Best of ESMO 2024: gynecologic cancers

PARP inhibitors (PARPi) have shown significant benefits in the treatment of high-grade serous ovarian cancer (HGSOC), particularly in patients with homologous recombination deficiency (HRD), as this subgroup experiences improved progression-free survival due to heightened sensitivity to DNA repair inhibition. In contrast, the benefit of PARPi is less pronounced in homologous recombination-proficient (HRP) tumors, highlighting the importance of HRD status in guiding treatment decisions and optimizing therapeutic outcomes.

Final overall survival (OS) data from the phase III PRIMA/ENGOT-OV26/GOG-3012 trial was presented at ESMO 2024 and demonstrated that niraparib significantly prolonged progression-free survival (PFS) in patients with newly diagnosed advanced ovarian cancer responding to first-line platinum-based chemotherapy, regardless of HRD status [7]. Final OS results, assessed after 60% maturity, showed no significant difference between niraparib (n = 487) and placebo (n = 246) in the overall population (hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.84–1.23; P = 0.8834). Subgroup analysis revealed OS HRs of 0.95 (95% CI 0.70–1.29) in the HRD population and 0.93 (95% CI 0.69–1.26) in the HR-proficient group. Subsequent PARPi therapy was more common in placebo-treated patients, with rates of 37.8% versus 11.7% in the overall population and 48.4% versus 15.8% in the HRD subgroup. At 5 years, PFS numerically favored niraparib, with rates of 22% versus 12% in the overall population and 35% versus 16% in the HRD subgroup. The incidence of myelodysplastic syndromes/acute myeloid leukemia was low (< 2.5%), and no new safety signals emerged.

In conclusion, while OS was comparable between arms, niraparib doubled the likelihood of 5‑year PFS in HRD patients. Long-term safety remained consistent with niraparib’s established profile. In a personalized treatment approach patient and tumor factors such as HRD status and response to platinum-based chemotherapy should be considered.

Immune checkpoint inhibitors have been approved for advanced (locoregional extension and residual disease after surgery), recurrent, and metastatic endometrial cancer in combination with chemotherapy followed by immune checkpoint inhibitor maintenance treatment with or without addition of PARPi therapy ([2] Esander R, et al. NEJM 2023; Westin SN, et al. JCO 2023). Pembrolizumab plus chemotherapy provides benefit as first-line therapy for mismatch repair-proficient (pMMR) and mismatch repair-deficient (dMMR) endometrial cancer, with greater magnitude of benefit in the dMMR phenotype. The phase III ENGOT-en11/GOG-3053/KEYNOTE-B21 study (ClinicalTrials.gov identifier: NCT04634877) evaluated the addition of pembrolizumab to adjuvant chemotherapy with or without radiation therapy among patients with newly diagnosed, high-risk endometrial cancer without any residual macroscopic disease following curative-intent surgery. Adjuvant pembrolizumab plus chemotherapy did not improve DFS in patients with newly diagnosed, high-risk, all-comer endometrial cancer.

At ESMO 2024 a protocol-specified subgroup analysis of patients with dMMR tumors from ENGOT-en11/GOG-3053/KEYNOTE-B21 study (ClinicalTrials.gov identifier: NCT04634877) in newly diagnosed, high-risk endometrial cancer (EC) after surgery with curative intent was presented and published subsequently ([3] Slomowitz BM, et al. JCO 2024). Patients were randomized to receive pembrolizumab 200 mg or placebo (six cycles) in combination with carboplatin–paclitaxel (four to six cycles) every 3 weeks, followed by pembrolizumab 400 mg or placebo every 6 weeks (six cycles). MMR status was a stratification factor, and radiotherapy was administered at the investigator’s discretion. The primary endpoint was investigator-assessed disease-free survival (DFS). No formal hypothesis testing was conducted for the subgroup analysis. In the intention-to-treat population, 141 patients in the pembrolizumab group and 140 in the placebo group had dMMR tumors. At this interim analysis, the hazard ratio for DFS favored pembrolizumab (HR 0.31; 95% CI 0.14–0.69). Median DFS was not reached in either group, with 2‑year DFS rates of 92.4% (95% CI 84.4–96.4) for pembrolizumab and 80.2% (95% CI 70.8–86.9) for placebo. No new safety signals were observed. Preplanned subgroup analysis based on stratification factors supports pembrolizumab plus chemotherapy as a clinically relevant treatment for patients with dMMR tumors in the curative-intent setting, with further outcomes to be evaluated at final analysis. The results of the prespecified subgroup analysis supports the use of checkpoint inhibitor treatment in dMMR tumors.

Antibody–drug conjugates (ADCs) are emerging as a promising therapeutic approach in endometrial cancer, particularly in advanced or recurrent cases with limited treatment options. By delivering cytotoxic agents directly to tumor-specific targets, ADCs have shown potential in improving efficacy while minimizing systemic toxicity, with ongoing trials evaluating their role in this malignancy. In endometrial cancer, ADCs targeting trophoblast cell surface antigen 2 (TROP2) and HER2 have shown promising results in early trials and are being investigated in phase 3 trials (NCT06132958, NCT05382268).

Pembrolizumab treatment in combination with chemotherapy and bevacizumab has been the standard treatment for recurrent and metastatic cervical cancer. The phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study evaluated the addition of pembrolizumab to chemoradiotherapy in patients with locally advanced cervical cancer. At the second interim analysis, the study demonstrated a statistically significant improvement in OS. Results were presented at the ESMO 2024 conference and published [1]. Patients with high-risk FIGO 2014 stage IB2–IIB node-positive or stage III–IVA disease were randomized 1:1 to pembrolizumab or placebo combined with chemoradiotherapy, followed by maintenance therapy.

These findings confirm an OS benefit when pembrolizumab is added to chemoradiotherapy, supporting its adoption as a new standard of care for high-risk locally advanced cervical cancer. The study underscores the efficacy and manageable safety of this immunochemoradiotherapy approach. Approval was recently granted by Food and Drug Administration (FDA) and European Medicines Agency (EMA) for use of pembrolizumab in addition to chemoradiotherapy in FIGO stage III–Iva cervical cancer.

Antibody–drug conjugates (ADCs) represent a novel therapeutic strategy in cervical cancer, targeting tumor-specific antigens to deliver cytotoxic agents directly to cancer cells. Clinical trials have demonstrated encouraging efficacy in advanced or recurrent cervical cancer, particularly in cases resistant to standard treatments, with manageable safety profiles. Tisotumab–vedotin an ADC directed against tissue factor has recently been approved by the FDA for the treatment of recurrent cervical cancer [6]. Additional targets of interest include TROP2 and have been investigated as monotherapy or in combination with pembrolizumab in early trials. Phase 3 trials are currently being conducted.