Neoadjuvant Darovasertib Produces Preliminary Responses in Uveal Melanoma

Neoadjuvant treatment with the investigational PKC inhibitor darovasertib (IDE196) was effective and generally well tolerated in patients with uveal melanoma, according to preliminary data from the plaque brachytherapy cohort of the ongoing phase 2 OptimUM-09 trial (NCT05907954).1

At the May 23, 2025, data cutoff 76% (n = 16/21) of efficacy-evaluable patients experienced ocular tumor shrinkage of at least 20% by product of diameters; this threshold was the response definition proposed for the phase 3 OptimUM-10 trial (NCT07015190). Moreover, 48% of patients achieved a minimum of 20% reduction in simulated radiation dose to at least 1 key visual structure (optic disc/nerve and/or fovea) and 86% experienced any reduction. Notably, a 20% reduction in radiation dose has been shown to correlate with improved visual outcomes.

Interim findings from OptimUM-09 supported the FDA’s decision to grant breakthrough therapy designation to neoadjuvant darovasertibfor uveal melanoma in March 2025.2

"The data presented in this study represents a potential breakthrough advance for subjects with primary uveal melanoma where there currently is no neoadjuvant therapy available that can shrink tumors in this setting," Arun D. Singh, MD, the director of the Department of Ophthalmic Oncology at the Cole Eye Institute at the Cleveland Clinic in Ohio, stated in a news release. 1

Unpacking the OptimUM-09 Study Design

OptimUM-09 is an ongoing multicenter, open-label study that is enrolling adult patients with uveal melanoma requiring either enucleation or plaque brachytherapy.3 Patients are also required to have an ECOG performance status of 0 or 1, no significant underlying ocular disease, and adequate organ function.

All patients are treated with oral darovasertib in the neoadjuvant setting for up to 6 months, or to maximum benefit, followed by primary local therapy. An additional 6 months of adjuvant treatment will follow and will include long-term follow-up to assess visual outcome, disease recurrence, and development of metastatic disease.

The study’s primary end point is the incidence of adverse effects and significant laboratory abnormalities. Moreover, the primary end point in cohort 1 (enucleation) is the number of patients converted from requiring enucleation to radiation; the primary end point in cohort 2 (plaque brachytherapy) is the estimated change in modeled radiation dose. Secondary end points include tumor response, assessment of visual acuity loss, rate of local disease recurrence, and rate of metastatic disease. Overall survival is also being assessed.

Additional Data and Future Plans for Darovasertib

Further preliminary findings from OptimUM-09 revealed that most efficacy-evaluable patients (n = 13/20) experienced any visual improvement during neoadjuvant darovasertib treatment, with a median of 6 letters gained.1 Additionally, 40% of patients achieved more than 5 letters gained at 2 consecutive visits.

At 3 years post-plaque brachytherapy, 67% (n = 14/21) patients who received darovasertib experienced any reduction in their risk of developing 20/200 vision. Thirty-eight percent had at least a 20% reduction in their risk of developing 20/200 vision.

In terms of safety, darovasertib was generally well-tolerated and displayed a manageable safety profile. Most treatment-related adverse effects (TRAEs) were grade 1 or 2 in severity; grade 3 TRAEs were observed in 4 patients in the safety population (n = 31). The most common any-grade TRAEs included diarrhea, nausea, fatigue, maculopapular rash, hypotension, and vomiting. Four patients discontinued treatment due to TRAEs; 2 patients discontinued treatment due to hepatic transaminase increase; 1 did so due to nausea, vomiting, and fatigue; and another discontinued due to hypotension, bradycardia, and decreased level of consciousness.

Additional findings from OptimUM-09 will be presented during a proffered paper oral presentation during the 2025 ESMO Congress, which will take place on October 17 to 21, 2025, in Berlin, Germany.

"We are delighted to see the progress we are making with darovasertib as a single agent in subjects with mid-sized tumors requiring plaque brachytherapy," Darrin Beaupre, MD, PhD, chief medical officer of IDEAYA Biosciences, added in the news release.1 "Darovasertib is generally well-tolerated and showing initial evidence of shrinking tumors effectively, and the results imply that the associated radiation reduction observed will likely lead to improvements in vision not only during therapy but post-plaque brachytherapy."

References

1. IDEAYA Biosciences announces positive interim phase 2 data for darovasertib in the neoadjuvant setting of primary uveal melanoma. News Release. IDEAYA Biosciences. September 8, 2025. Accessed September 8, 2025. https://media.ideayabio.com/2025-09-08-IDEAYA-Biosciences-Announces-Positive-Interim-Phase-2-Data-for-Darovasertib-in-the-Neoadjuvant-Setting-of-Primary-Uveal-Melanoma
2. IDEAYA Biosciences receives US FDA breakthrough therapy designation for darovasertib monotherapy in neoadjuvant uveal melanoma. News release. IDEAYA Biosciences, Inc. March 31, 2025. Accessed September 8, 2025. https://ir.ideayabio.com/2025-03-31-IDEAYA-Biosciences-Receives-US-FDA-Breakthrough-Therapy-Designation-for-Darovasertib-Monotherapy-in-Neoadjuvant-Uveal-Melanoma
3. (Neo)adjuvant IDE196 (darovasertib) in patients with localized ocular melanoma. CliincalTrials.gov. Updated August 3, 2025. Accessed September 8, 2025. https://www.clinicaltrials.gov/study/NCT05907954