Importance Advanced clear cell gynecological cancers (CCGCs) have a poor prognosis, with response rates to second-line chemotherapy less than 8%. Preliminary clinical activity with programmed cell death 1 protein (PD-1) inhibitors reported in CCGC merits further investigation. Objective To assess the clinical benefit of pembrolizumab in patients with previously treated advanced CCGC. Design, Setting, and Participants The PEACOCC trial is a single-arm multicenter phase 2 trial conducted at 5 UK centers investigating the clinical benefit and safety of pembrolizumab. PD-1 inhibitor-naive patients with histologically confirmed advanced CCGC, radiological disease progression following 1 or more prior courses of chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 to 1 were included. Patients were enrolled from March 2019 to October 2021, with data collected until July 2024. Interventions Pembrolizumab, 200 mg, intravenously every 21 days up to 2 years until progression, discontinuation due to toxic effects, or patient/clinician decision. Up to 1 year of retreatment on diseases progression, if stable disease, partial response, or complete response at 2 years. Main Outcomes and Measures The primary end point was progression-free survival (PFS) rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 to detect a 12-week PFS rate of 33% or greater and exclude a PFS rate of less than 15%, with 90% power and 1-sided 5% significance level. Secondary end points included objective response rate, duration of response, PFS, overall survival, safety, and quality of life. Results A total of 48 patients were eligible. The median (range) age was 58.5 (32-77) years, and 26 (54%) had an ECOG PS score of 0 and 22 (46%) had an ECOG PS score of 1; 41 (85%) had ovarian, 6 (13%) had endometrial, and 1 (2%) had cervical advanced CCGC. The median (range) courses prior therapy was 3 (1-6); 19 patients (40%) received prior anti-angiogenic therapy, and 19 (40%) had a platinum-free interval of more than 12 months. Grade 3 treatment-related adverse events were observed in 9 patients (19%), and no patients had grade 4 or 5 adverse events. A total of 45 of 46 patients (98%) had mismatch repair-proficient tumors. The 12-week PFS rate was 42% (95% CI, 28-57), and the best objective response rate was 25% (95% CI, 14-40), with 12 partial responses. After a median follow-up of 46.9 months (95% CI, 43.4-55.0), the median PFS was 2.7 months (95% CI, 1.3-5.4), and the median overall survival was 14.8 months (95% CI, 6.7-28.2). Conclusions and Relevance The PEACOCC trial showed clinical benefit with pembrolizumab in patients with previously treated advanced CCGC, of whom all except 1 had MMR-proficient disease. Clinical outcomes were durable with an overall tolerable safety profile, justifying further evaluation of pembrolizumab monotherapy for advanced CCGC in a randomized clinical trial.

OBJECTIVES:Low-grade serous ovarian carcinoma (LGSOC) is a distinct, rare, ovarian cancer type characterised by younger patient age and intrinsic chemoresistance. Understanding the molecular landscape is crucial for optimising targeted therapy. METHODS:Genomic data from whole exome sequencing of tumour tissue was analysed in a LGSOC cohort with detailed clinical annotation. RESULTS:63 cases were analysed and three subgroups identified based on single nucleotide variants: canonical MAPK mutant (cMAPKm: 52%, KRAS/BRAF/NRAS), MAPK-associated gene mutation (MAPK-assoc: 27%) and MAPK wild-type (MAPKwt: 21%). NOTCH pathway disruption occurred across all subgroups. Tumour mutational burden (TMB), mutational signatures and recurrent copy number (CN) changes varied across the cohort with co-occurrence of chromosome 1p loss and 1q gain (CN Chr1pq) a recurrent feature. Low TMB and CN Chr1pq were associated with inferior disease-specific survival (HR 6.43; p < 0.001 and HR 3.29, p = 0.011 respectively). Stepwise genomic classification in relation to outcome resulted in four groups (TMB low; CN Chr1pq; MAPKwt/MAPKassoc; cMAPKm). 5 year disease-specific survival was 46%, 55%, 79% and 100% respectively for these groups. The two most favourable genomic subgroups were enriched for the SBS10b mutational signature, particularly the cMAPKm subgroup. CONCLUSIONS:LGSOC comprises multiple genomic subgroups with distinct clinical and molecular features. Chr1pq CN arm disruption and TMB represent promising methods to identify individuals with poorer prognosis. Further investigation of the molecular basis for these observations is required. MAPKwt cases represent around a fifth of patients. NOTCH inhibitors represent a candidate therapeutic strategy worthy of exploration across these cases.

Low grade serous ovarian carcinoma (LGSOC) demonstrates unique clinical and molecular features compared to other ovarian cancer types. The relationship between common histological features of LGSOC and molecular events, such as hormone receptor expression patterns and MAPK gene mutation status, remains poorly understood. Recent data suggest some of these molecular features may be biomarkers of response to recently introduced biologically-targeted therapies, namely endocrine therapy and MEK inhibitors. We utilize a cohort of 63 pathologically-confirmed LGSOC cases with whole exome sequencing and hormone receptor expression data to investigate these relationships. LGSOC cases demonstrated uniformly high oestrogen receptor (ER) expression, but variable progesterone receptor (PR) expression intensity. 60% and 37% of cases demonstrated micropapillary and macropapillary patterns of stromal invasion, respectively. 63% of cases demonstrated desmoplasia, which was significantly associated with advanced disease stage and visible residual disease after cytoreductive surgery. MAPK-mutant cases (KRAS, BRAF, NRAS) more frequently demonstrated macropapillary stromal invasion, while Chr1p loss was associated with desmoplasia and low PR expression. Presence of micropapillary stromal invasion and low PR expression were associated with significantly poorer survival after accounting for stage and residual disease status. Together, these data identify novel relationships between histopathological features and molecularly-defined subgroups in LGSOC.

Background Low-grade serous ovarian carcinoma (LGSOC) is a distinct, under-investigated and relatively chemotherapy-resistant ovarian cancer type. Understanding the molecular landscape is crucial to maximise the impact of molecularly-targeted therapy. Methods Whole exome sequencing and copy number data were integrated with histopathological patterns, ER/PR expression, and detailed clinical annotation, including survival, in a carefully curated LGSOC cohort. Results 63 tumours were analysed in the largest comprehensive genomic LGSOC study to date. Three genomic subgroups were identified: canonical MAPK mutant (cMAPKm: 52%, KRAS / BRAF / NRAS ), MAPK-associated mutation (27%, 14 MAPK-associated genes) and MAPK wild-type (MAPKwt: 21%). MAPKwt patients were younger at diagnosis (median 47 versus 62 years in the cMAPKm subgroup) and demonstrated shorter survival [multivariable HR (mHR) 4.17]. The inferior survival in the MAPKwt subgroup was due to shorter post-relapse survival (mHR 5.22) rather than shorter time to first progression (mHR 1.15). Patients in the MAPK-associated mutation subgroup had similar survival to cMAPKm cases. The cMAPKm subgroup more frequently demonstrated macropapillary invasion. Desmoplasia and micropapillary invasion were independently associated with poor survival. NOTCH pathway activation occurred independently of MAPK subgroup. Conclusions LGSOC comprises multiple genomic subgroups with distinct clinical, molecular and histopathological features. True MAPKwt cases represent around a fifth of patients: they are younger but have poorer survival. New therapeutic strategies with activity in this subgroup are urgently required. NOTCH inhibitors represent a therapeutic strategy worthy of exploration.

Introduction/Background Advanced clear cell gynaecological cancers (CCGC) have poor prognosis with objective response rates (ORR) to second-line chemotherapy between 0–8%. Preliminary clinical activity with PD-1 inhibitors have been described in CCGC. We investigated pembrolizumab monotherapy for advanced CCGC. Methodology PEACOCC is a Phase II, multicentre, single-arm trial in patients with advanced CCGC who had ≥1 prior line of chemotherapy with progression (PD) at study entry. Pembrolizumab 200 mg iv q21 days was given until PD (RECIST v1.1), unacceptable adverse event (AE), 2 years (y) pembrolizumab completed, patient or clinician decision. Primary endpoint was progression-free survival (PFS) rate at 12 weeks (w) (H0≤15%; H1≥33%; 5% 1-sided α; 90% power). Secondary endpoints included ORR, duration of response (DOR), PFS, overall survival (OS) and safety. Results 49 patients were enrolled with 48 evaluable. Median age 58.5 y (32–77 y), ECOG 0/1 54.2%/45.8%, 85.4% ovarian CCGC. Median number of prior systemic therapy 2 (1–6); 19 patients (39.6%) had received anti-angiogenic therapy. 42 patients completed median of 4 cycles pembrolizumab (1–25), 6 patients (12.5%) continue pembrolizumab. 16.7% patients had Grade(G)3 treatment-related AE (TRAE) of hyperthyroidism, acute kidney injury, raised alanine aminotransferase, raised alkaline phosphatase, anaemia, encephalitis and diabetic ketoacidosis. There were no G4 or G5 TRAE. 3 patients (6.3%) discontinued pembrolizumab due to TRAEs. The PFS rate at 12w was 43.8% (90%CI:31.5–56.6) exceeding the pre-stated lower bound of 15%. Best ORR was 25.0% (90%CI:15.1–37.3) [1 complete, 11 partial], with 1 y DOR rate 47.7% (95%CI:14.1–75.6). After a median follow-up of 2.1 y, median PFS was 12.2w (95%CI:5.9–32.9) and median OS 71.0w (95%CI:29.1–137.6). Conclusion The PEACOCC trial suggests that pembrolizumab is effective in heavily pre-treated patients with advanced CCGC: 43.8% patients were alive and progression-free at 12w. Clinical outcomes were durable with limited toxicity. These promising results justify consideration of pembrolizumab monotherapy as a new standard-of-care for advanced CCGC.

Mucinous ovarian carcinoma (MOC) is a unique form of ovarian cancer. MOC typically presents at early stage but demonstrates intrinsic chemoresistance; treatment of advanced-stage and relapsed disease is therefore challenging. We harness a large retrospective MOC cohort to identify factors associated with recurrence risk and survival. A total of 151 MOC patients were included. The 5 year disease-specific survival (DSS) was 84.5%. Risk of subsequent recurrence after a disease-free period of 2 and 5 years was low (8.3% and 5.6% over the next 10 years). The majority of cases were FIGO stage I (35.6% IA, 43.0% IC). Multivariable analysis identified stage and pathological grade as independently associated with DSS (p < 0.001 and p < 0.001). Grade 1 stage I patients represented the majority of cases (53.0%) and demonstrated exceptional survival (10 year DSS 95.3%); survival was comparable between grade I stage IA and stage IC patients, and between grade I stage IC patients who did and did not receive adjuvant chemotherapy. At 5 years following diagnosis, the proportion of grade 1, 2 and 3 patients remaining disease free was 89.5%, 74.9% and 41.7%; the corresponding proportions for FIGO stage I, II and III/IV patients were 91.1%, 76.7% and 19.8%. Median post-relapse survival was 5.0 months. Most MOC patients present with low-grade early-stage disease and are at low risk of recurrence. New treatment options are urgently needed to improve survival following relapse, which is associated with extremely poor prognosis.

INTRODUCTION:PARP inhibition is an exciting new anticancer strategy. Olaparib has recently obtained a first in class license in Europe and the USA for the treatment of relapsed BRCA-mutant ovarian cancer.AREAS COVERED:We review the key preclinical and clinical data surrounding its use in the maintenance setting. Expert commentary: We also consider the market profile, regulatory issues surrounding the agent and offer a five year speculative viewpoint of its future development in ovarian cancer.