Conditional survival data from the RUBY trial is highly encouraging. For MSI-high patients, reaching the one-year survival mark implies an 84% chance of long-term survival, which skyrockets to nearly 95% for those who reach the three-year landmark.

Following the Keynote B21 trial, clinicians have become more selective with adjuvant immunotherapy in endometrial cancer. The study showed minimal benefit for pMMR patients and less impressive gains overall in its lower-risk population compared to advanced disease trials. This has led to a practice of reserving adjuvant chemo-IO primarily for stage 3 dMMR patients.

While antibody-drug conjugates (ADCs) are an exciting frontier in endometrial cancer, a critical challenge is emerging: determining optimal duration for maintenance therapies. Experts are concerned about committing patients to long-term, potentially toxic treatments without clear stopping rules, a key question for future trials.

As various maintenance therapies (immunotherapy, ADCs) are integrated into endometrial cancer treatment, the next major clinical question is defining how long these agents need to be continued to maximize benefit while minimizing long-term toxicity and patient burden.

While immunotherapy is transformational for DMMR endometrial cancer, its benefit is much smaller for the PMMR majority (two-thirds of patients). This reality requires more nuanced patient counseling and selective use in this population.

Despite significant interest, circulating tumor DNA (ctDNA) is not yet an actionable tool for guiding the duration of maintenance immunotherapy in endometrial cancer. While studies like DuoE show ctDNA levels correlate with outcomes, there is no evidence to support using its clearance to decide when to stop treatment. It remains a prognostic, not a predictive, biomarker for this purpose.

While PARP inhibitors plus immunotherapy (e.g., in the RUBY-2 trial) improved progression-free survival (PFS) in pMMR endometrial cancer, the overall survival (OS) curves crossed, showing no OS benefit. This cautionary signal suggests the combination may not be advantageous long-term and requires further investigation.

Clinical trials show a sustained overall survival benefit for upfront chemo-immunotherapy in dMMR patients, even with over 90% of the placebo group receiving immunotherapy upon progression. This demonstrates that delaying immunotherapy fails to rescue outcomes, making upfront use critical.

For dMMR endometrial cancer patients on combination therapy, clinicians are quicker to reduce or stop chemotherapy (like taxanes) when side effects arise. This practice reflects a growing confidence that immunotherapy is the primary driver of efficacy in this subgroup, allowing for a reduction in chemotherapy-related toxicity.