Endometrial cancer remains the most common gynecologic malignancy in the U.S., with both incidence and mortality rates continuing to rise. While carboplatin plus paclitaxel (CP) has long served as the standard frontline regimen for primary advanced or recurrent endometrial cancer, the emergence of immunotherapy-based combinations has begun to reshape expectations.
Immunotherapy reshapes treatment expectations
The underlying biology of endometrial cancer, which has a relatively high prevalence of mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) tumors, has made PD-1/PD-L1 immune checkpoint inhibitors a practical option. These agents work by restoring antitumor immune activity and have demonstrated significant activity in dMMR/MSI-H tumors compared with mismatch repair-proficient/microsatellite stable (MMRp/MSS) tumors.
However, the majority of patients with endometrial cancer have MMRp/MSS tumors, which are often less responsive to immunotherapy alone. This has driven the development of combination strategies, such as pairing checkpoint inhibitors with chemotherapy, to extend clinical benefit to an overall population of patients with MMRp/MSS and dMMR/MSI-H biomarker status.
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Jennifer MacDonald, PharmD, BCOP, Oncology Clinical Pharmacy Specialist, said the shift requires pharmacists to work with a more detailed evidence base. “Overall survival is one of the more meaningful endpoints we have and is critical for guiding treatment selection,” she said. “I frequently discuss with both providers and patients the OS results from clinical studies and whether the endpoint was adequately powered to detect a treatment difference with the comparator.”
The issue affects real patients. Those with aggressive subtypes, like carcinosarcoma, or individuals without measurable disease after surgery, often fall outside typical trial populations. Yet they still require effective treatment options.
A new standard emerges from trial data
The phase 3 RUBY trial evaluated JEMPERLI (dostarlimab-gxly), a programmed death receptor-1 (PD-1)-blocking antibody, in combination with CP in patients with primary advanced or recurrent endometrial cancer. The trial included a broader range of patients than many studies. About 9% of participants had carcinosarcoma, a rare and aggressive subtype, and some had no measurable disease after surgery—conditions that reflect real-world clinical practice.
In 2024, the FDA expanded JEMPERLI’s approval to cover all adult patients with primary advanced or recurrent endometrial cancer, regardless of biomarker status.
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For pharmacists, the change streamlines decision-making. However, it also increases responsibility. Immune-mediated side effects—such as pneumonitis, colitis, or thyroid disorders—require careful monitoring, sometimes long after treatment ends.
The safety profile, while manageable, is not without challenges. In the RUBY trial, 19% of patients discontinued JEMPERLI due to adverse reactions, and 37% required treatment pauses.
Pharmacists as the bridge between data and care
Oncology pharmacists play a central role in translating clinical evidence into real-world decisions—helping guide regimen selection, formulary use, and multidisciplinary discussions across care teams. At MacDonald’s institution, this involves presenting RUBY trial findings at monthly division meetings and tumor boards, where clinicians discuss how new evidence fits into existing protocols.
A patient’s molecular profile—whether their tumor is dMMR, MSI-H, or MMRp—can influence treatment choices. Practical factors, such as age, comorbidities, or logistical considerations, also play a role. “It’s not just about selecting the most effective drug,” MacDonald said. “It’s about finding the right balance for each individual.”
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Pharmacists also work to improve access. When formularies restrict options, they advocate for alternatives that reflect real-world patient diversity. “We need to ensure the right therapies are available for the right patients,” she said. “That means understanding trial details—who was included, who was excluded, and why.”
The evolution of frontline treatment in endometrial cancer involves more than new drugs. It requires rethinking how care is delivered. For patients with rare or aggressive subtypes, or those who don’t fit typical trial criteria, these changes can mean the difference between a one-size-fits-all approach and a tailored plan.
MacDonald views the progress as part of broader changes in oncology. “We’re finally seeing meaningful improvements in endometrial cancer, especially for groups that have been overlooked,” she said.
