Stephanie Gaillard

Molecular Profiling and Tumor Biomarker Analysis of GOG281/LOGS: A Positive Late-Phase Trial of Trametinib for Recurrent/Persistent Low-Grade Serous Ovarian Carcinoma

Abstract Purpose: Low-grade serous ovarian carcinoma (LGSOC) is a distinct form of ovarian cancer characterized by younger patient age and relative chemoresistance. The GOG281/LOGS trial (NCT02101788) investigated the efficacy of the MEK inhibitor trametinib compared with physician’s choice standard-of-care (SOC) in patients with LGSOC with persistent/recurrent disease. The study demonstrated significantly improved progression-free survival (PFS) in the trametinib-treated arm. Experimental Design: Two hundred and sixty patients with recurrent/persistent LGSOC were enrolled and randomly assigned in GOG281. We performed molecular analysis of 170 patients with available tumor specimens, comprising whole-exome sequencing and phospho-ERK (pERK) IHC, to identify biomarkers of clinical benefit from trametinib. The demographics of the translational cohort (n = 170) were comparable with those of the total trial cohort. Results: High tumor pERK expression (greater than the median histoscore of 140) was associated with significantly prolonged PFS with trametinib treatment versus SOC (median 20.1 vs. 5.6 months, log-rank P < 0.0001; test for interaction P = 0.023). Tumors harboring canonical RAS–RAF–MAPK mutations (KRAS/BRAF/NRAS: 44/134, 32.8% of cases) had a higher response rate to trametinib (50.0% vs. 8.3%; Barnard’s P = 0.0004; test for interaction P = 0.054), but KRAS/BRAF/NRAS status was not predictive of prolonged PFS (test for interaction P = 0.719). KRAS amplification (n = 5 without KRAS/NRAS/BRAF mutation) and mutation of MAPK-associated genes (n = 25 without KRAS/NRAS/BRAF mutation or KRAS copy number gain) expanded the number of cases with identifiable MAPK defects to 55.2%, but consideration of these events did not improve the discrimination of trametinib responders. Chr1p loss (49% of cases) was associated with lower pERK expression (P = 0.021). Conclusions: This exploratory analysis suggests that pERK expression and mutation of KRAS/BRAF/NRAS are candidate biomarkers of improved PFS and response to trametinib, respectively.

Genomic alterations, molecularly targeted therapy, and survival: a real-world Endometrial Cancer Molecularly Targeted Therapy Consortium cohort study

Next-generation sequencing and tumor testing to direct therapy in advanced/recurrent endometrial cancer are frequently used, but the impact of this approach is unclear. We sought to confirm the proportion of patients with at least 1 actionable alteration and whether the use of molecularly targeted therapy was associated with improved survival in metastatic endometrial cancer. A multidisciplinary consortium was formed to study tumor testing and treatment with targeted therapies in advanced/recurrent endometrial cancer. Tumor testing and therapeutic decisions were physician's recommendations. The abstracted data included age, stage, grade, histology, race, ethnicity, treatment, genomic alterations, protein expression for Her2, p53, mismatch repair, estrogen and progesterone receptors, and survival. Statistical analyses were performed using SAS v9.4. A total of 967 patients from 12 centers were included. The median age was 64 years (range; 22-93 years). Of the participants, 68.5% were White, 24.0% were Black, 2.0% were Asian, and 92.7% were non-Hispanic. A total of 656 (67.8%) patients had recurrent/persistent disease and received a median of two (range; 0-9) therapies. 902 (93.3%) underwent tumor testing. Overall, 576 (94.0%) patients with next-generation sequencing testing had at least 1 genomic alteration in 11 pre-specified genes. The most frequent alterations were PI3K (35.8%), TP53 (34.7%), and PTEN (26.5%) mutations, respectively. A subset of 233 patients received 292 matched biologic therapies, and the median follow-up was 29.7 months, while the median progression-free survival and overall survival were 6.9 and 20.5 months, respectively. The consortium facilitated the development of real-world data on the patterns of genomic testing and molecularly targeted therapy used in a racially and geographically diverse patient cohort with advanced/recurrent endometrial cancer. Survival improved for those receiving matched biologic therapies compared to chemotherapy.

Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: ASCO Guideline Update

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only) for more . PURPOSE To provide updated guidance regarding neoadjuvant chemotherapy (NACT) and primary cytoreductive surgery (PCS) among patients with stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer (epithelial ovarian cancer [EOC]). METHODS A multidisciplinary Expert Panel convened and updated the systematic review. RESULTS Sixty-one studies form the evidence base. RECOMMENDATIONS Patients with suspected stage III-IV EOC should be evaluated by a gynecologic oncologist, with cancer antigen 125, computed tomography of the abdomen and pelvis, and chest imaging included. All patients with EOC should be offered germline genetic and somatic testing at diagnosis. For patients with newly diagnosed advanced EOC who are fit for surgery and have a high likelihood of achieving complete cytoreduction, PCS is recommended. For patients fit for PCS but deemed unlikely to have complete cytoreduction, NACT is recommended. Patients with newly diagnosed advanced EOC and a high perioperative risk profile should receive NACT. Before NACT, patients should have histologic confirmation of invasive ovarian cancer. For NACT, a platinum-taxane doublet is recommended. Interval cytoreductive surgery (ICS) should be performed after ≤four cycles of NACT for patients with a response to chemotherapy or stable disease. For patients with stage III disease, good performance status, and adequate renal function treated with NACT, hyperthermic intraperitoneal chemotherapy may be offered during ICS. After ICS, chemotherapy should continue to complete a six-cycle treatment plan with the optional addition of bevacizumab. Patients with EOC should be offered US Food and Drug Administration–approved maintenance treatments. Patients with progressive disease on NACT should have diagnosis reconfirmed via tissue biopsy. Patients without previous comprehensive genetic or molecular profiling should be offered testing. Treatment options include alternative chemotherapy regimens, clinical trials, and/or initiation of end-of-life care. Additional information is available at www.asco.org/gynecologic-cancer-guidelines . This guideline has been endorsed by the Society of Gynecologic Oncology.

Dual Inhibition of SYK and EGFR Overcomes Chemoresistance by Inhibiting CDC6 and Blocking DNA Replication

Abstract Targeting multiple signaling pathways has been proposed as a strategy to overcome resistance to single-pathway inhibition in cancer therapy. A previous study in epithelial ovarian cancers identified hyperactivity of spleen tyrosine kinase (SYK) and EGFR, which mutually phosphorylate and activate each other. Given the potential for pharmacologic inhibition of both kinases with clinically available agents, this study aimed to assess the antitumor efficacy of both pharmacologic and genetic SYK and EGFR coinhibition using a multifaceted approach. We assessed the coinactivation effects in chemoresistant ovarian cancer cell lines, patient-derived organoids, and xenograft models. Dual inhibition of SYK and EGFR in chemoresistant ovarian cancer cells elicited a synergistic antitumor effect. Notably, the combined inhibition activated the DNA damage response, induced G1 cell-cycle arrest, and promoted apoptosis. The phosphoproteomic analysis revealed that perturbation of SYK and EGFR signaling induced a significant reduction in both phosphorylated and total protein levels of cell division cycle 6, a crucial initiator of DNA replication. Together, this study provides preclinical evidence supporting dual inhibition of SYK and EGFR as a promising treatment for chemoresistant ovarian cancer by disrupting DNA synthesis and impairing formation of the prereplication complex. These findings warrant further clinical investigation to explore the potential of this combination therapy in overcoming drug resistance and improving patient outcomes. Significance: SYK and EGFR coinhibition exerts synergistic anticancer effects in chemoresistant ovarian cancer, providing a strategy to treat chemotherapy-resistant ovarian cancers using clinically available agents by targeting critical signaling pathways involved in DNA replication.

Niraparib, Dostarlimab, and Bevacizumab as Combination Therapy in Pretreated, Advanced Platinum-Resistant Ovarian Cancer: Findings From Cohort A of the OPAL Phase II Trial

PURPOSE To report the results of OPAL (ClinicalTrials.gov identifier: NCT03574779 ) cohort A, a single-arm substudy of niraparib plus dostarlimab and bevacizumab for the treatment of advanced, platinum-resistant ovarian cancer (PROC). METHODS Participants with PROC who received 1-2 previous lines of therapy were treated with niraparib (200 or 300 mg once daily), dostarlimab (500 mg once every 3 weeks for four 21-day cycles, followed by 1,000 mg once every 6 weeks), and bevacizumab (15 mg/kg once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1. Safety was also assessed. Exploratory biomarker end points included evaluation of changes in the tumor molecular profile and microenvironment using baseline and on-treatment tumor samples. RESULTS Of 41 enrolled participants (median age, 66.0 years [range, 37-83 years]), 9.8% had tumors that were BRCA-mutated, 19.5% were homologous recombination (HR)–deficient, and 17.1% were HR repair (HRR)–mutated. As of the cutoff date, all participants discontinued treatment. The ORR was 17.1% (80% CI, 9.8 to 27.0), including one complete response (2.4%); the disease control rate was 73.2% (80% CI, 62.3 to 82.2). Two participants withdrew before first postbaseline scan because of adverse events (AEs). Grade ≥3 treatment-emergent AEs were reported in 92.7% of participants, with the most common being hypertension (26.8%). Response was not correlated with BRCA, HRR, HR deficiency (HRD), or PD-L1 status. Changes suggesting immune activation were observed in on-treatment samples after triplet therapy. CONCLUSION Results demonstrated modest activity of niraparib, dostarlimab, and bevacizumab in participants with PROC, many of whom had prognostic factors for poor treatment response. Most participants with response were bevacizumab-naïve. No association was found with HRD, BRCA, or PD-L1 status. AEs were consistent with previous monotherapy reports, except that hypertension was reported more frequently.

A working group report from the 2024 National Cancer Institute / Gynecologic Cancer Steering Committee endometrial cancer clinical trials planning meeting: refining the approach to endometrial cancer in the immunotherapy era

Abstract Endometrial cancer is now the leading cause of gynecologic cancer death in the United States. Recognizing the urgent need to improve outcomes for patients diagnosed with endometrial cancer, the National Cancer Institute Gynecologic Cancer Steering Committee convened a clinical trials planning meeting, Refining the Approach to Endometrial Cancer in the Immunotherapy Era, on January 8 and 9, 2024. Multidisciplinary experts were charged with addressing critical challenges to optimize treatment of endometrial cancer in the new immunotherapy landscape. As part of the clinical trials planning meeting, working groups were assembled to address several important aspects of clinical trial design. Working group 1 focused on translational science and was tasked with reviewing the scientific literature for data on validated discriminants of response to immunotherapy to inform trial concept development by the therapy-focused groups. The working group established that molecular subtyping of endometrial cancer is now the standard approach for classifying endometrial tumors. Molecular subtyping for prognostic and predictive applications should be considered when assessing biomarkers as well as therapeutic targets. Additionally, strategies to improve immune response like incorporation of radiation as well as therapy sequencing considerations should continue to be explored. A major key observation from working group 1 was lack of validated discriminants for immunotherapy response beyond mismatch repair status, and tumor mutational burden and exploration of additional discriminants of response and resistance will be critical with the increasing use of immunotherapy in endometrial cancer.

FOLR1 as a therapeutic target in platinum-resistant ovarian carcinoma: unique expression patterns across ovarian carcinoma histotypes and molecular subtypes of low-grade serous carcinoma

With the development of novel antibody-drug conjugates (ADCs), folate receptor alpha (FOLR1) is a promising therapeutic target for the treatment of platinum-resistant tubo-ovarian carcinomas. The main aims of this study were to assess FOLR1 protein expression in a large cohort of ovarian carcinoma histotypes. To inform future clinical trial design we identified molecular correlates of FOLR1 expression in low-grade serous carcinoma (LGSC). One thousand five hundred forty-seven ovarian carcinoma samples from 5 different Canadian cohorts were successfully evaluated by immunohistochemistry for FOLR1 expression using the PS2+ system. Statistical analyses with clinicopathological parameters, LGSC molecular subtypes, and overall survival (OS) were performed. High FOLR1 expression was detected in 44% of high-grade serous carcinomas, and in 30% LGSC, 8% clear cell, 6% endometrioid, and 0% mucinous and/or mesonephric-type adenocarcinomas. In 160 LGSC cases, FOLR1 expression was more frequent in cases with normal MAPK pathway status (37% MAPK wild type vs. 14% canonical MAPK pathway mutations; p=0.002), low progesterone receptor (PR) expression (41%) vs. 23% (Allred score >2; p A significant proportion of LGSC express high FOLR1 levels supporting the development of clinical trials to investigate ADCs targeting FOLR1 as novel agents for treating this disease. In LGSC, high FOLR1 expression was associated with fewer MAPK pathway alterations, low PR expression, and p16 loss.

Rare Uterine Tumors: What to Do?

Rare uterine malignancies present treatment challenges because of their clinical and biological heterogeneity. Among the rarest of the uterine cancers are leiomyosarcomas, uterine stromal tumors, and the mesonephric-like and serous carcinomas. In this article, we review recent advancements in diagnostic precision, risk stratification, and identification of biomarker-guided therapeutic options for these rare subtypes of uterine tumors. The improved understanding of the molecular profile of these tumors has led to the development of targeted treatment approaches. Further progress will depend on a coordinated, global effort to further characterize these diseases and enroll patients on biomarker-driven clinical trials.

C ombination A TR (ceralasertib) and P A R P (olaparib) I nhibitor (CAPRI) Trial in Acquired PARP Inhibitor–Resistant Homologous Recombination–Deficient Ovarian Cancer

Abstract Purpose: Addition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to PARP inhibitors (PARPi) overcomes PARPi resistance in high-grade serous ovarian cancer (HGSOC) cell and mouse models. We present the results of an investigator-initiated study of combination PARPi (olaparib) and ATRi (ceralasertib) in patients with acquired PARPi-resistant HGSOC. Patients and Methods: Eligible patients had recurrent, platinum-sensitive BRCA1/2 mutated or homologous recombination (HR)–deficient (HRD) HGSOC and clinically benefited from PARPi (response by imaging/CA-125 or duration of maintenance therapy; > 12 months first-line or > 6 months ≥ second-line) before progression. No intervening chemotherapy was permitted. Patients received olaparib 300 mg twice daily and ceralasertib 160 mg daily on days 1 to 7 of a 28-day cycle. Primary objectives were safety and objective response rate (ORR). Results: Thirteen patients enrolled were evaluable for safety and 12 for efficacy; 62% (n = 8) had germline BRCA1/2 mutations, 23% (n = 3) somatic BRCA1/2 mutations, and 15% (n = 2) tumors with positive HRD assay. Prior PARPi indication was treatment for recurrence (54%, n = 7), second-line maintenance (38%, n = 5) and first-line treatment with carboplatin/paclitaxel (8%, n = 1). There were 6 partial responses yielding an ORR of 50% (95% confidence interval, 0.15–0.72). Median treatment duration was 8 cycles (range 4–23+). Grade (G) 3/4 toxicities were 38% (n = 5); 15% (n = 2) G3 anemia, 23% (n = 3) G3 thrombocytopenia, 8% (n = 1) G4 neutropenia. Four patients required dose reductions. No patient discontinued treatment due to toxicity. Conclusions: Combination olaparib and ceralasertib is tolerable and shows activity in HR-deficient platinum-sensitive recurrent HGSOC that benefited and then progressed with PARPi as the penultimate regimen. These data suggest that ceralasertib resensitizes PARPi-resistant HGSOCs to olaparib, warranting further investigation.

Inhibition of the MYC-Regulated Glutaminase Metabolic Axis Is an Effective Synthetic Lethal Approach for Treating Chemoresistant Ovarian Cancers

Abstract Amplification and overexpression of the MYC oncogene in tumor cells, including ovarian cancer cells, correlates with poor responses to chemotherapy. As MYC is not directly targetable, we have analyzed molecular pathways downstream of MYC to identify potential therapeutic targets. Here we report that ovarian cancer cells overexpressing glutaminase (GLS), a target of MYC and a key enzyme in glutaminolysis, are intrinsically resistant to platinum-based chemotherapy and are enriched with intracellular antioxidant glutathione. Deprivation of glutamine by glutamine-withdrawal, GLS knockdown, or exposure to the GLS inhibitor CB-839 resulted in robust induction of reactive oxygen species in high GLS-expressing but not in low GLS-expressing ovarian cancer cells. Treatment with CB-839 rendered GLShigh cells vulnerable to the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, and prolonged survival in tumor-bearing mice. These findings suggest consideration of applying a combined therapy of GLS inhibitor and PARP inhibitor to treat chemoresistant ovarian cancers, especially those with high GLS expression. Significance: Targeting glutaminase disturbs redox homeostasis and nucleotide synthesis and causes replication stress in cancer cells, representing an exploitable vulnerability for the development of effective therapeutics.

A Study to Evaluate the Efficacy and Safety of Novel Treatment Combinations in Participants With Ovarian Cancer

This study will evaluate the efficacy and safety of niraparib and novel treatment combinations of niraparib as described within each cohort-specific supplement in participants with ovarian, fallopian tube, or primary peritoneal cancer. Cohort A (single arm) includes participants with recurrent ovarian cancer. Cohort B will not be initiated. Cohort C (randomized-2 arms) includes participants with newly diagnosed ovarian cancer.