IDEAYA Biosciences Unveils OptimUM-02 Data: Darovasertib/Crizotinib Doubles PFS in Uveal Melanoma

Key Points

• Darovasertib plus crizotinib significantly improved efficacy, with median PFS of 6.9 vs 3.1 months (HR 0.42, p<0.0001) and ORR 37.1% vs 5.8%, including five complete responses versus none in the control arm.
• Safety was consistent with prior experience but included hypotension and syncope likely related to PKC inhibition; investigators reported management strategies (hydration, dosing with food, holding or adjusting blood-pressure meds) and will provide detailed safety data at a conference.
• IDEAYA is pursuing expedited regulatory pathways using the PFS-driven accelerated approval route while OS data mature (interim OS planned mid‑next year) and plans to expand development into neoadjuvant, adjuvant, and HLA-A2 positive programs.

IDEAYA Biosciences NASDAQ: IDYA shared top-line results from its randomized phase II/III OptimUM-02 study evaluating darovasertib in combination with crizotinib as a frontline treatment for HLA-A2 negative metastatic uveal melanoma. The webcast featured prepared remarks from Founder, President, and CEO Yujiro S. Hata and Chief Medical Officer Darrin M. Beaupre, with clinical perspective during Q&A from Meredith McKean, Associate Director of the Melanoma and Skin Cancer Research Program at Sarah Cannon Research Institute.

Company highlights trial context and unmet need

Hata described the results as the culmination of more than five years of clinical development and said IDEAYA worked closely with the U.S. FDA, the patient community, and global investigators. He also emphasized that OptimUM-02 is, in IDEAYA’s view, the first frontline randomized registrational trial in HLA-A2 negative metastatic uveal melanoma, and the first to use ipilimumab/nivolumab (ipi/nivo) in the control arm as an investigator’s choice option in the U.S., rather than PD-1 monotherapy alone.

Beaupre provided background on the disease, calling uveal melanoma “an aggressive form of cancer with a poor prognosis.” He said there are about 3,000 newly diagnosed cases per year in the U.S. and approximately 10,000 cases globally. About half of patients develop metastases, which he said is associated with a median overall survival of roughly 10 to 12 months and a five-year survival rate of about 15% to 20%.

Beaupre noted that for HLA-A2 positive patients there is an approved therapy, which he referred to as Kimmtrak, while “for HLA-A2 negative subjects, there are no approved therapies,” adding that checkpoint inhibitors are often used off-label with “very limited clinical activity.”

Rationale for darovasertib and MET inhibition

Beaupre said most uveal melanoma tumors harbor mutations in G protein-coupled receptors that lead to constitutive activation of protein kinase C (PKC), which he described as a driver of tumor growth and survival. Darovasertib, he said, is a “potent and selective” PKC inhibitor that demonstrated anti-tumor activity in preclinical models.

He added that overexpression of MET is often found in advanced uveal melanoma and is thought to play a role in metastatic spread. In preclinical testing, Beaupre said the combination of darovasertib and crizotinib, a MET inhibitor, showed greater anti-tumor activity than either agent alone, supporting the rationale for the randomized study.

OptimUM-02 design and top-line efficacy results

OptimUM-02 completed enrollment in December 2025, according to Beaupre. The trial randomized 313 HLA-A2 negative metastatic uveal melanoma patients 2:1 to darovasertib (300 mg twice daily) plus crizotinib (200 mg twice daily), versus investigator’s choice standard-of-care therapy: pembrolizumab, ipilimumab plus nivolumab, or dacarbazine for patients not able to tolerate immunotherapy.

The primary endpoint was progression-free survival (PFS) by blind independent central review (BICR) for a potential accelerated approval pathway, Beaupre said. For the phase III portion, he said overall survival (OS) is the key endpoint for potential full approval. Secondary endpoints included additional PFS measures, overall response rate (ORR), duration of response, disease control rate, safety, and quality-of-life questionnaires.

On the primary endpoint, Beaupre reported that median PFS by BICR was 6.9 months in the darovasertib/crizotinib arm versus 3.1 months in the investigator’s choice arm, corresponding to a hazard ratio of 0.42 (95% CI: 0.3–0.59) with a p-value less than 0.0001. He characterized the result as a 58% reduction in the risk of tumor progression in the treatment arm.

Beaupre also highlighted ORR results: 37.1% for darovasertib plus crizotinib versus 5.8% for investigator’s choice, with a p-value less than 0.0001. He said there were five complete remissions in the treatment arm and none in the control arm. Beaupre added there was “a trend in improvement in overall survival,” and said the full dataset will be presented at a future medical conference.

Safety observations and management considerations

Beaupre said both study arms showed safety profiles consistent with prior experience. During Q&A, Hata said safety metrics including discontinuation rates and dose intensity were “very consistent” with prior disclosures, but noted the company planned to share more detail at an upcoming major medical conference.

In response to questions about hypotension and syncope, Beaupre said the company believes these events are “likely more darovasertib” mechanistically and may relate to PKC inhibition effects on smooth muscle cells. He described management strategies including hydration and adjusting blood pressure medications. McKean said operational learnings—such as taking the medication with food and holding blood pressure medications—helped reduce hypotension and syncopal events, and noted that short half-lives allow temporary holds and restarts to manage side effects.

Regulatory timing, OS maturity, and broader development plans

Management said OS data are still maturing. Hata said the company would not quantify OS separation at the upcoming medical conference and described “about roughly 10 months of follow-up” at this stage, with an “early trend” that he called encouraging. Beaupre said an interim OS analysis is planned for mid-year next year and suggested timing could evolve based on data maturity and discussions with the FDA.

On regulatory steps, Beaupre said IDEAYA will work with the FDA on how to “most expeditiously get this filing completed,” and indicated expedited options are under discussion. Hata said the company would evaluate RTOR, while Beaupre listed multiple FDA designations for darovasertib, including Breakthrough Therapy, Fast Track, and Orphan.

Beaupre and McKean also discussed how the results could enable exploration in additional settings. Beaupre said IDEAYA is studying darovasertib in primary (neoadjuvant) uveal melanoma with endpoints including eye and vision preservation, and plans to test darovasertib plus crizotinib in an adjuvant setting for high-risk patients to determine whether relapse can be reduced. He also referenced the ongoing OptimUM-01 study in HLA-A2 positive patients, and said IDEAYA has dosed around 100 HLA-A2 positive patients to date in that program.

McKean said the randomized trial represents “a huge day” for metastatic uveal melanoma patients, citing the limited systemic options historically available, and added that prior datasets presented at ESMO 2023 and SMR 2024 included both HLA-A2 positive and negative patients with “similar response rates.” She also described the limited set of subsequent therapy options available to patients after progression, often relying on liver-directed approaches or other local therapies, rather than multiple lines of systemic treatments typical in other cancers.

About IDEAYA Biosciences NASDAQ: IDYA

IDEAYA Biosciences is a clinical-stage precision oncology company dedicated to the discovery and development of novel therapies that exploit synthetic lethality in cancer cells. By targeting key DNA damage response pathways, the company aims to selectively kill tumor cells exhibiting specific genetic vulnerabilities while sparing healthy tissue. IDEAYA's pipeline includes small-molecule inhibitors designed to address underserved tumor types, and its lead programs are advancing through Phase 1 and Phase 2 clinical trials in multiple oncology indications.

Central to IDEAYA's approach is its Modular Approach to Precision (MAP) platform, which integrates proprietary genomic and functional screening technologies to identify critical cancer-specific dependencies.

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