GSK's Mo-Rez Shows Promising Phase 1 Data in Ovarian and Endometrial Cancers

GSK's Mo-Rez Shows Strong Phase 1 Efficacy in Ovarian and Endometrial Cancers

GSK's novel antibody-drug conjugate (ADC) mocertatug rezetecan (Mo-Rez), targeting B7-H4, demonstrated encouraging results in its Phase 1 BEHOLD-1 dose-escalation trial. The drug achieved a confirmed objective response rate (cORR) of 62% in patients with platinum-resistant ovarian cancers (PROC) and 67% in those with endometrial cancer. These findings, presented at the Society for Gynecological Oncology’s annual meeting, also indicated initial signs of good durability. GSK plans to initiate five Phase 3 trials for Mo-Rez this year across both ovarian and endometrial cancer indications.

• In the BEHOLD-1 dose-escalation trial, Mo-Rez achieved a confirmed objective response rate (cORR) of 62% in patients with platinum-resistant ovarian cancers (PROC) and 67% in those with endometrial cancer. These positive efficacy signals were accompanied by initial indications of promising durability, suggesting a sustained clinical benefit for patients in these difficult-to-treat gynecological malignancies.
• Mo-Rez is a novel antibody-drug conjugate (ADC) that specifically targets the B7-H4 antigen, which is overexpressed in the vast majority of ovarian cancer cells, making it an attractive therapeutic target. The ADC carries a topoisomerase inhibitor payload, designed to deliver potent cytotoxic effects directly to cancer cells expressing B7-H4, thereby minimizing off-target toxicities and enhancing therapeutic efficacy.
• Following the encouraging Phase 1 data, GSK is significantly advancing the development of Mo-Rez by launching five new Phase 3 trials this year. These trials will evaluate Mo-Rez across both ovarian and endometrial cancers, including specific studies like BEHOLD-Ovarian01 for PROC and BEHOLD-Ovarian02 for platinum-sensitive ovarian cancer, underscoring the company's commitment to addressing unmet needs in these indications.

Recent Approvals Reshape the Platinum-Resistant Ovarian Cancer Landscape

Over the past five years, the ovarian cancer treatment landscape has undergone substantial transformation, driven primarily by the expanded role of PARP inhibitors (PARPi) in first-line maintenance therapy. Olaparib, niraparib, and rucaparib have been evaluated across multiple phase 2 and phase 3 trials, establishing PARPi as the standard of care in the maintenance setting. Landmark trials including PRIMA (niraparib), PAOLA (olaparib), and ATHENA-MONO (rucaparib) demonstrated meaningful progression-free survival (PFS) benefits, with niraparib achieving a median PFS of 21.0 months and rucaparib 12.8 months in the treatment setting. Real-world data from a multicenter Turkish cohort of 179 patients (January 2014–March 2025) corroborated these findings, reporting overall PFS rates of 91.0%, 83.0%, and 64.0% at 6, 12, and 24 months respectively, with no cases of myelodysplastic syndrome or acute myeloid leukemia observed. Across all trials and real-world datasets, BRCA-mutant status, R0 resection, FIGO stage III disease, and higher CA-125 elimination rate constant (KELIM >1) emerged as independent predictors of prolonged PFS. Importantly, overall survival data from PRIMA and PAOLA are now available, further informing long-term benefit assessments.

Beyond PARPi, antiangiogenic and combination immunotherapy strategies have continued to evolve with mixed but notable results. Bevacizumab-based regimens — evaluated in a systematic review of seven RCTs encompassing 5,110 patients — demonstrated a statistically significant improvement in PFS (HR: 0.73; 95% CI: 0.58–0.92; p=0.008) when combined with carboplatin and paclitaxel, though no overall survival benefit was observed. A triplet maintenance regimen of bevacizumab plus olaparib and durvalumab was associated with longer PFS than bevacizumab alone in patients without tumor BRCA mutations, suggesting a potential niche for combination approaches in biomarker-unselected populations. In the platinum-resistant setting — where recent trials have largely yielded negative outcomes since bevacizumab's original approval in combination with chemotherapy — low-dose lenvatinib (8 or 12 mg daily) combined with anti-PD-1 therapy demonstrated an objective response rate of 46.7% (95% CI 21.3%–73.4%) and a median PFS of 4.1 months in heavily pre-treated patients (median three prior lines), with no grade 4 or 5 adverse events reported. Pembrolizumab monotherapy, evaluated in a pooled analysis of 617 patients, yielded an ORR of 24% and median OS of 13.54 months, with response rates showing no statistically significant difference between PD-L1-positive and PD-L1-negative subgroups.

Surgical and biomarker-guided strategies have also gained renewed attention as determinants of outcome. Pafolacianine, a folate receptor-targeted intraoperative near-infrared imaging agent evaluated in a phase 3, 11-center study, identified additional cancer in 33.0% of patients (95% CI: 24.3–42.7; p<0.001) on tissue not planned for resection and undetected by standard white-light assessment, with a sensitivity of 83% for ovarian cancer detection. In parallel, homologous recombination deficiency (HRD) testing has become increasingly central to treatment selection, with HRD positivity rates declining with advancing patient age — from 36.2% in patients under 50 years to 24.2% in those aged 70 and above (p<0.0001). Chemotherapy modifications, occurring in 44.8% of patients in one real-world cohort, were associated with significantly worse OS and PFS even after adjustment for prognostic factors, underscoring the clinical importance of tolerability management. Collectively, these data reflect a field moving toward increasingly biomarker-stratified, combination-based, and surgically optimized treatment paradigms.

Novel Candidates and Early Clinical Wins in Ovarian Cancer

Recent clinical and real-world evidence in ovarian cancer spans a broad spectrum — from immune checkpoint inhibition and PARP inhibitor optimization to surgical intensification and novel cell-based therapies. The studies highlighted below reflect meaningful advances across treatment lines, with several offering practice-changing or hypothesis-generating findings for both BRCA-mutated and unselected populations.

• ENGOT-ov65/KEYNOTE-B96 Trial — Evaluating pembrolizumab plus weekly paclitaxel in platinum-resistant recurrent ovarian cancer, this Phase 3 trial delivered the first statistically significant overall survival improvement with an immune checkpoint inhibitor in this setting, establishing the combination as a new standard of care for platinum-resistant recurrent disease.

• Pembrolizumab Monotherapy Meta-Analysis (2025) — A pooled analysis of nine studies (625 patients; 617 efficacy-evaluable, 592 safety-evaluable) assessed pembrolizumab monotherapy in advanced or recurrent ovarian cancer. Pooled ORR was 24% (95% CI 0.13–0.35), DCR 63% (95% CI 0.49–0.77), mPFS 4.82 months (95% CI 3.29–6.35), and mOS 13.54 months (95% CI 10.35–16.73). ORR was 24% in PD-L1-positive and 18% in PD-L1-negative subgroups, with no statistically significant difference between the two. The 200 mg q3w regimen yielded a higher ORR (26%) than the 10 mg/kg q2w schedule (12%). Any-grade adverse reactions occurred in 81% of patients; grade ≥3 events were reported in 32%, reflecting an acceptable safety profile.

• NCT04611126 — TIL Therapy with PD-1/LAG-3 Inhibition (2026) — This early-phase study evaluated tumor-infiltrating lymphocyte (TIL) therapy combined with up to four cycles of dual PD-1/LAG-3 inhibition in five patients with platinum-resistant recurrent ovarian cancer (including HGSOC and LGSOC). Tumor burden decreased in 80% (4/5) of patients, with two unconfirmed partial responses; one response was corroborated by in vitro reactivity of infused TILs against the autologous tumor cell line. Treatment was safe and feasible with expected treatment-related toxicity, though a relatively high rate of non-treatment-related complications was noted. Results are considered hypothesis-generating, supporting the rationale for larger trials.

• Olaparib Dose Reduction Retrospective Analysis (2026) — This real-world analysis of 87 patients with BRCA-mutated platinum-sensitive recurrent ovarian cancer (2019–2022) examined the oncological impact of olaparib dose modifications across three groups: 600 mg (standard), 500 mg (reduction level 1), and 400 mg (reduction level 2). Median PFS was 27, 28, and 32 months respectively (HR 1.587, 95% CI 0.673–2.744, p = 0.323); median OS was 44, 52, and 43 months respectively (HR 0.737, 95% CI 0.413–1.317, p = 0.296). Dose reduction did not adversely affect oncological outcomes. Grade ≥3 adverse events occurred in 4.7% of the standard-dose group, with fatigue (35.7%) and nausea (33.3%) as the most common any-grade toxicities, supporting dose reduction as a viable management strategy for treatment-related adverse events.

• Multicenter Retrospective Study of First-Line Maintenance PARPi — Olaparib vs. Niraparib (2026) — Conducted across 33 centers in Türkiye (January 2014–March 2025), this 179-patient study evaluated first-line maintenance olaparib (n = 110) or niraparib (n = 69) in newly diagnosed epithelial ovarian cancer (88.3% BRCA-mutant). With a median follow-up of 16.5 months, median PFS was not reached; estimated PFS for the overall cohort was 91.0%, 83.0%, and 64.0% at 6, 12, and 24 months respectively. In BRCA-mutant patients, olaparib yielded PFS rates of 89%, 78%, 73%, and 64% at 6, 12, 18, and 24 months; niraparib achieved 87% and 75% at 6 and 12 months. Patients with pathogenic (vs. likely pathogenic) BRCA variants experienced longer PFS. Any-grade adverse events occurred in 73.7% of patients; grade 3–4 events in 29.6%, predominantly hematologic. Dose interruptions were more frequent with niraparib, though discontinuation rates were low in both cohorts. No cases of MDS or AML were observed.

• Prognostic Nomogram Study for First-Line PARPi Maintenance (2026) — This retrospective cohort of 145 advanced epithelial ovarian cancer patients receiving first-line PARP inhibitor maintenance therapy (August 2018–May 2024) achieved a median PFS of 48.53 months. Independent prognostic factors for prolonged PFS were BRCA mutations, R0 resection, FIGO stage III (vs. IV), and a CA-125 elimination rate constant (KELIM) score >1. BRCA mutation status and younger age independently predicted better OS. Notably, longer PARPi duration (>12 months) appeared associated with poorer prognosis in subsequent lines of therapy, and platinum-based second-line chemotherapy combined with bevacizumab improved outcomes in the recurrent setting.

• ROSELLA Trial — Investigating glucocorticoid receptor modulation as a novel therapeutic mechanism in ovarian cancer, this trial demonstrated remarkable efficacy, representing an emerging mechanistic approach in the ovarian cancer treatment landscape.

• REJOICE-Ovarian01 Trial — Evaluating cadherin-6-targeted antibody-drug conjugates, this trial also demonstrated remarkable efficacy, reinforcing the growing interest in ADC-based strategies for ovarian cancer.

Designing Trials for Differentiation in Ovarian Cancer's Crowded Pipeline

Clinical trial design in ovarian cancer has evolved considerably, with endpoint selection representing one of the most consequential—and contested—decisions in late-phase development. Across key trials, progression-free survival (PFS) and overall survival (OS) remain the dominant efficacy endpoints, though each carries distinct feasibility and interpretive challenges in a disease defined by long natural history, active post-progression therapy sequences, and a substantial proportion of asymptomatic patients.