Darovasertib Poised to Revolutionize Uveal Melanoma Treatment: Positive Phase 2 Data from ESMO 2025 Reveals High Rates of Eye and Vision Preservation

Introduction: A Paradigm Shift at ESMO 2025

The field of oncology was electrified today by a landmark presentation at the 2025 European Society of Medical Oncology (ESMO) Congress in Berlin. IDEAYA Biosciences, Inc. (Nasdaq: IDYA), a precision medicine oncology leader, unveiled transformative positive data from its Phase 2 OptimUM-09 trial. The study evaluates darovasertib, a potential first-in-class therapy, in the neoadjuvant setting (treatment before primary local therapy) for primary uveal melanoma (UM).

The data, presented by Dr. Marcus Butler, M.D., of the Princess Margaret Cancer Center, offers profound hope in a disease space plagued by a critical unmet need. For decades, patients diagnosed with primary uveal melanoma—the most common eye cancer in adults—have faced a devastating choice: remove the eye (enucleation) or undergo radiation (plaque brachytherapy) that often leads to severe vision loss. There are currently no approved systemic therapies for primary UM.

Darovasertib is set to challenge this brutal standard of care. The new Phase 2 data demonstrates that neoadjuvant treatment with darovasertib not only achieves significant tumor shrinkage but, most critically, leads to unprecedented rates of eye preservation and a reduced risk of vision loss. With a 57% eye preservation rate for patients previously recommended for eye removal—a figure that jumps to 95% in high-responders—darovasertib is positioning itself as the most significant advancement in primary uveal melanoma in recent history.

This potential is already recognized at the highest levels. Darovasertib has received the U.S. FDA's prestigious Breakthrough Therapy Designation in the neoadjuvant setting for enucleation-eligible patients, signaling its importance and expediting its path toward potential approval.

The Decades-Old Dilemma: The Unmet Need in Primary Uveal Melanoma

To understand the magnitude of the ESMO 2025 presentation, one must first grasp the grim reality for patients diagnosed with primary uveal melanoma. While considered a "rare" cancer, it is the most common primary intraocular malignancy in adults. The primary tumor is confined to the eye, but it carries a high risk of metastasizing, most commonly to the liver, at which point it becomes exceptionally difficult to treat.

However, even before the threat of metastasis, the local treatment is life-altering.

Enucleation (Eye Removal): For patients with large tumors or tumors located in difficult-to-treat areas (like near the optic nerve), the standard of care is the complete surgical removal of the eye. This procedure is physically and psychologically traumatic, resulting in monocular vision (loss of depth perception) and the need for a prosthesis.
Plaque Brachytherapy (PB): For smaller or medium-sized tumors, the alternative is radiation. This involves surgically implanting a small, radioactive disc (a "plaque") onto the outer wall of the eye, directly over the tumor. While it can control the tumor and save the eye, the radiation is highly toxic to the delicate structures of the eye. A large percentage of patients who undergo PB suffer from radiation-induced complications, such as radiation retinopathy, cataracts, and neovascular glaucoma, which often lead to severe, progressive vision loss—sometimes culminating in legal blindness in the treated eye.

For years, the field has been desperate for a systemic therapy—a pill or infusion—that could be given to shrink the primary tumor, making local treatments less destructive or, in some cases, unnecessary. This is the "neoadjuvant" approach, and it is precisely where darovasertib is proving its worth.

The OptimUM-09 Trial: A Deep Dive into the Darovasertib Data

The OptimUM-09 trial is a Phase 2 study that enrolled 95 patients with primary UM. These patients were stratified into two cohorts based on the local therapy recommended by their investigator at baseline:

Cohort 1 (EN Cohort): 56 patients who were recommended for enucleation (eye removal).
Cohort 2 (PB Cohort): 39 patients who were eligible for plaque brachytherapy.

Patients received oral neoadjuvant darovasertib for up to 12 cycles (or until maximum benefit) before undergoing their definitive local therapy. The goal was simple: shrink the tumor and improve outcomes.

As of the June 13, 2025 data cut-off, 94 patients were evaluable for efficacy. The results presented at ESMO were stunning across the board.

Overall Efficacy: Robust and Consistent Tumor Shrinkage

Across the entire study population, darovasertib demonstrated powerful anti-tumor activity.

83% (78/94) of all patients demonstrated ocular tumor shrinkage of any amount.
54% (51/94) of all patients achieved $\geq$ 20% tumor shrinkage.

This $\geq$ 20% shrinkage figure is not an arbitrary number. It represents a clinically meaningful reduction. Based on this data and discussions with the FDA, IDEAYA has proposed this $\geq$ 20% shrinkage threshold as the primary definition of response for its ongoing Phase 3 trial, underscoring its clinical relevance.

"We are highly encouraged by the data from OptimUM-09 demonstrating meaningful tumor shrinkage, eye preservation and reduced predicted risk of severe vision loss," said Darrin Beaupre, M.D., Ph.D., Chief Medical Officer of IDEAYA Biosciences. "We believe these results strongly support the potential for darovasertib as the first systemic therapy for the neoadjuvant treatment of primary uveal melanoma."

Cohort 1 Analysis: Saving the Eye

The most dramatic and life-changing results came from Cohort 1—the 56 patients who were told they would likely need their eye removed.

Treatment with neoadjuvant darovasertib achieved significant tumor reductions in this high-risk group:

84% (47/56) experienced any reduction in tumor size.
50% (28/56) achieved a $\geq$ 20% reduction.
37.5% (21/56) achieved a $\geq$ 30% reduction.

These reductions translated directly into saved eyes. Among the 42 patients in this cohort who had completed their primary local therapy by the data cut-off, an astonishing 57.1% (24/42) eye preservation rate was observed.

This means 24 individuals who were on track for enucleation did not have their eye removed. Instead, their tumors shrank enough to become eligible for other, eye-sparing treatments: 75% (18/24) received plaque brachytherapy, and 25% (6/24) received external beam radiation.

The Responder Analysis: A 95% Preservation Rate

The data gets even more compelling. When researchers looked specifically at the 20 patients in this cohort who had a $\geq$ 20% tumor shrinkage and had completed local therapy, the eye preservation rate skyrocketed to 95% (19/20).

This finding is a clear, powerful correlation: meaningfully shrink the tumor with darovasertib, and you can almost certainly save the eye. It is this specific, practice-changing data that formed the basis for the FDA granting Breakthrough Therapy Designation.

Cohort 2 Analysis: Preserving Vision

For patients in Cohort 2, the goal was different. These 39 patients were already eligible for plaque brachytherapy (PB), so saving the eye was likely. The new, critical goal was to save their vision from the destructive side effects of radiation.

The logic is that by shrinking the tumor with darovasertib before radiation, the radiation plaque can be smaller or placed differently, delivering a lower, safer dose to critical eye structures like the optic nerve, fovea (center of vision), and lens.

The data confirms this hypothesis. Darovasertib treatment led to significant tumor shrinkage in this cohort as well:

82% (31/38) achieved any tumor reduction.
60.5% (23/38) achieved a $\geq$ 20% reduction.
44.7% (17/38) achieved a $\geq$ 30% reduction.
This shrinkage had a direct, measurable impact on the predicted radiation toxicity. Among 37 evaluable patients with paired dosimetry (measurements of radiation dose):
70% (26/37) observed a reduction in the predicted dose of radiation to critical eye structures.
Approximately 35-40% of patients experienced a $\geq$ 20% reduction in this predicted dose, a magnitude known to be associated with improved visual outcomes.

Most importantly, this technical dosimetry data was translated into a long-term patient benefit. Using a validated vision prognostic tool from the Cleveland Clinic, the study found that 64.9% (24/37) of patients had a reduced predicted risk of vision loss (developing 20/200 vision or worse) 3-years post-radiation treatment.

Darovasertib didn't just shrink the tumor; it provided a "radiation-sparing" effect that could preserve sight for years to come.

A Surprising Bonus: Improving Vision During Treatment

Perhaps one of the most remarkable findings of the OptimUM-09 trial was that many patients didn't just preserve vision—they actively gained it while on darovasertib, even before their local therapy. This suggests the drug itself may be alleviating tumor-related symptoms, such as retinal detachment or pressure, that were already impacting sight.

In the EN Cohort (Cohort 1), 54.7% (29/53) of patients demonstrated an improvement in their baseline Visual Acuity Scores (VAS). For those who improved, the mean gain was 17 letters on an eye chart—a significant, life-enhancing improvement (equivalent to reading more than 3 additional lines).
In the PB Cohort (Cohort 2), 60.5% (23/38) of patients showed improved VAS, with a mean gain of 10 letters (2 lines on an eye chart).

This finding is exceptional. In cancer treatment, success is often defined as simply "not making things worse." Darovasertib is actively improving patients' quality of life and vision during the neoadjuvant phase.

Safety and Tolerability: A Manageable Profile

A systemic therapy is only viable if it can be tolerated. The data presented at ESMO 2025 confirms that darovasertib is generally well-tolerated, with a manageable safety profile.

The most common treatment-related adverse events (TRAEs) were low-grade and included predictable side effects such as diarrhea, nausea, vomiting, and fatigue.

Crucially, the rates of severe or-discontinuation-causing events were low:

Grade 3 or higher TRAEs: Occurred in 16.8% (16/95) of patients.
Treatment-related serious adverse events (SAEs): 5.3%
Treatment discontinuation due to AEs: 6.3%

These low rates suggest that the vast majority of patients can stay on darovasertib long enough to derive maximum benefit, a critical factor for a neoadjuvant therapy.

Expert Perspective and The Path Forward

The excitement from the investigators involved in the study is palpable.

"These data highlight the potential of neoadjuvant darovasertib to significantly improve the treatment paradigm for patients requiring enucleation or plaque brachytherapy in primary uveal melanoma," said Dr. Marcus O. Butler, the study's lead investigator. "Helping them preserve their eye and preserve their vision with a single therapy."

With this robust Phase 2 data in hand, IDEAYA Biosciences is moving forward on multiple fronts.

Phase 3 (OptimUM-10) in Primary UM: The company is actively conducting a global, registrational-intent Phase 3 trial, named OptimUM-10, to confirm these findings in the neoadjuvant setting. This trial will be the final step toward seeking full regulatory approval.
Metastatic Disease (OptimUM-02): The promise of darovasertib is not limited to primary disease. IDEAYA is also evaluating darovasertib in combination with crizotinib for patients with first-line metastatic uveal melanoma (MUM). This registration-enabling Phase 2/3 trial (OptimUM-02) is also progressing rapidly. The company is targeting the report of topline median Progression-Free Survival (PFS) data from this trial by the end of 2025 or the first quarter of 2026, which could enable a potential accelerated approval filing in the United States for this deadly condition.

Conclusion: A New Standard of Care is on the Horizon

The data for neoadjuvant darovasertib presented at ESMO 2025 is not just an incremental update; it represents a fundamental shift in the management of primary uveal melanoma. For the first time, a systemic, precision-medicine pill has demonstrated a profound ability to shrink ocular tumors, directly leading to historic rates of eye preservation for patients facing enucleation and a significant reduction in the predicted risk of vision loss for those undergoing radiation.

The findings from OptimUM-09 offer a clear, evidence-based path away from the destructive, decades-old standards of care. Backed by an FDA Breakthrough Therapy Designation and a clear-cut Phase 3 trial design, darovasertib is on the precipice of becoming the first-ever approved systemic therapy for primary uveal melanoma. For patients, this news provides something that has long been in short supply: a realistic hope of not only surviving their cancer but doing so with their eye, and their vision, intact.