Bevacizumab increases the sensitivity of olaparib to homologous recombination-proficient ovarian cancer by suppressing CRY1 via PI3K/AKT pathway.

PARP inhibitors have changed the management of advanced high-grade epithelial ovarian cancer (EOC), especially homologous recombinant (HR)-deficient advanced high-grade EOC. However, the effect of PARP inhibitors on HR-proficient (HRP) EOC is limited. Thus, new therapeutic strategy for HRP EOC is desired. In recent clinical study, the combination of PARP inhibitors with anti-angiogenic agents improved therapeutic efficacy, even in HRP cases. These data suggested that anti-angiogenic agents might potentiate the response to PARP inhibitors in EOC cells. Here, we demonstrated that anti-angiogenic agents, bevacizumab and cediranib, increased the sensitivity of olaparib in HRP EOC cells by suppressing HR activity. Most of the γ-H2AX foci were co-localized with RAD51 foci in control cells. However, most of the RAD51 were decreased in the bevacizumab-treated cells. RNA sequencing showed that bevacizumab decreased the expression of CRY1 under DNA damage stress. CRY1 is one of the transcriptional coregulators associated with circadian rhythm and has recently been reported to regulate the expression of genes required for HR in cancer cells. We found that the anti-angiogenic agents suppressed the increase of CRY1 expression by inhibiting VEGF/VEGFR/PI3K pathway. The suppression of CRY1 expression resulted in decrease of HR activity. In addition, CRY1 inhibition also sensitized EOC cells to olaparib. These data suggested that anti-angiogenic agents and CRY1 inhibitors will be the promising candidate in the combination therapy with PARP inhibitors in HR-proficient EOC.

Survival and modelled cancer antigen-125 ELIMination rate constant K score in ovarian cancer patients in first-line before poly(ADP-ribose) polymerase inhibitor era: A Gynaecologic Cancer Intergroup meta-analysis.

BACKGROUND: In patients with advanced ovarian cancer, the modelled CA-125 ELIMination rate constant K (KELIM) is an early indicator of the tumour intrinsic chemosensitivity. We assessed the prognostic and surrogate values of KELIM with respect to those of surgery outcome (based on post-operative residual lesions) in the Gynaecologic Cancer Intergroup (GCIG) individual patient data meta-analysis MAOV (Meta-Analysis in OVarian cancer) built before the emergence of poly(ADP-ribose) polymerase (PARP) inhibitors. METHODS: The dataset was split into learning and validation cohorts (ratio 1:2). The individual modelled KELIM values were estimated, standardised by the median value, then scored as unfavourable (<1.0) or favourable (≥1.0). Overall survival (OS) and progression-free survival (PFS) analyses were performed with a two-step meta-analytic approach and surrogacy through a two-level meta-analytic model. RESULTS: KELIM was assessed in 5884 patients from eight first-line trials (learning, 1962; validation, 3922). A favourable KELIM score was significantly associated with longer OS (validation set, median, 78.8 versus 28.4 months, hazard-ratios [HR] 0.46, 95% confidence interval [CI], 0.41-0.50, C-index 0.68), and longer PFS (validation set, median 30.5 versus 9.8 months, HR 0.49, 95% CI, 0.45-0.54, C-index 0.68), as were International Federation of Gynaecology and Obstetrics (FIGO) stage and debulking surgery outcome. Three prognostic groups were identified based on the surgery outcome and KELIM score, with large differences in OS (105.1, ∼45.0, and 22.1 months) and PFS (58.1, ∼15.0, and 8.0 months). Surrogacy for OS and for PFS was not established. CONCLUSION: KELIM is an independent prognostic biomarker for survival, complementary to surgery outcome, representing a new determinant of first-line treatment success.

CA-125 Early Dynamics to Predict Overall Survival in Women with Newly Diagnosed Advanced Ovarian Cancer Based on Meta-Analysis Data.

(1) Background: Cancer antigen 125 (CA-125) is a protein produced by ovarian cancer cells that is used for patients' monitoring. However, the best ways to analyze its decline and prognostic role are poorly quantified. (2) Methods: We leveraged individual patient data from the Gynecologic Cancer Intergroup (GCIG) meta-analysis (N = 5573) to compare different approaches summarizing the early trajectory of CA-125 before the prediction time (called the landmark time) at 3 or 6 months after treatment initiation in order to predict overall survival. These summaries included observed and estimated measures obtained by a linear mixed model (LMM). Their performances were evaluated by 10-fold cross-validation with the Brier score and the area under the ROC (AUC). (3) Results: The estimated value and the last observed value at 3 months were the best measures used to predict overall survival, with an AUC of 0.75 CI 95% [0.70; 0.80] at 24 and 36 months and 0.74 [0.69; 0.80] and 0.75 [0.69; 0.80] at 48 months, respectively, considering that CA-125 over 6 months did not improve the AUC, with 0.74 [0.68; 0.78] at 24 months and 0.71 [0.65; 0.76] at 36 and 48 months. (4) Conclusions: A 3-month surveillance provided reliable individual information on overall survival until 48 months for patients receiving first-line chemotherapy.

Paclitaxel sensitizes homologous recombination-proficient ovarian cancer cells to PARP inhibitor via the CDK1/BRCA1 pathway.

OBJECTIVE: An effective treatment strategy for epithelial ovarian cancer (EOC) with homologous recombination (HR)-proficient (HRP) phenotype has not been established, although poly (ADP-ribose) polymerase inhibitors (PARPi) impact the disease course with HR-deficient (HRD) phenotype. Here, we aimed to clarify the cellular effects of paclitaxel (PTX) on the DNA damage response and the therapeutic application of PTX with PARPi in HRP ovarian cancer. METHODS: Two models with different PTX dosing schedules were established in HRP ovarian cancer OVISE cells. Growth inhibition and HR activity were analyzed in these models with or without PARPi. BRCA1 phosphorylation status was examined in OVISE cells by inhibiting CDK1, which was reduced by PTX treatment. CDK1 expression was evaluated in EOC patients treated with PTX-based neoadjuvant chemotherapy. RESULTS: PTX suppressed CDK1 expression resulting in impaired BRCA1 phosphorylation in OVISE cells. The reduced CDK1 activity by PTX could decrease HR activity in response to DNA damage and therefore increase the sensitivity to PARPi. Immunohistochemistry showed that CDK1 expression was attenuated in samples collected after PTX-based chemotherapy compared to those collected before chemotherapy. The decrease in CDK1 expression was greater with dose-dense PTX schedule than with the conventional PTX schedule. CONCULSIONS: PTX could act synergistically with PARPi in HRP ovarian cancer cells, suggesting that the combination of PTX with PARPi may be a novel treatment strategy extending the utility of PARPi to EOC. Our findings provide cules for future translational clinical trials evaluating the efficacy of PTX in combination with PARPi in HRP ovarian cancer.

Antenatal screening timeline and cutoff scores of the Edinburgh Postnatal Depression Scale for predicting postpartum depressive symptoms in healthy women: a prospective cohort study.

BACKGROUND: It is worthwhile to identify women at risk of developing postpartum depression during pregnancy. This study aimed to determine the optimal time and cutoff score for antenatal screening for prediction of postpartum depressive symptoms (PDS) using the Edinburgh Postnatal Depression Scale (EPDS) and to identify risk factors for PDS. METHODS: The target population was healthy pregnant women receiving antenatal care at a university hospital in Tokyo, Japan. During the first, second, and third trimesters, 3-4 days postpartum, and one month postpartum, they were asked to take the Japanese version of the EPDS questionnaire. The primary outcome of the study was PDS, defined as an EPDS score ≥ 9 at one month postpartum. The area under the receiver operating characteristics curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of EPDS scores at each antenatal screening time were calculated. RESULTS: From 139 pregnant women, 129 were successfully followed up throughout the study. The number of women with an EPDS score ≥ 9 during the first, second, and third trimesters, 3-4 days postpartum, and one month postpartum were 6/126 (4.8%), 9/124 (7.3%), 5/117 (4.3%), 17/123 (13.8%), and 15/123 (12.2%), respectively. Screening during the second trimester had the highest AUC to predict PDS (0.89) among antenatal screenings. The optimal EPDS cutoff score during the second trimester was 4/5 (sensitivity: 85.7%; specificity: 77.1%; PPV: 33.3%; NPV: 97.6%). An EPDS score ≥ 5 during the second trimester (adjusted odds ratio [aOR]: 15.9; 95% confidence interval [95%CI]: 3.2-78.1) and a family history of mental illness (aOR: 4.5; 95%CI: 1.2-17.5) were significantly associated with PDS. CONCLUSIONS: Our study suggests that the EPDS score at the second trimester with the cutoff value of 4/5 may be adequate for initial screening for prediction of PDS. Women with an EPDS score ≥ 5 at the second trimester require more elaborate follow-up.

Scoring Systems of Peritoneal Dissemination for the Prediction of Operative Completeness in Advanced Ovarian Cancer.

BACKGROUND/AIM: We investigated the predictive value of scoring systems of peritoneal disseminations for complete surgery (CS) at primary debulking surgery (PDS) in advanced ovarian cancer. PATIENTS AND METHODS: We retrospectively enrolled eligible patients with clinical stages III or IVA selected for PDS from January 2015 to December 2019. Concern variables were predictive index value (PIV) and peritoneal cancer index (PCI) from operative and pathological reports. Primary endpoints were cutoffs to predict operative completeness using the receiver operating characteristic curve. RESULTS: Among 111 patients, PIV ≥8 and PCI ≥13 were the best predictors of incomplete PDS, including optimal and suboptimal surgeries (AUC=0.821 and 0.855, respectively). CS rates in PIV ≤6 and PCI ≤12 were significantly higher than in PIV ≥8 (89.3% vs. 47.2%; p<0.05) and PCI ≥13 (90.9% vs. 41.2%: p<0.05). CONCLUSION: PIV and PCI are potential predictors for CS at PDS.

A case of relapsing aseptic meningitis under excellent tumor response to pembrolizumab in microsatellite instability-high recurrent endometrial cancer.

•This is the first report of aseptic meningitis due to immune checkpoint inhibitor treatment in endometrial cancer.•The meningitis was severe and relapsed multiple times unlike in other reported cases.•Oncologic outcome was excellent after overcoming this severe adverse event.

Clinical Availability of Tumour Biopsy Using Diagnostic Laparoscopy for Advanced Ovarian Cancer.

BACKGROUND/AIM: Tumour biopsy using laparoscopy before neoadjuvant chemotherapy for advanced ovarian cancer has been widely accepted. However, there are few reports about its operative outcome compared to biopsy with laparotomy. We investigated the advantage of laparoscopic biopsy for advanced ovarian cancer. PATIENTS AND METHODS: We included 23 patients who underwent laparoscopy and 27 who underwent exploratory laparotomy before neoadjuvant chemotherapy between January 2012 and August 2020. We reviewed their medical records and evaluated their operative outcomes. RESULTS: Blood loss was significantly lower in the laparoscopy group (5 ml vs. 320 ml, p<0.05). The period until the initiation of neoadjuvant chemotherapy was significantly shorter in the laparoscopy group (12 days vs. 16 days, p<0.05). Overall survival did not differ significantly between the two groups (25.4 months vs. 24.7 months, p=0.53). CONCLUSION: Laparoscopic tumour biopsy is useful and safe for histological diagnosis, thereby allowing for early introduction to neoadjuvant chemotherapy.

A report on the 73th Annual Congress of the Japan Society of Obstetrics and Gynecology International Workshop for Junior Fellows: Risk-reducing surgery for hereditary breast and ovarian cancer.

At the 73rd Annual Congress of the Japan Society of Obstetrics and Gynecology, young doctors from Japan and South Korea made presentations on the present condition of risk-reducing surgery for hereditary breast and ovarian cancer (RRSO) in their respective country. RRSO was insured in Japan in April 2020, whereas in South Korea, it was insured 7 years earlier in 2013. In Japan, certification criteria have been set for facilities that perform RRSO, and the number of facilities is increasing, but regional disparities still exist in its distribution. The number of gBRCA1/2 testing facilities is larger, and the cost is more affordable in South Korea than in Japan. Additionally, South Korea provides genetic counseling to a wider range of relatives compared to Japan. In the future, as the indications for the gBRCA1/2 test have expanded as a companion diagnostic for the use of PARP inhibitors, it is expected that the number of candidates for the gBRCA1/2 mutation test and RRSO will increase in Japan. It is important to increase the number of BRCA tests while maintaining the quality of genetic counseling in order to provide adequate information on BRCA mutations and RRSO for patients to support their decision. For the development of hereditary breast and ovarian cancer (HBOC) medical care, it is necessary to publish a nationwide database in Japan and continue to analyze and discuss the data based on the results.

Initiatives and achievements of the Japanese Society of Obstetrics and Gynecology, Obstetrics and Gynecology MIRAI Committee 2020.

BACKGROUNDS: In 2013, the total number of obstetrician-gynecologists decreased. The Japanese Society of Obstetrics and Gynecology established the Obstetrics and Gynecology MIRAI Committee in 2015. Within the MIRAI Committee, Japanese Trainees in Obstetrics and Gynecology (JTOG) was established; it was comprised of 20 promising young obstetrician-gynecologists recommended from regions across Japan. The office term is 2 years. OBJECTIVE: The purpose of this report is to learn and inform about the results of MIRAI's activities. METHODS: We surveyed the trends in new obstetrician-gynecologists and also matched each seminar participant with them. RESULT: The number of new memberships has been increasing since the nadir in 2016. In particular, there are over 100 more new physicians specializing in the field in 2020 than there were at the nadir in 2016. It was revealed that approximately 50% of the participants in the summer school specialized in obstetrics and gynecology. Furthermore, approximately 70% of POP2 participants specialized in obstetrics and gynecology, which shows that these two recruitment seminars are extraordinarily effective events that result in an increase in the number of new obstetricians and gynecologists. CONCLUSION: We conclude that the activities of this MIRAI Committee and JTOG have been effective. With the spread of COVID-19 and the inability of obstetrician-gynecologists and students/clinical trainees to perform social distancing, it is currently difficult to hold hands-on seminars. However, we hope that new JTOG members will be able to create a new seminar format.

A survey of Japanese interns to prepare for mandatory clinical training in obstetrics and gynecology.

AIM: Obstetrics and gynecology (Ob/Gyn) training became compulsory for Japanese physician interns from April 2020 to improve medical competence in treating women's diseases. This study aims to understand the Ob/Gyn training needs of postgraduate year 1-2 physicians (interns) and thereby improve training efficiency. METHODS: This study was administered to interns at Ob/Gyn training facilities from December 2019 to February 2020. An original questionnaire was used to evaluate their assessment of training needs. In analyses, interns were categorized according to whether they were willing to major in Ob/Gyn. RESULTS: Of the 1154 participants, 163 (14.1%) would major in Ob/Gyn (Ob/Gyn applicants) and 967 (83.8%) would not (non-Ob/Gyn applicants). At the time of the survey, 634 (54.9%) had rotated in Ob/Gyn, 253 (21.9%) planned to rotate, and 267 (23.1%) chose not to rotate. The two most favorable training experiences were "experience in surgical procedures" (81/141, 57.4%) and "wide treatment areas covered by Ob/Gyn" (78/141, 55.3%) among the Ob/Gyn applicants, and "specificity of women's treatment" (308/488, 63.1%) among the non-Ob/Gyn applicants. CONCLUSIONS: Ob/Gyn applicants and non-Ob/Gyn applicants differed in their assessment of Ob/Gyn rotations. It is crucial to provide medical training based on interns' needs to improve their skills for treating female patients.

Interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) that is associated with elevated interleukin-6 (IL-6) expression, resistance to chemotherapy, and increased mortality. Although bevacizumab (Bev) is a widely used anti-angiogenic agent for EOC, the efficacy of Bev and the role of IL-6 in modulating angiogenesis in OCCC are unknown. We performed tube formation assays using human umbilical vein endothelial cells (HUVEC) cultured in OCCC cell-conditioned medium and using cells directly co-cultured with OCCC cells. We observed that IL-6 inhibition significantly mitigated the ability of Bev to impede tube formation in both cases. Furthermore, IL-6 blockade disrupted the anti-angiogenic efficacy of Bev and its concomitant anti-tumor activity. In addition, IL-6 inhibition resulted in a significant increase in angiopoietin-1 (Ang1) secretion and decreased vascular endothelial growth factor (VEGF) expression. Clinical specimens also exhibited this reciprocal relationship between IL-6 and Ang1 expression. Finally, depletion of Ang1 abrogated the effects of IL-6 inhibition on Bev activity, demonstrating that IL-6 supports the anti-angiogenic activity of Bev by suppressing Ang1 expression and promoting dependence on VEGF for angiogenesis. Altogether, our data suggest that OCCC tumors with high IL-6 levels are candidates for Bev therapy.

Re-thinking the prognostic significance of positive peritoneal cytology in endometrial cancer.

BACKGROUND: Whether abnormal peritoneal cytology (PC) is an independent prognostic factor in endometrial cancer (EC) remains controversial. This study aimed to re-think the prognostic significance of PC in not only all EC patients but also in various subgroups with similar clinicopathological and biological characteristics. METHODS: EC patients who underwent primary surgery of at least a hysterectomy and were pathologically diagnosed with EC in four hospitals affiliated with the Jikei University School of Medicine were retrospectively reviewed. The prognostic significance of PC was evaluated with univariate and multivariate analyses in the entire cohort and subgroups stratified by surgical stages (early/advanced stages), tumor types (types 1/2), and risk classifications (low/intermediate/high). RESULTS: Of 1963 EC cases, 1616 met the inclusion criteria. Positive PC was identified as an adverse prognostic factor in analyses of all EC cases and in all subgroup analyses stratified by surgical stages and tumor types. In survival curve comparisons, the progression-free survival (PFS) and disease-specific survival in early-stage patients with positive PC were clearly located between those of stage II patients with negative PC and stage III patients. In the subgroup analyses stratified by risk classification in early-stage EC, positive PC was related to poorer PFS in the intermediate- and high-risk groups but not in the low-risk group. CONCLUSION: PC status was an independent prognostic factor of EC in all stages and tumor types. Early PC-positive cases, except for the low-risk group, may be recommended for upstaging and should be carefully managed compared with PC-negative cases.

Vaginal Transmission of Cancer from Mothers with Cervical Cancer to Infants.

Two cases of pediatric lung cancer (in 23-month-old and 6-year-old boys) resulting from mother-to-infant transmission of uterine cervical tumors were incidentally detected during routine next-generation sequencing of paired samples of tumor and normal tissue. Spontaneous regression of some lesions in the first child and slow growth of the tumor mass in the second child suggested the existence of alloimmune responses against the transmitted tumors. Immune checkpoint inhibitor therapy with nivolumab led to a strong regression of all remaining tumors in the first child. (Funded by the Japan Agency for Medical Research and Development and others; TOP-GEAR UMIN Clinical Trials Registry number, UMIN000011141.).

Analysis of risk factors for patients with early-stage cervical cancer: A study of 374 patients.

AIM: This study aimed to identify the postoperative histological features affecting the prognosis of patients with early-stage cervical cancer who underwent open radical hysterectomy. METHODS: This retrospective study enrolled 374 patients with pT1a, 1b1 and 2a1 early-stage cervical cancer who underwent open radical hysterectomy between 2001 and 2018. Survival outcomes were analyzed by Kaplan-Meier method and compared with log-rank test. Using the Cox proportional hazards regression test, we conducted a multivariate analysis for disease-free survival and overall survival. RESULTS: Others histology, including other epithelial tumors and neuroendocrine tumors, had a significantly worse prognosis in both disease-free survival and overall survival than those of squamous cell carcinoma and adenocarcinoma (hazard ratio, 4.37 and 11.76; P = 0.006 and P = 0.002, respectively), along with lymph node metastasis (hazard ratio, 2.99 and 7.03; P = 0.009 and P = 0.001, respectively). CONCLUSION: Others histology including adenosquamous carcinoma had a poor prognosis in early-stage cervical cancer as with high-risk factors.

Prevention and practice during the COVID-19 emergency declaration period in Japanese obstetrical/gynecological facilities.

AIM: A nationwide questionnaire survey was performed to evaluate how Japanese Society of Obstetrics and Gynecology (JSOG) members dealt with the coronavirus disease (COVID-19) pandemic during the declared nationwide emergency. METHODS: We sent questionnaires to members of JSOG via official email. Participants answered anonymously using Google forms. RESULTS: Two (0.08%) JSOG members had contracted COVID-19. There was a clear decrease in the number of patients scheduled for operation, not only for malignant but also for benign diseases. A decrease in the number of outpatients for infertility treatment was also observed. Polymerase chain reaction testing for severe acute respiratory syndrome coronavirus 2 was available in 20.4% of the facilities. Inpatients and outpatients were requested to wear masks, limit the number of contacts and check body temperature when visiting hospitals/clinics. During parturition care, caregivers and physicians wore gloves, masks (other than N-95), face shields and gowns. About 66% and 80% of the facilities decided to transfer pregnant women if they had asymptomatic and symptomatic infection, respectively. Cesarean section was typically chosen as delivery mode in infected women. CONCLUSION: The COVID-19 pandemic provoked significant changes in obstetrics and gynecology practices in Japan. Apparently, nosocomial infections were largely prevented due to these changes, although some of them might not have been necessary.

Neoadjuvant Chemotherapy for Patients With Diaphragmatic Lesions: A Prognostic Postoperative Analysis.

BACKGROUND/AIM: We aimed to analyse the prognosis of patients who underwent primary debulking surgery (PDS) and those who underwent interval debulking surgery (IDS) following four courses of paclitaxel+ carboplatin as preoperative chemotherapy to examine the usefulness of preoperative chemotherapy. PATIENTS AND METHODS: We included 45 patients with epithelial ovarian and peritoneal cancers accompanied with diaphragmatic lesions who underwent standard surgery combined with diaphragmatic surgery at two related institutions in January 2010-December 2013. Using medical records, we surveyed the recurrence period, recurrence site, and date of last confirmed survival, and analysed prognosis. RESULTS: The PDS and IDS groups comprised 32 and 13 patients (overall survival, 61.2 and 43.2 months), respectively. Progression-free survival in the PDS and IDS groups was 31.2 and 16.8 months, respectively. CONCLUSION: NAC-IDS can be a standard treatment option for patients with a tumour in the triangular ligament, in whom complete surgery is difficult.

Rethinking of treatment strategies and clinical management in ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (OCCC), with unique clinical and molecular characteristics compared with other histological types of epithelial ovarian cancer (EOC), behaves like a distinct entity and has a poorer prognosis than other EOC types, especially in advanced stages. In addition, OCCC comprises approximately 27% of all EOC cases in Japan, compared with 12% in Western countries. Historically, patients with OCCC have been eligible for chemotherapeutic and surgical trials of EOC. It has been difficult to evaluate the specific impact of these trials on the prognosis of women with OCCC because of its rarity and unique molecular characteristics. Recent studies of OCCC revealed significant molecular variations related to carcinogenesis and molecular targets that could directly facilitate patient stratification and subsequent precision medicine. Thus, treatment strategies specific for OCCC based on its clinical and molecular characteristics are urgently needed. In this review, we highlight the management and treatment of OCCC from clinical aspects.

Assessment of Progression-Free Survival as a Surrogate End Point of Overall Survival in First-Line Treatment of Ovarian Cancer: A Systematic Review and Meta-analysis.

Importance: The Gynecologic Cancer InterGroup (GCIG) recommended that progression-free survival (PFS) can serve as a primary end point instead of overall survival (OS) in advanced ovarian cancer. Evidence is lacking for the validity of PFS as a surrogate marker of OS in the modern era of different treatment types. Objective: To evaluate whether PFS is a surrogate end point for OS in patients with advanced ovarian cancer. Data Sources: In September 2016, a comprehensive search of publications in MEDLINE was conducted for randomized clinical trials of systematic treatment in patients with newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer. The GCIG groups were also queried for potentially completed but unpublished trials. Study Selection: Studies with a minimum sample size of 60 patients published since 2001 with PFS and OS rates available were eligible. Investigational treatments considered included initial, maintenance, and intensification therapy consisting of agents delivered at a higher dose and/or frequency compared with that in the control arm. Data Extraction and Synthesis: Using the meta-analytic approach on randomized clinical trials published from January 1, 2001, through September 25, 2016, correlations between PFS and OS at the individual level were estimated using the Kendall τ model; between-treatment effects on PFS and OS at the trial level were estimated using the Plackett copula bivariate (R2) model. Criteria for PFS surrogacy required R2 ≥ 0.80 at the trial level. Analysis was performed from January 7 through March 20, 2019. Main Outcomes and Measures: Overall survival and PFS based on measurement of cancer antigen 125 levels confirmed by radiological examination results or by combined GCIG criteria. Results: In this meta-analysis of 17 unique randomized trials of standard (n = 7), intensification (n = 5), and maintenance (n = 5) chemotherapies or targeted treatments with data from 11 029 unique patients (median age, 58 years [range, 18-88 years]), a high correlation was found between PFS and OS at the individual level (τ = 0.724; 95% CI, 0.717-0.732), but a low correlation was found at the trial level (R2 = 0.24; 95% CI, 0-0.59). Subgroup analyses led to similar results. In the external validation, 14 of the 16 hazard ratios for OS in the published reports fell within the 95% prediction interval from PFS. Conclusions and Relevance: This large meta-analysis of individual patient data did not establish PFS as a surrogate end point for OS in first-line treatment of advanced ovarian cancer, but the analysis was limited by the narrow range of treatment effects observed or by poststudy treatment. These results suggest that if PFS is chosen as a primary end point, OS must be measured as a secondary end point.