B J Rimel

Phase 3 clinical trials evaluating poly(ADP-ribose) polymerase inhibition plus immunotherapy for first-line treatment of advanced ovarian cancer

Abstract Background Ovarian cancer is the second deadliest gynecologic malignancy globally. The current standard of care first-line therapy for newly diagnosed advanced epithelial ovarian cancer is surgery and platinum-based chemotherapy (±bevacizumab), followed by maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor, bevacizumab, or a combination of the two. Although anti-programmed cell death (PD) protein 1 and anti–PD ligand 1 antibodies (PD-[L]1 inhibitors) have shown benefit in several solid tumors, their effect in ovarian cancer remains uncertain. Several trials are evaluating PD-(L)1 inhibitors in combination with first-line platinum-based chemotherapy and PARP inhibitor maintenance treatment. Here, we review trial designs to understand key similarities and differences for future assessments of the results. Materials and Methods The clinical trials registry “ClinicalTrials.gov” was searched using keywords, including ovarian cancer and niraparib, olaparib, or rucaparib. Search results were then filtered for phase 3 and manually reviewed to identify trials evaluating combinations of PARP inhibitors and PD-(L)1 inhibitors in the first-line setting. Results Four trials, ENGOT-OV44/FIRST (NCT03602859), ENGOT-OV46/AGO-OVAR 23/GOG-3025/DUO-O (NCT03737643), ENGOT-OV43/GOG-3036/KEYLYNK-001 (NCT03740165), and ENGOT-OV45/GOG-3020/ATHENA (NCT03522246), were identified. Of these, FIRST, DUO-O, and KEYLYNK-001 are evaluating both first-line use in combination with chemotherapy and maintenance, whereas ATHENA focuses on maintenance after a response to chemotherapy; however, DUO-O and KEYLYNK-001 do not include a PARP inhibitor in the comparator arm, limiting the ability to compare the added benefit of immunotherapy over the current standard of care. Conclusions Results of these trials will determine whether PARP inhibitor and PD-(L)1 inhibitor combination with or without bevacizumab can improve patient outcomes.

The missing data: A review of gender and sex disparities in research

AbstractThis article highlights the gender data gaps in clinical trial inclusion and funding, with a particular focus on gynecologic oncology. Female patients have historically been excluded from clinical trials across all medical domains. Despite recent improvements, female patients remain underrepresented in key diseases, including several cancer types, despite experiencing increased burden of disease. Lack of representation is particularly stark for patients in racial, ethnic, and gender minoritized populations, including in gynecologic cancer trials. Furthermore, female health conditions receive disproportionately small amounts of funding relative to their disease burden. Despite their high lethality, gynecologic cancers, including ovarian, cervical, and uterine malignancies, rank among the lowest funded cancer sites from the National Cancer Institute. Likewise, there is significant bias against female investigators with regard to funding, publication, and academic advancement, which affects the prioritization of women’s health. In combination, gender disparities at multiple steps along the research pathway from investigator and disease funding to trial inclusion to publication and dissemination of research perpetuate a significant data gap in the diagnosis, treatment, and prevention of diseases affecting female patients, including gynecologic cancers. Strategies to improve this gender gap and prioritize women’s health funding include increasing female representation in clinical trials with a specific focus on inclusion of patients from historically marginalized backgrounds, considering disease burden–based funding policies, and prioritizing female academic leadership opportunities.

NRG‐GY012: Randomized phase 2 study comparing olaparib, cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent, or metastatic endometrial cancer

AbstractPurposeThis paper reports the efficacy of the poly (ADP‐ribose) polymerase inhibitor olaparib alone and in combination with the antiangiogenesis agent cediranib compared with cediranib alone in patients with advanced endometrial cancer.MethodsThis was open‐label, randomized, phase 2 trial (NCT03660826). Eligible patients had recurrent endometrial cancer, received at least one (<3) prior lines of chemotherapy, and were Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned (1:1:1), stratified by histology (serous vs. other) to receive cediranib alone (reference arm), olaparib, or olaparib and cediranib for 28‐day cycles until progression or unacceptable toxicity. The primary end point was progression‐free survival in the intention‐to‐treat population. Homologous repair deficiency was explored using the BROCA‐GO sequencing panel.ResultsA total of 120 patients were enrolled and all were included in the intention‐to‐treat analysis. Median age was 66 (range, 41–86) years and 47 (39.2%) had serous histology. Median progression‐free survival for cediranib was 3.8 months compared with 2.0 months for olaparib (hazard ratio, 1.45 [95% CI, 0.91‐2.3] p = .935) and 5.5 months for olaparib/cediranib (hazard ratio, 0.7 [95% CI, 0.43–1.14] p = .064). Four patients receiving the combination had a durable response lasting more than 20 months. The most common grade 3/4 toxicities were hypertension in the cediranib (36%) and olaparib/cediranib (33%) arms, fatigue (20.5% olaparib/cediranib), and diarrhea (17.9% cediranib). The BROCA‐GO panel results were not associated with response.ConclusionThe combination of cediranib and olaparib demonstrated modest clinical efficacy; however, the primary end point of the study was not met. The combination was safe without unexpected toxicity.

The Impact of JAK1 Pathogenic Variants and MHC-I Expression on Response to Immune Checkpoint Inhibition in Endometrial Cancer

Abstract Purpose: Immune checkpoint inhibitors (ICI) have increasing application in endometrial cancer, underscoring the need for robust biomarkers for patient selection. JAK1 pathogenic variants (PV) have previously been implicated in immune evasion. In this study, we identify biomarkers predictive of ICI response in endometrial cancer and the implications of JAK1 PVs in this context. Experimental Design: This is a translational study of tumors from 84 patients with endometrial cancer treated with ICIs. High-throughput proteomic-based profiling was used to quantify 193 phosphoprotein/protein expression levels, including key JAK/STAT signaling pathway components. Associations with clinical outcomes were assessed using multivariate regression analysis. The functional consequences of JAK1 PVs were explored through in vitro signaling assays and analyses of The Cancer Genome Atlas database. Results: MHC-I expression correlated with improved progression-free survival (P = 0.035), validated in orthogonal approaches. Notably, a subset of patients harboring JAK1 PVs demonstrated exceptional survival on ICIs. In The Cancer Genome Atlas cohort of microsatellite instability–high and DNA polymerase epsilon–mutated tumors, homozygous loss of JAK1 trended toward decreased survival, whereas heterozygous loss of JAK1 was associated with significantly improved survival (P = 0.026), suggesting partial retention of antigen presentation pathways. Among our ICI-treated microsatellite instability–high tumor samples, NK cell marker NCAM1 was associated with improved survival (P = 0.02). Conclusions: These data support MHC-I as a potential predictive biomarker for ICI response in endometrial cancer. Additionally, we show that partial retention of JAK1 signaling in JAK1 tumors with heterozygous loss is associated with improved survival, potentially attributable to enhanced NK cell activity in tumors with low MHC-I expression.

Testing the Combination of Olaparib and Durvalumab, Cediranib and Durvalumab, Olaparib and Capivasertib, and Cediranib Alone in Recurrent or Refractory Endometrial Cancer Following the Earlier Phase of the Study That Tested Olaparib and Cediranib in Comparison to Cediranib Alone, and Olaparib Alone

This phase II trial studies the effects of the combination of olaparib and durvalumab, cediranib and durvalumab, olaparib and capivasertib, and cediranib alone in treating patients with endometrial cancer that has come back (recurrent) or does not respond to treatment (refractory). Olaparib, cediranib, and capivasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Durvalumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Testing the combinations may lower the chance of endometrial cancer growing or spreading compared to usual care.