Oral PKC inhibitor darovasertib preserved the eye in 57% of patients facing enucleation and cut projected radiation doses in 70.3% in the phase 2 OptimUM-09 trial.
Neoadjuvant
No neoadjuvant therapy is approved to shrink primary uveal melanoma before definitive treatment, and both enucleation and brachytherapy carry a substantial visual cost. About 95% of these tumors harbor GNAQ or GNA11 mutations, which drive constitutive activation of PKC, the target of darovasertib. The trial builds on a pilot study in which the drug preserved the eye in 75% of patients facing enucleation.1
OptimUM-09 is a single-arm study of darovasertib 300 mg twice daily in 28-day cycles, given before definitive therapy in patients needing enucleation (cohort 1) or plaque brachytherapy (cohort 2).1 Treatment was planned for 6 cycles and could extend to 12, with patients treated to maximum benefit before surgery or radiation and then offered 6 adjuvant cycles. As of a June 13, 2025, data cutoff, 95 patients had received treatment (56 in cohort 1, 39 in cohort 2), with a mean age of 57 years and most tumors staged T3 (46.3%) or T4 (29.5%).
In cohort 1, 84% (47/56) of patients had some degree of tumor shrinkage, measured as the product of apical height and largest basal diameter. Half (28/56) had a reduction of 20% or more, and 38% (21/56) had a reduction of 30% or more.1 Of 42 patients evaluable for the eye-preservation end point, 24 avoided enucleation and received brachytherapy (n = 18) or external beam radiation (n = 6), including 95% (19/20) of those with at least 20% shrinkage.1
In cohort 2, 82% (31/38) of patients had tumor shrinkage, and 61% (23/38) had a reduction of 20% or more.1 Projected radiation doses fell by at least 20% at the fovea in 35% (13/37), the disc center in 38% (14/37), and the lens in 41% (15/37) of patients. Using a vision prognostic tool, the investigators found a reduced predicted risk of severe vision loss 3 years after brachytherapy in 65% (24/37).1
Visual acuity improved during neoadjuvant treatment in 54.7% (29/53) of patients in cohort 1 and 60.5% (23/38) in cohort 2. Among patients with improvement, mean gains were 17 and 10 ETDRS letters, respectively. According to the investigators, darovasertib can affect four of the five predictive factors for severe vision loss after brachytherapy: tumor basal diameter, dose to the disc, dose to the fovea, and baseline vision.
Adverse events occurred in 97.9% (93/95) of patients, most commonly low-grade diarrhea (69.5%), nausea (63.2%), fatigue (33.7%), and vomiting (30.5%), and 26.3% (25/95) had a grade 3 or higher event.1 Treatment-related serious adverse events occurred in 5.3% (5/95), mainly hypotension in four patients, and 6.3% (6/95) discontinued because of treatment-related adverse events.1 Grade 3 or higher hypotension occurred in 6.3% (6/95).
"Neoadjuvant darovasertib demonstrated antitumor activity across both primary [uveal melanoma] cohorts, leading to eye preservation in over half of participants otherwise requiring enucleation and substantial radiation dose reduction in participants treated with [plaque brachytherapy]," the investigators wrote.1
The results led to OptimUM-10 (NCT07015190), a randomized, open-label phase 3 trial of neoadjuvant darovasertib vs local therapy alone.1,2 Its primary end points are vision preservation, measured as the proportion of patients losing 15 or more letters, in the brachytherapy cohort and eye preservation in the enucleation cohort. IDEAYA Biosciences funded OptimUM-09, and Dalvin disclosed consulting for the company.1
