Durvalumab and olaparib with chemotherapy improve progression-free survival in first-line metastatic endometrial cancer: a new promising combination strategy?

Endometrial cancer (EC) represents the sixth most common cancer among women, and the most common gynaecological tumour in high-income countries, accounting for 4.5% of all new cancer diagnoses. EC incidence is expected to rise by around 40% in the next 20 years, with a relevant impact on the worldwide female population. Around 1 out of 5 patients with EC is diagnosed in an advanced stage, with a dismal prognosis (1). The current standard of care for the first-line metastatic setting is the combination of carboplatin and paclitaxel (CP). Immune checkpoint inhibitors (ICIs) have been recently authorized by the Regulatory Agencies after platinum progression depending on mismatch repair genes (MMR)/microsatellite (MS) status: as single agents in deficient MMR (dMMR), whereas the combination of pembrolizumab plus lenvatinib has been approved regardless of MMR/MS status (1,2).

Westin et al. presented the results of the randomized phase III DUO-E/GOG34 3041/ENGOT-EN10 study (NCT04269200), assessing the efficacy of the anti-programmed death-ligand 1 (PD-L1) durvalumab added to standard first-line CP and used in maintenance, either alone or with the Poly (ADP-ribose) polymerases (PARP) inhibitor (PARPi) olaparib (3,4). No maintenance strategy nor first-line combination with ICIs was approved for EC at the time of this study design.

In the DUO-E trial, patients with measurable FIGO stage III/newly diagnosed stage IV or recurrent EC were randomized in three arms:

• CP + placebo (PBO)/durvalumab followed by maintenance PBO/durvalumab + PBO/olaparib;
• CP + durvalumab followed by maintenance durvalumab + PBO/olaparib;
• CP + durvalumab followed by maintenance durvalumab + olaparib.

The progression-free survival (PFS) was assessed as a dual primary endpoint for CP + durvalumab vs. CP and CP + durvalumab + olaparib vs. CP in the intention-to-treat (ITT) population. Overall survival (OS) was a secondary endpoint. Patients were stratified for MMR status, and planned subgroup analyses were performed: DUO-E authors planned a pre-specified exploratory analysis comparing CP + durvalumab + olaparib and CP + durvalumab. 718 patients were enrolled.

After a median follow-up (mFU) of 15.4 months, the addition of durvalumab to CP significantly improved median PFS (mPFS) compared to CP alone in the ITT population [10.2 vs. 9.6 months; hazard ratio (HR) 0.71; 95% confidence interval (CI): 0.57–0.89; P=0.003]. Moreover, adding olaparib to durvalumab and CP further improved mPFS to 15.1 vs. 9.6 months (HR 0.55; 95% CI: 0.43–0.69; P<0.0001). Subgroup analyses based on MMR status showed PFS benefits in dMMR patients of CP + durvalumab and CP + durvalumab + olaparib compared to CP alone (mPFS NR and 31.8 months, respectively, vs. 7.0 months). In proficient MMR (pMMR) patients there was also a more robust benefit with CP + durvalumab + olaparib (mPFS 15.0 months) compared to CP (9.7 months), than with CP + durvalumab (mPFS 9.9 months).

Even if direct comparisons between CP + durvalumab + olaparib and CP + durvalumab arms were not planned by the study, adding olaparib to CP + durvalumab did not seem to confer a consistent additional benefit in the dMMR subgroup (HR 0.42 vs. 0.41, 12-month PFS rate 70.0% vs. 67.9%, and 18-month PFS rate 62.7% vs. 67.9%). On the contrary, there was a consistent benefit in the pMMR subgroup with a reduction of the PFS-HR (0.57 vs. 0.77), and a PFS advantage at 12 (59.4% vs. 44.4%) and 18 months (42.0% vs. 31.3%). Safety profiles were in line with individual treatment components. Interim OS data showed a trend towards benefit for both combination arms compared to CP alone (P=0.12 with CP + durvalumab versus CP; HR, 0.77; P=0.003 with CP + durvalumab + olaparib vs. CP; HR, 0.59; however, only 27.7% of OS data were available at the interim analysis).

The authors concluded that the DUO-E study met its primary endpoints, demonstrating significant and clinically meaningful PFS improvement by adding durvalumab to standard chemotherapy followed by maintenance therapy with durvalumab ± olaparib compared to CP alone (3). The study design appears robust, with clear primary endpoints and a well-defined patient population. The trend towards improved OS is encouraging but needs further validation with mature data. No safety concerns emerged, as expected. Different combination strategies are under investigation in naïve metastatic EC patients, and studies investigating the combination of PARPis and ICIs are showing promising results in early-phase trials. The randomized phase III ENGOT79 EN6/GOG-3031/NSGO-CTU-RUBY (NCT03981796) trial (part 2) evaluated the efficacy and safety of the anti-programmed death-1 (PD-1) dostarlimab plus CP followed by dostarlimab + the PARPi niraparib versus CP + PBO followed by PBO, in a similar population to DUO-E (5). The trial met its primary endpoint with a statistically significant and clinically meaningful PFS improvement for the overall patient population and the pMMR/MSS subpopulation. Of note, this result is in line with the DUO-E trial. DUO-E OS data are currently immature (4).

The combination of such agents aims to exploit the synergistic effects in targeting cancer cells and improving the immune response against tumors, by enhancing DNA damage response, inducing immunogenic cell death, releasing tumor-associated antigens and danger signals, and modulating the tumor microenvironment: PARPis have been shown to increase the expression of PD-L1, making cancer cells more susceptible to ICIs (3,6). EC is one of the tumor subtypes 3 with the highest rate of dMMR/microsatellite instability (MSI) (around 15–30%). Indeed, the MMR/MS status plays a prognostic role in survival and is very useful for screening Lynch syndrome. First-line studies of ICIs plus CP combination show a good response to ICI-based combinations for dMMR/MSI patients (7). Still, data on the combination of ICIs and PARPis were not available before the DUO-E trial and indeed should be further elucidated in this setting.

In PD-L1 positive patients, a PFS benefit emerged with durvalumab compared to control (HR, 0.63), and durvalumab + olaparib versus control. No other biomarkers have been explored in this study, such as breast cancer gene (BRCA)1/2 or homologous repair recombination (HRR) gene mutations, and overall molecular classification by The Cancer Genome Atlas Group (TCGA), which indeed individuates different EC groups, with a proper potential to respond to various treatments (7,8). Small proportions of the participants in the DUO-E and the other published studies are reported to have HRR alterations; however, further investigation is needed to better understand the interplay between HRR and MMR alterations, and the potential synergy of treatment strategies that target these pathways. Finally, no data for sequencing strategies can be retrieved from the published abstract, as subsequent therapeutic options were not indicated in the published abstract, but it would be of interest to investigate the post-immunotherapy and post-PARPis setting. In conclusion, the DUO-E study underscores the importance of exploring novel treatment approaches, such as the combination of PARPis and ICIs, to improve outcomes for advanced EC patients, candidating such strategy as a potential game-changer for treating this disease (3,4). More results from ulterior trials and a longer follow-up are awaited with interest.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gynecology and Pelvic Medicine. The article has undergone external peer review.

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-22/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-22/coif). The authors have no conflicts of interest to declare.

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