How to optimize and evaluate diversity in gynecologic cancer clinical trials: statements from the GCIG Barcelona Meeting.

Findings from clinical trials have led to advancement of care for patients with gynecologic malignancies. However, restrictive inclusion of patients into trials has been widely criticized for inadequate representation of the real-world population. Ideally, patients enrolled in clinical trials should represent a broader population to enhance external validity and facilitate translation of outcomes across all relevant groups. Specifically, there has been a systematic lack of data for underrepresented groups, with many studies failing to report or differentiate study participants based on sociodemographic domains, such as race and ethnicity. As such, the impact of treatment in these underrepresented groups is poorly understood, and clinical outcomes according to various sociodemographic factors are infrequently assessed. Inclusion of diverse trial participants, with different racial and ethnic background, is essential for the understanding of factors that may impact clinical outcomes. Therefore, we conducted a multi-national meeting of clinical trial groups and industry with the goal of increasing equity, diversity, and inclusion in gynecologic cancer clinical trials and to address barriers to recruitment, participation, and harmonization of data collection and reporting. These Gynecologic Cancer Intergroup (GCIG) statements present recommendations and strategies for the gynecologic cancer research community to improve equity, diversity, and inclusion in gynecologic cancer clinical trials.

How long is long enough? An international survey exploring practice variations on the recommended duration of maintenance therapy with PARP inhibitors in patients with platinum sensitive recurrent ovarian cancer and long-term outcomes.

OBJECTIVE: There are no data, and thus no consensus, on the optimal duration of poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy for exceptional responders (here defined as progression-free for 5 years or longer) with platinum sensitive recurrent ovarian cancer. The current licence is to continue PARP inhibitors until progression or toxicity; however, international practice varies considerably. The risks of late progression and late-onset myeloid malignancies, defined as occurring beyond 5 years of PARP inhibition, are unknown. This study aims to examine the practice patterns and opinions regarding the management and surveillance protocols of exceptional responders with platinum sensitive recurrent ovarian cancer. METHODS: An online international survey of experts from June 2023 to June 2024 was carried out, disseminated at Gynaecologic Cancer Intergroup meetings and by Chairs of Cooperative Groups. RESULTS: 210 responses were received from 26 countries including Australia (27 respondents), Germany (24), the UK (21), the Netherlands (16), France (13), Spain (12), Canada (12), Italy (11), Japan (11), and other countries (63). Most respondents did not have institutional or trials group guidelines regarding duration of PARP inhibitors (154, 73.3%). For the minority with guidelines, recommendations varied: 1 year (2), 2 years (13), 3 years (4), and indefinite treatment (22). Individual practice varied considerably for those without guidelines: most (116, 76.3%) recommended ≥5 years of PARP inhibition, of which 73 (48.0%) recommended indefinite PARP inhibition. Sixty-six respondents (31.4%) reported having patients with late progression and 46 (22.0%) had cases with late-onset myeloid malignancies. Surveillance practices varied widely across all respondents. CONCLUSIONS: This international survey highlights the diverse practice variations and disparate views on the optimal duration of maintenance therapy with PARP inhibitors in platinum sensitive recurrent ovarian cancer. The responses suggest a notable risk of late progression and myelodysplastic syndrome/acute myeloid leukemia among exceptional responders which needs confirmation. Detailed individual patient data is required to draw more reliable conclusions; another study is underway addressing this.

GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301: a phase 3, randomized trial evaluating avutometinib plus defactinib compared with investigator's choice of treatment in patients with recurrent low grade serous ovarian cancer.

BACKGROUND: There are no approved treatments specifically for low grade serous ovarian cancer; current standard of care treatment options are limited in efficacy and tolerability. The combination of avutometinib with defactinib has demonstrated efficacy and a consistent safety profile in two clinical trials in recurrent low grade serous ovarian cancer, and a lower discontinuation rate due to adverse events compared with historical rates for standard of care. PRIMARY OBJECTIVE: To compare the progression free survival of the combination of avutometinib with defactinib versus investigator's choice of treatment in patients with recurrent low grade serous ovarian cancer. STUDY HYPOTHESIS: Combination treatment with avutometinib-defactinib will significantly improve progression free survival compared with investigator's choice of treatment in patients with recurrent low grade serous ovarian cancer. TRIAL DESIGN: GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301 is a phase 3, randomized, international, open label study designed to compare avutometinib with defactinib versus investigator's choice of treatment in patients with recurrent low grade serous ovarian cancer who have progressed on a previous platinum based therapy. On confirmation of disease progression using a blinded independent central review, patients on the investigator's choice of treatment arm may cross over to the avutometinib-defactinib arm. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients must have recurrent low grade serous ovarian cancer (KRAS mutant or wild-type) and have documented progression (radiographic or clinical) or recurrence of low grade serous ovarian cancer after at least one platinum based chemotherapy regimen. Unlimited additional previous lines of therapy are allowed, including previous MEK/RAF inhibitor. Patients will be excluded if they have co-existing high grade ovarian cancer or had previous treatment with avutometinib, defactinib, or any other FAK inhibitor. PRIMARY ENDPOINT: Progression free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded-independent central review. SAMPLE SIZE: Approximately 270 patients will be randomized in a 1:1 fashion to either the combination avutometinib with defactinib arm (n~135) or the investigator's choice of treatment arm (n~135). ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The estimated primary completion date of RAMP 301 is 2028, and the estimated study completion date is 2031. TRIAL REGISTRATION: ClinicalTrials.gov NCT06072781.

Safety and tolerability of mirvetuximab soravtansine monotherapy for folate receptor alpha-expressing recurrent ovarian cancer: An integrated safety summary.

OBJECTIVE: Mirvetuximab soravtansine-gynx (MIRV) is a novel antibody-drug conjugate targeting folate receptor alpha (FRα), which is overexpressed in epithelial ovarian cancer (EOC), with limited expression on normal tissues. This integrated safety summary sought to characterize the safety profile of MIRV monotherapy in participants with FRα-expressing recurrent EOC. METHODS: Safety data were retrospectively analyzed from 4 clinical studies (phase 1 trial [NCT01609556], phase 3 FORWARD I [NCT02631876], phase 2 SORAYA [NCT04296890], phase 3 MIRASOL [NCT04209855]) that evaluated participants with FRα-expressing recurrent EOC who received ≥1 dose of MIRV 6 mg/kg adjusted ideal body weight every 3 weeks. RESULTS: In this analysis of 682 participants, 94 % had platinum-resistant ovarian cancer (PROC). Blurred vision (43 %), nausea (41 %), diarrhea (39 %), and fatigue (35 %) were the most common treatment-emergent adverse events (TEAEs) and were primarily grade 1-2 in severity. Grade ≥ 3 TEAEs occurred in 48 % of participants, with the most common being keratopathy and blurred vision (5 % each). Most TEAEs were managed with supportive care and dose modifications, and only 12 % of participants experienced a TEAE leading to discontinuation (1 % due to ocular events). No corneal ulcerations or perforations have been reported. Median time to onset of blurred vision and keratopathy was 5.9 and 6.7 weeks, respectively. Most blurred vision events and keratopathy events resolved completely (71 % and 66 %, respectively) or partially (15 % and 14 %, respectively). CONCLUSIONS: As demonstrated among 682 participants, the safety profile of MIRV is well tolerated and consists primarily of low-grade gastrointestinal, fatigue, headache, peripheral neuropathy, and resolvable ocular adverse events.

Consensus on drivers of maintenance treatment choice and patterns of care in advanced ovarian cancer.

OBJECTIVES: Maintenance therapies, including poly (ADP-ribose) polymerase (PARP) inhibitors and/or bevacizumab, have substantially improved the prognosis of patients with advanced ovarian cancer. Owing to the variability in treatment strategies across Europe, a Delphi study was conducted among European experts to understand the heterogeneity of clinical practice and identify key factors driving maintenance treatment decisions for advanced ovarian cancer. METHODS: A pragmatic literature review was conducted to identify key questions regarding maintenance treatment strategies in patients with advanced ovarian cancer. Utilizing a Delphi methodology, consensus was assessed among a panel of 16 experts using a questionnaire based on results of the pragmatic literature review. RESULTS: Panelists agreed that BRCA mutation and homologous recombination status should be assessed in parallel at diagnosis, and that first-line platinum chemotherapy may be initiated concurrently. There was a consensus that alternative homologous recombination deficiency tests are acceptable provided they are clinically validated. Panelists agreed that Response Evaluation Criteria in Solid Tumors (RECIST) and CA-125 elimination rate constant K (KELIM) scores can help assess tumor chemosensitivity and guide treatment-related decisions. Panelists defined high-risk disease as International Federation of Gynecology and Obstetrics (FIGO) stage IV disease or stage III with residual disease after initial/interval cytoreduction. Risk of disease progression was a key determinant of choice between PARP inhibitor, bevacizumab, or both in combination, as maintenance therapy in advanced ovarian cancer. CONCLUSIONS: Key drivers for selecting advanced ovarian cancer maintenance treatments include tumor mutational status as a key biomarker and clinician perception of the risk for early disease progression.

Impact of metformin, statins, and beta blockers on survival in patients with primary ovarian cancer: combined analysis of four prospective trials of AGO-OVAR and ENGOT/GCIG collaborators.

OBJECTIVE: The aim of this study was to investigate the association of co-medication with metformin, a statin, or beta blocker with survival in patients with primary ovarian cancer. METHODS: Individual data from three phase III, randomized controlled trials (AGO-OVAR 11, AGO-OVAR 12, and AGO-OVAR 16) and one phase II trial (AGO-OVAR 15) were pooled and analyzed. Patients were classified as ever user if the specific co-medication was documented at least once during the trial, and were compared with never users as controls. Association of co-medications and outcomes were adjusted for potential confounders (age, International Federation of Gynecology and Obstetrics stage, histology, residual disease after surgery, Eastern Cooperative Oncology Group (ECOG) performance status, body mass index, Charlson Comorbidity Index, and assigned treatment within the trial) in multivariate Cox regression analyses. RESULTS: Overall, n=2857 patients were included. Ever users were: 100 patients received metformin (3.5%), 226 patients received statins (7.9%), and 475 (16.6%) patients received beta blockers (n=391 selective beta blockers; 84 non-selective beta blockers) as co-medication. There were no significant differences regarding the baseline characteristics except that ever users were significantly older, more obese, and had more comorbidities, according to the Charlson Comorbidity Index, compared with controls. Multivariate analyses for progression free survival and overall survival revealed neither a significant impact of metformin on survival (progression free survival hazard ratio (HR) 0.94, 95% confidence interval CI 0.69 to 1.29, p=0.7; overall survival HR 0.82, 95% CI 0.58 to 1.17, p=0.28) nor for statins (progression free survival HR 0.98, 95% CI 0.82 to 1.18, p=0.87; overall survival HR 0.91, 95% CI 0.74 to 1.12, p=0.37). In contrast, ever users of selective beta blockers had a significantly higher risk for recurrence and death (progression free survival HR 1.22, 95% CI 1.05 to 1.41, p=0.009; overall survival HR 1.25 95% CI 1.06 to 1.47, p=0.009). CONCLUSIONS: In this analysis, co-medication with metformin or statins had no significant impact on survival in patients with primary ovarian cancer. In contrast, co-medication with a beta blocker was associated with worse survival. However, whether this observation is related to the underlying condition rather than a direct negative impact on tumor biology remains unclear.

Fertility-sparing treatment and follow-up in patients with cervical cancer, ovarian cancer, and borderline ovarian tumours: guidelines from ESGO, ESHRE, and ESGE.

The European Society of Gynaecological Oncology, the European Society of Human Reproduction and Embryology, and the European Society for Gynaecological Endoscopy jointly developed clinically relevant and evidence-based guidelines focusing on key aspects of fertility-sparing strategies and follow-up of patients with cervical cancers, ovarian cancers, and borderline ovarian tumours. The developmental process of these guidelines is based on a systematic literature review and critical appraisal involving an international multidisciplinary development group consisting of 25 experts from relevant disciplines (ie, gynaecological oncology, oncofertility, reproductive surgery, endoscopy, imaging, conservative surgery, medical oncology, and histopathology). Before publication, the guidelines were reviewed by 121 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover oncological aspects of fertility-sparing strategies during the initial management, optimisation of fertility results and infertility management, and the patient's desire for future pregnancy and beyond.

Reproductive outcomes after fertility-sparing surgery for cervical cancer - results of the multicenter FERTISS study.

INTRODUCTION: Fertility-sparing treatment (FST) for patients with cervical cancer intends to achieve oncologic outcomes comparable to those after radical treatment while maximizing reproductive outcomes, including the ability to conceive and minimizing the risk of prematurity. METHODOLOGY: International multicentre retrospective FERTISS study focused on patients treated with FST analysed timing of FST relative to pregnancy, conception attempts and methods, abortion rates, prophylactic procedures reducing the risk of severe prematurity, pregnancy duration, and delivery mode. RESULTS: Of the 733 patients treated at 44 centres in 13 countries, 49.7% attempted to conceive during median follow-up of 72 months and 22.6% (166/733) patients achieved a successful pregnancy. Success rate was significantly higher after non-radical surgery (63.2%; 122/193) compared to radical trachelectomy (25.7%; 44/171, p < 0.001). Available perinatological data shows that 89.5% (111/124) of the patients became pregnant naturally. There was no significant difference in the abortion rate in the first pregnancy nor delivery success rates between non-radical and radical procedures patients. Preterm delivery (<38 weeks gestation) occurred more frequently after radical than non-radical procedures (76.5% vs. 57.7%, p = 0.15). Almost all patients (97.3%; 73/75) who underwent regular ultrasound cervicometry in pregnancy with subsequent prophylactic procedures delivered a live fetus, compared to 30.6% (15/49) women without such management, p < 0.001. CONCLUSION: Patients who underwent non-radical surgery had significantly higher pregnancy rates. Most pregnancies resulted in a viable fetus, but radical trachelectomy led to a higher rate of preterm births in the severe prematurity range. Half of the patients did not attempt pregnancy after FST.

Mirvetuximab soravtansine in folate receptor alpha (FRα)-high platinum-resistant ovarian cancer: final overall survival and post hoc sequence of therapy subgroup results from the SORAYA trial.

OBJECTIVE: The single-arm, phase II SORAYA trial (NCT04296890) of mirvetuximab soravtansine-gynx in folate receptor alpha (FRα)-high platinum-resistant ovarian cancer (n=105 (efficacy-evaluable)) met its primary endpoint with an objective response rate of 32.4% (95% CI, 23.6 to 42.2). Here we report final SORAYA trial results for overall survival and post hoc objective response rates in subgroups by sequence and number of prior therapies. METHODS: Eligible patients had high-grade serous platinum-resistant ovarian cancer with high FRα expression and one to three prior therapies (prior bevacizumab required). Enrolled participants received 6 mg/kg mirvetuximab soravtansine-gynx adjusted ideal body weight intravenously once every 3 weeks until progressive disease, unacceptable toxicity, withdrawal of consent, or death. Final overall survival and post hoc objective response rates were assessed in efficacy-evaluable participants. The safety population included all patients who received ≥1 dose of mirvetuximab soravtansine-gynx. RESULTS: At data cut-off (December 22, 2022; n=105), final median overall survival was 15.0 months (95% CI, 11.5 to 18.7). Median overall survival in participants with one to two prior therapy lines was 18.7 months (95% CI, 13.8 to not estimable (NE)) and 11.6 months (95% CI, 7.1 to 16.7) with three prior therapy lines. Median overall survival was 15.0 months (95% CI, 11.5 to NE) in participants with prior poly (ADP-ribose) polymerase inhibitor (PARPi) treatment versus 14.0 months (95% CI, 7.1 to NE) in those without. Objective response rate (data cut-off: November 17, 2021) differed among participants who received mirvetuximab soravtansine-gynx as their first treatment in the platinum-resistant setting (34.8%; 95% CI, 23.5 to 47.6) versus a different first treatment (28.2%; 95% CI, 15.0 to 44.9) or had received prior bevacizumab in a platinum-sensitive (34.0%; 95% CI, 24.6 to 44.5) versus platinum-resistant setting (17.6%; 95% CI, 3.8 to 43.4). No new safety signals were observed. CONCLUSION: These results support the clinically meaningful efficacy of mirvetuximab soravtansine-gynx in FRα-expressing platinum-resistant ovarian cancer, irrespective of prior treatment or sequence.

Clinical characteristics and survival outcome of early-stage, high-grade, serous tubo-ovarian carcinoma according to BRCA mutational status.

OBJECTIVE: To investigate the role of BRCA1/2 mutations in early ovarian cancer (eOC) (International Federation of Gynecology and Obstetrics FIGO 2014 stage I-II), and its impact on prognosis after relapse. METHODS: In this multicenter retrospective study, clinical and survival data from high-grade serous (HGS)-eOC patients at presentation and recurrence were compared according to BRCA status: BRCA-mutated (BRCAmut) vs. BRCA wild-type (BRCAwt). RESULTS: Among 191 HGS-eOC patients, 89 were BRCAmut and 102 BRCAwt. There was no significant difference according to the BRCA status in terms of Progression-Free Survival (PFS). A longer Overall Survival (OS) was found in BRCAmut patients. Stage I patients had significantly improved PFS vs stage II, regardless of BRCA status. At multivariate analysis, stage at diagnosis was the only variable with a significant effect on PFS. No factors were significantly relevant on OS, albeit younger age and BRCA mutation showed a slight impact. Post-Recurrence Survival (PRS) in the BRCAmut population was significantly improved compared with BRCAwt. At multivariate analysis, Secondary Cytoreductive Surgery was the strongest predictor for longer PRS, followed by PARPi maintenance at recurrence. CONCLUSIONS: BRCA-status is not a prognostic factor in early ovarian cancer regarding PFS. However, our data suggest a better prognosis after relapse in BRCAm population.

Role of fertility-sparing surgery and further prognostic factors in borderline tumors of the ovary.

OBJECTIVE: Borderline tumors of the ovary are a rare group of ovarian neoplasms with distinctive histological features. Considering their favorable prognosis and occurrence at a younger age, fertility-sparing surgery may be considered. Several risk factors have been identified as contributing to a higher recurrence rate, while the impact of pathohistological features varies in the literature. This study aimed to analyze risk factors for recurrence in patients with borderline tumors of the ovary. METHODS: Analysis included patients treated with first diagnosis of a borderline tumor at our center between January 1997 and December 2022 to analyze disease-free survival and to identify the role of fertility-sparing surgery, defined as preservation of at least one ovary, pathohistological features, and other prognostic factors for relapse. All stages classified according to the International Federation of Gynecology and Obstetrics (FIGO) were included. RESULTS: Among 507 patients, 26 patients (5.2%) had a recurrence, with 21 (4.1%) showing borderline histology and 5 (1%) with invasive relapses. Recurrence rate was higher following fertility-sparing surgery (p<0.0001). Median follow-up period was 49.2 (range 42.0-57.6) months. Among 153 patients (30.2%) who had fertility-sparing surgery, 21 (13.7%) experienced a recurrence (including one invasive relapse). Fertility-sparing surgery (HR 20; 95% CI 6.9 to 60; p<0.001), FIGO stage I with bilateral presence of tumor (HR 6.4; 95% CI 1.3 to 31; p=0.020), FIGO stage II (HR 15; 95% CI 3.4 to 68; p<0.001), FIGO stages III-IV (HR 38; 95% CI 10 to 140; p<0.001) in comparison with FIGO stage I with unilateral tumor, microinvasion (HR 8.6; 95% CI 2.7 to 28; p<0.001), and micropapillary growth patterns (HR 4.4; 95% CI 1.8 to 10; p=0.001) were identified as independent risk factors for recurrence in multivariate analysis. None of these factors were associated with an increased risk of disease-related death. CONCLUSIONS: Our study showed that although a fertility-preserving approach is associated with increased recurrence rates of a borderline tumor, it does not affect overall survival and can therefore be regarded as oncologically safe for patients desiring to preserve fertility. Additionally, presence of micropapillary patterns and microinvasion were identified as prognostic risk factors.

Gene expression markers in peripheral blood and outcome in patients with platinum-resistant ovarian cancer: A study of the European GANNET53 consortium.

Disease progression is a major problem in ovarian cancer. There are very few treatment options for patients with platinum-resistant ovarian cancer (PROC), and therefore, these patients have a particularly poor prognosis. The aim of the present study was to identify markers for monitoring the response of 123 PROC patients enrolled in the Phase I/II GANNET53 clinical trial, which evaluated the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone. In total, 474 blood samples were collected, comprising baseline samples taken before the first administration of the study drugs and serial samples taken during treatment until further disease progression (PD). After microfluidic enrichment, 27 gene transcripts were analyzed using quantitative polymerase chain reaction and their utility for disease monitoring was evaluated. At baseline, ERCC1 was associated with an increased risk of PD (hazard ratio [HR] 1.75, 95% confidence interval [CI]: 1.20-2.55; p = 0.005), while baseline CDH1 and ESR1 may have a risk-reducing effect (CDH1 HR 0.66, 95% CI: 0.46-0.96; p = 0.024; ESR1 HR 0.58, 95% CI: 0.39-0.86; p = 0.002). ERCC1 was observed significantly more often (72.7% vs. 53.9%; p = 0.032) and ESR1 significantly less frequently (59.1% vs. 78.3%; p = 0.018) in blood samples taken at radiologically confirmed PD than at controlled disease. At any time during treatment, ERCC1-presence and ESR1-absence were associated with short PFS and with higher odds of PD within 6 months (odds ratio 12.77, 95% CI: 4.08-39.97; p < 0.001). Our study demonstrates the clinical relevance of ESR1 and ERCC1 and may encourage the analysis of liquid biopsy samples for the management of PROC patients.

Olaparib Addition to Maintenance Bevacizumab Therapy in Ovarian Carcinoma With BRCA-Like Genomic Aberrations.

Importance: Testing for homologous recombination deficiency is required for the optimal treatment of high-grade epithelial ovarian cancer. The search for accurate biomarkers is ongoing. Objective: To investigate whether progression-free survival (PFS) and overall survival (OS) of patients with high-grade epithelial ovarian cancer treated with maintenance olaparib or placebo differed between patients with a tumor BRCA-like genomic profile and patients without a tumor BRCA-like profile. Design, Setting, and Participants: This cohort study was a secondary analysis of the PAOLA-1 randomized clinical trial that compared olaparib plus bevacizumab with placebo plus bevacizumab as maintenance treatment in patients with advanced high-grade ovarian cancer after a good response to first-line platinum with taxane chemotherapy plus bevacizumab, irrespective of germline or tumor BRCA1/2 mutation status. All patients with available tumor DNA were included in the analysis. The current analysis tested for an interaction between BRCA-like status and olaparib treatment on survival outcomes. The original trial was conducted between July 2015 and September 2017; at the time of data extraction for analysis in March 2022, a median follow-up of 54.1 months (IQR, 28.5-62.2 months) and a total follow-up time of 21 711 months was available, with 336 PFS and 245 OS events. Exposures: Tumor homologous recombination deficiency was assessed using the BRCA-like copy number aberration profile classifier. Myriad MyChoice CDx was previously measured. The trial was randomized between the olaparib and bevacizumab and placebo plus bevacizumab groups. Main Outcomes and Measures: This secondary analysis assessed hazard ratios (HRs) of olaparib vs placebo among biomarker strata and tested for interaction between BRCA-like status and olaparib treatment on PFS and OS, using Cox proportional hazards regression. Results: A total of 469 patients (median age, 60 [range 26-80] years) were included in this study. The patient cohort consisted of women with International Federation of Gynaecology and Obstetrics stage III (76%) high-grade serous (95%) ovarian cancer who had no evaluable disease or complete remission at initial or interval debulking surgery (76%). Thirty-one percent of the tumor samples (n = 138) harbored a pathogenic BRCA mutation, and BRCA-like classification was performed for 442 patients. Patients with a BRCA-like tumor had a longer PFS after olaparib treatment than after placebo (36.4 vs 18.6 months; HR, 0.49; 95% CI, 0.37-0.65; P < .001). No association of olaparib with PFS was found in patients with a non-BRCA-like tumor (17.6 vs 16.6 months; HR, 1.02; 95% CI, 0.68-1.51; P = .93). The interaction was significant (P = .004), and HRs and P values (for interaction) were similar in the relevant subgroups, OS, and multivariable analyses. Conclusions and Relevance: In this secondary analysis of the PAOLA-1 randomized clinical trial, patients with a BRCA-like tumor, but not those with a non-BRCA-like tumor, had a significantly longer survival after olaparib plus bevacizumab treatment than placebo plus bevacizumab treatment. Thus, the BRCA1-like classifier could be used as a biomarker for olaparib plus bevacizumab as a maintenance treatment.

Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease.

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10-8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.

Clinical evaluation of a low-coverage whole-genome test for detecting homologous recombination deficiency in ovarian cancer.

BACKGROUND: The PAOLA-1/ENGOT-ov25 trial showed that maintenance olaparib plus bevacizumab increases survival of advanced ovarian cancer patients with homologous recombination deficiency (HRD). However, decentralized solutions to test for HRD in clinical routine are scarce. The goal of this study was to retrospectively validate on tumor samples from the PAOLA-1 trial, the decentralized SeqOne assay, which relies on shallow Whole Genome Sequencing (sWGS) to capture genomic instability and targeted sequencing to determine BRCA status. METHODS: The study comprised 368 patients from the PAOLA-1 trial. The SeqOne assay was compared to the Myriad MyChoice HRD test (Myriad Genetics), and results were analyzed with respect to Progression-Free Survival (PFS). RESULTS: We found a 95% concordance between the HRD status of the two tests (95% Confidence Interval (CI); 92%-97%). The Positive Percentage Agreement (PPA) of the sWGS test was 95% (95% CI; 91%-97%) like its Negative Percentage Agreement (NPA) (95% CI; 89%-98%). In patients with HRD-positive tumors treated with olaparib plus bevacizumab, the PFS Hazard Ratio (HR) was 0.38 (95% CI; 0.26-0.54) with SeqOne assay and 0.32 (95% CI; 0.22-0.45) with the Myriad assay. In patients with HRD-negative tumors, HR was 0.99 (95% CI; 0.68-1.42) and 1.05 (95% CI; 0.70-1.57) with SeqOne and Myriad assays. Among patients with BRCA-wildtype tumors, those with HRD-positive tumors, benefited from olaparib plus bevacizumab maintenance, with HR of 0.48 (95% CI: 0.29-0.79) and of 0.38 (95% CI: 0.23 to 0.63) with the SeqOne and Myriad assay. CONCLUSION: The SeqOne assay offers a clinically validated approach to detect HRD.

Diagnostic Accuracy of 68Ga-FAPI Versus 18F-FDG PET in Patients with Various Malignancies.

To assess the diagnostic accuracy of 68Ga-labeled fibroblast activation protein inhibitor (FAPI) and 18F-labeled FDG PET for the detection of various tumors, we performed a head-to-head comparison of both imaging modalities across a range of tumor entities as part of our ongoing 68Ga-FAPI PET observational trial. Methods: The study included 115 patients with 8 tumor entities who received imaging with 68Ga-FAPI for tumor staging or restaging between October 2018 and March 2022. Of those, 103 patients received concomitant imaging with 68Ga-FAPI and 18F-FDG PET and had adequate lesion validation for accuracy analysis. Each scan was evaluated for the detection of primary tumor, lymph nodes, and visceral and bone metastases. True or false positivity and negativity to detected lesions was assigned on the basis of histopathology from biopsies or surgical excision, as well as imaging validation. Results: 68Ga-FAPI PET revealed higher accuracy than 18F-FDG PET in the detection of colorectal cancer (n = 14; per-patient, 85.7% vs. 78.6%; per-region, 95.6% vs. 91.1%) and prostate cancer (n = 22; per-patient, 100% vs. 90.9%; per-region, 96.4% vs. 92.7%). 68Ga-FAPI PET and 18F-FDG PET had comparable per-patient accuracy in detecting breast cancer (n = 16, 100% for both) and head and neck cancers (n = 10, 90% for both modalities). 68Ga-FAPI PET had lower per-patient accuracy than 18F-FDG PET in cancers of the bladder (n = 12, 75% vs. 100%) and kidney (n = 10, 80% vs. 90%), as well as lymphoma (n = 9, 88.9% vs. 100%) and myeloma (n = 10, 80% vs. 90%). Conclusion: 68Ga-FAPI PET demonstrated higher diagnostic accuracy than 18F-FDG PET in the diagnosis of colorectal cancer and prostate cancer, as well as comparable diagnostic performance for cancers of the breast and head and neck. Accuracy and impact on management will be further assessed in an ongoing prospective interventional trial (NCT05160051).

Systematic Analysis of Homologous Recombination Deficiency Testing in Ovarian Cancer-Development of Recommendations for Optimal Assay Performance.

Homologous recombination deficiency (HRD) assays are an important element of personalized oncology in ovarian carcinomas, but the optimal tissue requirements for these complex molecular assays remain unclear. As a result, a considerable percentage of assays are not successful, leading to suboptimal diagnoses for these patients. In this study, we have systematically analyzed tumor and tissue parameters for HRD analysis in a large cohort of real-world cancer samples. The aim of this study is to give recommendations for pathologists and gynecologic oncologists for selection of tissue samples to maximize the success rate of HRD analyses. Tumor samples from 2702 patients were sent to the Institute of Pathology of the Philipps-University Marburg between October 2020 and September 2022, of which 2654 were analyzed using the Myriad MyChoice HRD+ CDx assay. A total of 2396 of 2654 samples (90.3%) were successfully tested, of which 984 of 2396 (41.1%) were HRD positive and 1412 (58.9%) were HRD negative. Three hundred sixty-three of 2396 samples (15.2%) were BRCA1/2-mutated; 27 samples had a BRCA1/2 mutation and a genomic instability score (GIS) < 42. Twenty-two samples (0.9%) failed GIS measurement but displayed a BRCA1/2 mutation. BRCA1/2-mutated samples showed significantly (P < .0001) higher GIS values than those with a wild-type BRCA1/2 status. Tumor cell content, tumor area, and histology significantly (P < .0001) affected the probability of successfully analyzing a sample. Based on a systematic analysis of tumor cell content and tumor area, we recommend selecting patient high-grade serous ovarian cancer samples that display a tumor cell content ≥30% and a tumor area ≥0.5 cm2 (based on their hematoxylin and eosin) for HRD testing to allow for optimal chances of a successful analysis and conclusive results. Considering histologic and sample conditions, success rates of up to 98% can be achieved. Our comprehensive evaluation contributes to further standardization of recommendations on HRD testing in ovarian cancer, which will have a large impact on personalized therapeutic strategies in this highly aggressive tumor type.

Statement of the AGO Kommission Ovar, AGO Study Group, NOGGO, AGO Austria, Swiss AGO, BGOG, CEEGOG, GEICO, and SFOG regarding the use of hyperthermic intraperitoneal chemotherapy (HIPEC) in epithelial ovarian cancer.

An international joint statement about the use of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer was published in 2016, warning about the uncritical use of HIPEC outside controlled studies. This statement has now been updated after the most recent literature was reviewed by the participating study groups and societies. HIPEC became a treatment option in patients with advanced colon cancer after positive results of a randomized trial comparing surgery and HIPEC versus palliative treatment alone. Although this trial did not compare the added value of HIPEC to surgery alone, HIPEC for the treatment of peritoneal metastases was in the subsequent years generalized to many other cancer types associated with peritoneal carcinomatosis including epithelial ovarian cancer (EOC). In the meantime, new evidence from prospective randomized trials specifically for EOC-patients emerged, with however contradicting results and several quality aspects that made the interpretation of their findings critical. Moreover, three additional trials in colorectal cancer failed to confirm the previously presumed survival benefit through the implementation of HIPEC in peritoneally disseminated colorectal cancers. Based on a still unclear and inconsistent landscape, the authors conclude that HIPEC should remain within the remit of clinical trials for EOC-patients. Available evidence is not yet sufficient to justify its broad endorsement into the routine clinical practice.

Fibroblast Growth Factor Receptors and Ligands in Context of Bevacizumab Response in Ovarian Carcinoma: An Exploratory Analysis of AGO-OVAR11/ICON-7.

With more novel drugs being approved for the treatment of ovarian carcinoma, the question remains to what extent patients benefit from antiangiogenic treatment with bevacizumab, either in combination with poly-(ADP-ribose) polymerase inhibitors or as single-agent maintenance. As fibroblast growth factor receptors and their ligands (FGFRs/FGFs) are key players in angiogenic signaling and have been linked to resistance to several drugs, we investigated the prognostic or predictive potential of FGFs/FGFRs signaling in the context of bevacizumab treatment within the prospective phase III AGO-OVAR11/ICON-7 study. FGFR1, FGFR2, FGFR3, FGFR4, FGF1, and FGF19 gene expressions were determined in 380 ovarian carcinoma tumor samples collected from German centers in the multicenter phase III AGO-OVAR11 trial/ICON-7 trial. All patients received carboplatin and paclitaxel, administered every 3 weeks for 6 cycles, and were randomized to bevacizumab. Expressions of FGFR1, FGFR2, FGF1, and FGF19 were associated with progression-free survival in both uni- and multivariate (FGFR1: HR, 1.6, P < .001; FGFR2: HR, 1.6, P = .002; FGF1: HR, 2.3, P < .001; and FGF19: HR, 0.7; P = .007) analysis. A signature built by FGFR1, FGFR4, and FGF19 defined a subgroup (n = 62) of patients that derived the greatest bevacizumab-associated improvement of progression-free survival (HR, 0.3; P = .004). In this exploratory analysis of a prospective randomized phase III trial, we provide evidence that the expression of FGFRs/FGFs might have independent prognostic values. An FGFR/FGF-based gene signature identified in our study appears to predict long-term benefit from bevacizumab. This observation is hypothesis-generating and requires validation on independent cohorts.

Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.

OBJECTIVE: In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and homologous recombination deficiency (HRD)-positive tumors, irrespective of clinical risk. Subsequently, a clinically meaningful improvement in overall survival was reported with olaparib plus bevacizumab in the HRD-positive subgroup. We report updated progression-free survival and overall survival by clinical risk and HRD status. METHODS: Patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab received maintenance olaparib (up to 24 months) plus bevacizumab (up to 15 months in total) or placebo plus bevacizumab. This post hoc analysis evaluated 5-year progression-free survival and mature overall survival in patients classified by clinical risk and HRD status. RESULTS: Of 806 randomized patients, 74% were higher-risk and 26% were lower-risk. In higher-risk HRD-positive patients, the hazard ratio (HR) for progression-free survival was 0.46 (95% confidence interval (95% CI) 0.34 to 0.61), with 5-year progression-free survival of 35% with olaparib plus bevacizumab versus 15% with bevacizumab alone; and the HR for overall survival was 0.70 (95% CI 0.50 to 1.00), with 5-year overall survival of 55% versus 42%, respectively. In lower-risk HRD-positive patients, the HR for progression-free survival was 0.26 (95% CI 0.15 to 0.45), with 5-year progression-free survival of 72% with olaparib plus bevacizumab versus 28% with bevacizumab alone; and the HR for overall survival was 0.31 (95% CI 0.14 to 0.66), with 5-year overall survival of 88% versus 61%, respectively. No benefit was seen in HRD-negative patients regardless of clinical risk. CONCLUSION: This post hoc analysis indicates that in patients with newly diagnosed advanced HRD-positive ovarian cancer, maintenance olaparib plus bevacizumab should not be limited to those considered at higher risk of disease progression. Five-year progression-free survival rates support long-term remission and suggest an increased potential for cure with particular benefit suggested in lower-risk HRD-positive patients.