[Interview] Will Lynparza combo therapy fill treatment gap in pMMR endome...

While immunotherapy has become a key pillar of first-line treatment for endometrial cancer, experts say additional therapeutic strategies are still needed for patients with mismatch repair-proficient (pMMR) disease.

The treatment landscape for advanced or recurrent endometrial cancer has changed rapidly in recent years. Previously, paclitaxel- and carboplatin-based chemotherapy served as the standard first-line treatment, but the addition of immunotherapy has demonstrated the potential to improve outcomes.

However, not all patients derive the same degree of benefit. In particular, patients with mismatch repair-deficient (dMMR) tumors show marked responses to immunotherapy, whereas those with pMMR disease continue to experience relatively limited responses and remain a major challenge in clinical practice.

As a result, efforts are underway to enhance treatment efficacy in pMMR endometrial cancer by combining immunotherapy with additional mechanisms of action. One leading strategy combines the PD-L1 inhibitor durvalumab (Imfinzi) with the PARP inhibitor Lynparza (olaparib).

In the DUO-E trial, adding durvalumab to chemotherapy followed by maintenance therapy with durvalumab plus Lynparza demonstrated a reduction in the risk of disease progression or death in patients with pMMR disease. More recently, indirect comparison analyses presented at ESGO 2026 have further fueled interest in expanding PARP inhibitor-based combination strategies across immunotherapy regimens.

Korea Biomedical Review interviewed Professor Park Jeong-yeol of the Department of Obstetrics and Gynecology at Asan Medical Center about unmet needs and future treatment strategies for pMMR endometrial cancer.

Professor Park Jeong-yeol of the Department of Obstetrics and Gynecology at Asan Medical Center explained unmet needs and future treatment strategies for pMMR endometrial cancer during an interview with Korea Biomedical Review. (Courtesy of AstraZeneca Korea)

pMMR patients still face unmet needs despite immunotherapy

Question: Immunotherapy has emerged as a key treatment option in endometrial cancer, but unmet needs reportedly remain in the pMMR population. What are the key treatment strategies for these patients?

Answer:

The biggest issue in pMMR patients is that conventional paclitaxel-carboplatin chemotherapy alone does not provide sufficient efficacy. In the past, chemotherapy alone achieved an overall response rate of around 55 percent, a median progression-free survival (PFS) of approximately 7.5 months, and a median overall survival (OS) of about 36 months. Considering current treatment goals, these outcomes remain inadequate.

Subsequent studies showed that adding immunotherapy agents such as durvalumab to chemotherapy reduced the risk of death or recurrence by roughly 25 percent. However, compared with the more than 50 percent reduction observed in dMMR patients, there remains a substantial unmet need to further improve outcomes in the pMMR population.

Immunotherapy remains important even for pMMR patients, but the magnitude of benefit is not as pronounced as in dMMR disease. That is why ongoing efforts are focused on further improving efficacy.

Q: Is the combination therapy with Lynparza gaining attention because the efficacy of immuno-oncology drugs is more limited in pMMR patients than in dMMR patients?

A:

When durvalumab was added to chemotherapy in pMMR patients, the risk of death or recurrence was reduced by 25 percent compared with chemotherapy alone. In the DUO-E trial, adding Lynparza further reduced the risk by 43 percent.

At ESGO 2026, indirect comparison analyses were presented to evaluate whether adding the PARP inhibitor Lynparza to other immunotherapy-based regimens, such as pembrolizumab (Keytruda) or dostarlimab (Jemperli), could improve outcomes further. Since these were indirect comparisons, the results should be interpreted cautiously. Nonetheless, they suggested that combining immunotherapy with a PARP inhibitor may significantly reduce the risk of death or recurrence compared with immunotherapy alone.

Because this was not a head-to-head comparison study, careful interpretation of relative hazard ratios is necessary. Still, the findings are meaningful because they indicate the potential for additional reductions in mortality or recurrence risk with the addition of a PARP inhibitor. In other words, the results provide evidence that combining durvalumab with Lynparza may offer advantages beyond existing immunotherapy-based approaches in pMMR endometrial cancer.

Q: Why could adding the PARP inhibitor Lynparza to immunotherapy create synergy?

A:

In dMMR tumors, PD-L1 inhibition alone -- that is, immunotherapy -- can produce substantial efficacy. Because dMMR tumors have impaired DNA repair mechanisms, they accumulate numerous DNA errors and neoantigens, creating an environment in which immune cells can effectively recognize and eliminate cancer cells. Blocking the tumor’s PD-L1-mediated immune evasion mechanism in this context can therefore generate strong responses with immunotherapy alone.

In contrast, pMMR tumors retain DNA repair function, resulting in fewer DNA errors and fewer neoantigens. This makes it harder for immune cells to recognize and effectively attack the cancer. In such cases, cancer cells evade immune surveillance through PD-L1, and durvalumab helps restore immune activity by blocking this pathway.

Adding the PARP inhibitor Lynparza further inhibits DNA repair, increasing DNA damage within tumor cells. As cancer cells die, more tumor antigens are exposed within the tumor microenvironment, potentially enhancing the efficacy of immunotherapy. Put simply, this strategy may help convert tumors that are poorly recognized by the immune system into more “immune-active” or so-called “hot tumors.”

DUO-E shows meaningful signals in PFS, response durability, and ctDNA reduction

Q: What clinical benefits were observed with the Lynparza-durvalumab combination in pMMR patients in the DUO-E trial?

A:

In the DUO-E trial, the four-drug regimen group -- patients who received initial treatment with durvalumab plus carboplatin and paclitaxel followed by maintenance therapy with Lynparza and durvalumab -- showed the highest overall response rate and longest duration of response.

The most notable finding involved progression-free survival. The Lynparza combination group achieved the longest median PFS. Regarding overall survival, there was no significant difference between the two-drug regimen (initial carboplatin and paclitaxel followed by placebo maintenance) and the three-drug regimen. However, when the two-drug regimen was compared with the Lynparza combination group, the results approached statistical significance and demonstrated clinically meaningful differences.

Although the addition of Lynparza to the three-drug regimen improved efficacy, concerns about toxicity also existed. In practice, rates of grade 3 or higher adverse events and serious adverse events were somewhat higher than with the three-drug regimen alone, but the differences were not substantial. Most adverse events were manageable grade 1 or 2 toxicities.

The treatment discontinuation rate due to adverse events was also low. Notably, the incidence of hematologic malignancies such as acute myeloid leukemia or myelodysplastic syndrome, which are often concerns during maintenance therapy, was 0 percent. Overall, the safety profile showed that adverse events were generally manageable and that the regimen could be continued safely.

Recently, there has also been growing interest in using circulating tumor DNA (ctDNA) testing to evaluate maintenance therapy efficacy and determine whether to continue maintenance treatment. In the DUO-E trial, ctDNA was measured four times: twice during the initial six cycles of chemotherapy and twice during maintenance therapy.

In general, patients with detectable ctDNA at treatment initiation tend to have poorer prognoses. The DUO-E trial evaluated how much ctDNA levels decreased and remained suppressed in the two-drug, three-drug, and Lynparza combination groups.

The results showed that ctDNA levels remained lowest in the Lynparza combination group across the overall population and in both dMMR and pMMR subgroups. Particularly in pMMR patients, ctDNA reductions were greatest and remained well suppressed over time. I believe this suggests that adding a PARP inhibitor may contribute to long-term suppression of recurrence.

Q: Various immunotherapies such as durvalumab, pembrolizumab, and dostarlimab are now used in endometrial cancer. Should these agents be viewed as belonging to the same class? Are there certain patient groups that may benefit more from one approach?

A:

Mechanistically, pembrolizumab and dostarlimab are PD-1 inhibitors, whereas durvalumab is a PD-L1 inhibitor. Looking solely at the immunotherapy agents themselves, it is difficult to say that one is clearly superior in a specific patient population.

However, because immunotherapy alone may be insufficient in pMMR patients, the key question becomes which subgroups could derive greater benefit from adding a PARP inhibitor.

In the DUO-E trial, the efficacy of the three-drug regimen and the Lynparza combination regimen was assessed by biomarker. While the three-drug regimen demonstrated benefit overall, some subgroups showed even greater benefit with the Lynparza combination.

For example, stronger efficacy signals were observed in patients with serous histology, as well as in those with biomarkers such as p53 mutations, PD-L1 positivity, and homologous recombination repair (HRR) or BRCA mutations associated with homologous recombination deficiency (HRD). In these populations, adding a PARP inhibitor may maximize therapeutic benefit.

Professor Park Jeong-yeol (Courtesy of AstraZeneca Korea)

Q: What did the indirect comparison analysis presented at ESGO 2026 show?

A:

Within the DUO-E trial itself, direct comparisons could be made between immunotherapy alone and immunotherapy combined with a PARP inhibitor. Naturally, questions then arose about whether adding a PARP inhibitor to pembrolizumab- or dostarlimab-based regimens could also improve outcomes.

To address this, indirect treatment comparison analyses were conducted. Researchers first selected patients from each clinical trial who met criteria similar to those used in DUO-E, and then adjusted for differences between patient populations using propensity score weighting methods. This approach aims to align patient characteristics across separate clinical studies -- including DUO-E, pembrolizumab trials, and dostarlimab trials -- as closely as possible before comparing treatment effects.

For instance, even when selecting comparable patient populations from DUO-E and the RUBY trial of dostarlimab, baseline characteristics remained different. DUO-E included approximately 30 percent Asian patients, whereas the RUBY trial included only around 3 percent. Propensity score weighting was used to adjust for such differences and create more comparable cohorts.

Researchers then calculated PFS hazard ratios for the treatment and control groups within the adjusted DUO-E and RUBY cohorts and compared the relative hazard ratios across studies. A relative hazard ratio below 1 would suggest that adding a PARP inhibitor may represent a more effective strategy.

The analysis showed hazard ratios of 0.64 and 0.66 for the Lynparza-durvalumab combination compared with the dostarlimab and pembrolizumab trials, respectively. These findings suggest potential reductions of 36 percent and 34 percent in the risk of death or recurrence.

However, the study did not conclude that the durvalumab-Lynparza combination is superior to pembrolizumab or dostarlimab. Rather, the indirect comparison suggests the possibility of additional benefit when Lynparza is added to immunotherapy.

The paper also noted that these indirect comparison analyses reinforce previous findings that the Lynparza-durvalumab combination may be more effective than durvalumab alone in pMMR patients. Nevertheless, the limitations inherent to indirect comparison analyses require careful interpretation.

Q: Have you had experience using the Lynparza-durvalumab combination in real-world clinical practice?

A:

We have several stage IVB patients who continue to maintain complete remission. However, since Lynparza was approved and introduced into clinical practice for endometrial cancer only in 2024, even the patients treated the longest have received therapy for just over a year.

We have seen a number of patients achieve meaningful clinical benefit, and they have generally tolerated treatment well without severe adverse events. I understand that long-term follow-up results will be presented soon, and I am hopeful that the outcomes will be positive.

Q: While you mentioned that there are no major safety concerns, are there any aspects that still require close monitoring?

A:

Although the Lynparza-durvalumab combination demonstrated synergistic efficacy, the adverse events were consistent with the known safety profiles of the individual drugs. No new safety signals emerged. Therefore, toxicity management is not substantially different from what clinicians already handle with existing immunotherapies or PARP inhibitors.

In summary, adverse event rates may be slightly higher, but most toxicities were already well recognized and manageable as low-grade events. The rate of treatment discontinuation due to adverse events was also low, suggesting that the regimen is generally sustainable in clinical practice.

Q: Any final message for patients with endometrial cancer?

A:

In endometrial cancer treatment, I believe the most important point is to use immunotherapy in the first-line setting regardless of biomarker status, whether dMMR or pMMR. In patient groups expected to gain additional benefit -- especially those with pMMR disease -- adding a PARP inhibitor is also important.

Using the most effective treatment from the beginning may offer the best chance of cure while also improving progression-free survival and quality of life. Therefore, selecting the most effective first-line therapy is critical.

Cost is also an issue. It appears that the government is increasingly willing to expand reimbursement for therapies with clearly demonstrated efficacy. The Ministry of Health and Welfare has been holding multiple related discussions, so I am hopeful that reimbursement policies will improve. I also hope patients do not lose hope.

Hong Sook