PRISM Clinical Insights

The phase III DUO-E trial's findings on the efficacy of durvalumab plus carboplatin/paclitaxel, followed by maintenance durvalumab with or without olaparib in advanced or recurrent endometrial cancer, represent a significant advancement in the treatment landscape of this malignancy. To contextualize these results, it's essential to compare them against the backdrop of current standard treatments as per the latest clinical guidelines, which predominantly include surgery, radiation therapy, and chemotherapy with agents such as carboplatin and paclitaxel. Targeted therapies and immunotherapies have been emerging as promising approaches, but their integration into first-line treatment has been an area of active research.

The DUO-E trial's use of durvalumab, an immune checkpoint inhibitor, in combination with chemotherapy (carboplatin/paclitaxel) and the potential addition of olaparib, a PARP inhibitor, indicates a shift towards a more personalized and targeted approach in endometrial cancer treatment. The reported hazard ratios (HRs) for progression-free survival (PFS) – 0.71 for durvalumab and 0.55 for durvalumab + olaparib – are particularly noteworthy. These figures suggest a substantial improvement in PFS compared to the control arm, indicating a potential paradigm shift in the management of this disease.

To understand the magnitude of this advancement, it is instructive to compare these results with seminal studies that have defined current treatment standards. For instance, the GOG-0218 trial (1), which evaluated the addition of bevacizumab to standard chemotherapy in ovarian cancer, a related gynecologic malignancy, reported a modest improvement in PFS. The ICON7 trial (2) further substantiated the role of bevacizumab in ovarian cancer. In endometrial cancer specifically, studies like GOG-258 (3) have explored the efficacy of combining chemotherapy and radiation therapy, offering insights into multimodal treatment approaches. The PORTEC-3 trial (4), which investigated the addition of chemotherapy to radiotherapy, provided further evidence in this regard. More recently, the KEYNOTE-775 study (5), evaluating pembrolizumab and lenvatinib in advanced endometrial cancer, marked a significant step towards integrating immunotherapy into treatment regimens.

The effect sizes observed in the DUO-E trial surpass those typically seen in these foundational studies. The improved PFS in both the MMR-deficient and MMR-proficient subgroups is particularly compelling, as it suggests the potential for broad applicability of this regimen across different genetic profiles of endometrial cancer. This could lead to a reevaluation of first-line treatment strategies, emphasizing the role of immunotherapy and targeted agents alongside traditional chemotherapy.

In summary, the DUO-E trial's findings could herald a new era in the management of advanced or recurrent endometrial cancer. The substantial PFS benefit observed with the combination of durvalumab, carboplatin/paclitaxel, and possibly olaparib, marks a significant leap from the traditional chemotherapy-based approaches. These results could reshape clinical guidelines, favoring a more personalized and multimodal treatment strategy that integrates immunotherapy and targeted therapies from the outset.

References

  1. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473-83.

  2. Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365(26):2484-96.

  3. Matei D, Filiaci V, Randall ME, Mutch D, Steinhoff MM, DiSilvestro PA, et al. Adjuvant Chemotherapy plus Radiation for Locally Advanced Endometrial Cancer. N Engl J Med. 2019;380(24):2317-26.

  4. de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, et al. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(3):295-309.

  5. Makker V, Colombo N, Casado Herráez A, Santin AD, Colomba E, Miller DS, et al. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022;386(5):437-48.