Darovasertib combination shows progression-free survival benefit in metastatic uveal melanoma

IDEAYA Biosciences and Servier announced positive topline results from the phase 2/3 OptimUM-02 trial (NCT05987332) of darovasertib in combination with crizotinib in patients with first-line HLA-A*02:01-negative metastatic uveal melanoma—a population for which no approved systemic therapies currently exist.¹

The data represent what could be the first regulatory submission for a targeted therapy in this setting, with an NDA filing planned for the second half of 2026 to support US accelerated approval. Full data from OptimUM-02 are expected to be presented at a major medical conference later in 2026.

OptimUM-02: Trial Design and Primary Results

OptimUM-02 is a global, randomized phase 2/3 trial enrolling 313 patients in the phase 2b/3 portion. The darovasertib combination arm included 210 patients; the investigator choice of therapy (ICT) control arm included 103 patients, reflecting real-world clinical practice. The ICT arm was composed of 76% ipilimumab plus nivolumab and 24% pembrolizumab—the regimens most likely to be used in the absence of an approved targeted option.

The primary end point was median progression-free survival as assessed by blinded independent central review (BICR). The darovasertib combination achieved a median PFS of 6.9 months versus 3.1 months for ICT (HR, 0.42; 95% CI: 0.30-0.59; P <.0001), a 58% reduction in the risk of progression or death.

The secondary end point of overall response rate was also strongly positive: ORR by BICR was 37.1% for the darovasertib combination versus 5.8% for ICT (P <.0001), including 5 complete responses in the darovasertib combination arm, with a median duration of response of 6.8 months. Overall survival data showed an early trend favoring the combination, though those findings are preliminary.

The safety profile was consistent with previously reported adverse events across the darovasertib program, with the combination described as well-tolerated and manageable. Serious treatment-related adverse events were reported in single-digit percentages.

"Metastatic uveal melanoma is an area of high unmet medical need with poor prognosis and short overall survival, and there are currently no approved therapies for HLA-A*02:01-negative mUM patients. The data from the OptimUM-02 study provides potential practice-changing results for the treatment of first-line metastatic uveal melanoma," Meredith McKean, MD, MPH, of the Sarah Cannon Research Institute, said in a statement.¹

Darovasertib's Expanding Program

For ophthalmologists, the OptimUM-02 results arrive alongside a growing body of evidence that darovasertib may have utility across multiple stages of uveal melanoma—not only at the metastatic end of the disease spectrum but potentially much earlier, in the primary tumor setting, where globe and vision preservation are the primary goals.

In October 2025, IDEAYA reported on positive phase 2 data from OptimUM-09, evaluating darovasertib as neoadjuvant therapy in primary uveal melanoma patients facing enucleation or plaque brachytherapy.²

At that time, the data showed that approximately 84% of patients in the enucleation cohort experienced any reduction in tumor size, with an eye preservation rate of 57.1% overall—rising to 95% in patients who achieved at least a 20% tumor reduction. Cohort 2, comprising brachytherapy-eligible patients, showed similarly meaningful reductions in predicted radiation dose to critical ocular structures, including the fovea, optic disc, and lens, along with visual acuity gains of up to a mean of 17 letters in Cohort 1. IDEAYA has also advanced a phase 3 trial, OptimUM-10 (NCT07015190), evaluating single-agent darovasertib in the neoadjuvant primary uveal melanoma setting.

The Unmet Need in Context

Uveal melanoma is a rare and aggressive ocular cancer, with approximately 95% of cases driven by activating mutations in GNAQ/11 GTPase proteins that fuel downstream PKC signaling and tumor growth. While local treatment has been effective at controlling primary disease and preserving the globe, patients who develop metastatic disease face a starkly different prognosis. Median overall survival in metastatic uveal melanoma is typically less than 1 year, and until now, no systemic therapy had demonstrated sufficient benefit in randomized trials to earn regulatory approval in the HLA-A*02:01-negative population, which represents the majority of metastatic uveal melanoma patients.

The available options—immunotherapy regimens including ipilimumab plus nivolumab, or pembrolizumab—have produced limited response rates in this disease, a reflection of the immunologically distinct nature of uveal melanoma compared with cutaneous melanoma. This context makes the OptimUM-02 results particularly significant.

The significance of OptimUM-02 extends beyond its trial metrics. As Kapil Mishra, MD, noted in a conversation with Ophthalmology Times in the context of radiation retinopathy in uveal melanoma: the field has historically prioritized life over globe, and globe over vision—a hierarchy that reflects the severity of the disease rather than a lack of ambition for better outcomes. Effective systemic therapy for metastatic disease is the piece that has been most stubbornly missing from that hierarchy.

With darovasertib now demonstrating significant PFS and response rate benefits over current immunotherapy standards in a randomized registrational trial, and with active phase 3 development in the primary disease setting, the treatment landscape for uveal melanoma is beginning a meaningful shift.

REFERENCES

1. IDEAYA Biosciences and Servier Announce Positive Topline Results from Phase 2/3 Registrational Trial (OptimUM-02) of Darovasertib in Combination with Crizotinib in First-line HLA-A*02:01-Negative Metastatic Uveal Melanoma. IDEAYA Biosciences, Inc. News release. April 13, 2026. Accessed April 13, 2026. https://www.prnewswire.com/news-releases/ideaya-biosciences-and-servier-announce-positive-topline-results-from-phase-23-registrational-trial-optimum-02-of-darovasertib-in-combination-with-crizotinib-in-first-line-hla-a0201-negative-metastatic-uveal-melanoma-302739905.html

2. DEAYA Biosciences Announces Positive Phase 2 Data for Darovasertib in the Neoadjuvant Setting of Primary Uveal Melanoma in a Proffered Paper Oral Presentation at ESMO 2025. IDEAYA Biosciences, Inc. News release. October 20, 2025. Accessed October 28, 2025. Accessed April 13, 2026. https://www.prnewswire.com/news-releases/ideaya-biosciences-announces-positive-phase-2-data-for-darovasertib-in-the-neoadjuvant-setting-of-primary-uveal-melanoma-in-a-proffered-paper-oral-presentation-at-esmo-2025-302588310.html