivalent maximum tolerated dose range established in AstraZeneca trials, and exhibit plasma pharmacokinetics comparable to those in humans. Importantly, AZD5438 at 9.4 mg/kg b.i.d. does not reduce cisplatin’s anti-tumor efficacy in a testicular cancer xenograft model, consistent with in vitro findings. These results support AZD5438 as a promising candidate for clinical trials to prevent cisplatin-induced hearing loss while preserving cancer treatment efficacy.