Extended-duration antibiotics are not associated with a reduction in surgical site infection in patients with ovarian cancer undergoing cytoreductive surgery with large bowel resection.

OBJECTIVE(S): To evaluate whether extended dosing of antibiotics (ABX) after cytoreductive surgery (CRS) with large bowel resection for advanced ovarian cancer is associated with reduced incidence of surgical site infection (SSI) compared to standard intra-operative dosing and evaluate predictors of SSI. METHODS: A retrospective single-institution cohort study was performed in patients with stage III/IV ovarian cancer who underwent CRS from 2009 to 2017. Patients were divided into two cohorts: 1) standard intra-operative dosing ABX and 2) extended post-operative ABX. All ABX dosing was at the surgeon's discretion. The impact of antibiotic duration on SSI and other postoperative outcomes was assessed using univariate and multivariable Cox regression models. RESULTS: In total, 277 patients underwent cytoreductive surgery (CRS) with large bowel resection between 2009 and 2017. Forty-nine percent (n = 137) received standard intra-operative ABX and 50.5% (n = 140) received extended post-operative ABX. Rectosigmoid resection was the most common large bowel resection in the standard ABX (89.9%, n = 124) and extended ABX groups (90.0%, n = 126), respectively. No significant differences existed between age, BMI, hereditary predisposition, or medical comorbidities (p > 0.05). No difference was appreciated in the development of superficial incisional SSI between the standard ABX and extended ABX cohorts (10.9% vs. 12.9%, p = 0.62). Of patients who underwent a transverse colectomy, a larger percentage of patients developed a superficial SSI versus no SSI (21% vs. 6%, p = 0.004). CONCLUSION(S): In this retrospective study of patients with advanced ovarian cancer undergoing CRS with LBR, extended post-operative ABX was not associated with reduced SSI, and prolonged administration of antibiotics should be avoided unless clinically indicated.

Carboplatin, paclitaxel, and pembrolizumab followed by pembrolizumab maintenance for primary treatment of incompletely resected epithelial ovarian cancer.

Objective: Incompletely resected epithelial ovarian cancer represents a poor prognostic subset of patients. Novel treatment strategies are needed to improve outcomes for this population. We evaluated a treatment strategy combining platinum-based chemotherapy with pembrolizumab followed by pembrolizumab maintenance therapy in the first-line treatment after incomplete resection of epithelial ovarian cancer patients. Methods: This was a single-arm, non-randomized pilot study of carboplatin, taxane, and immune checkpoint inhibitor, pembrolizumab, followed by 12 months of maintenance pembrolizumab in patients with incompletely resected epithelial ovarian cancer (EOC). Results: A total of 29 patients were enrolled and evaluated for efficacy and safety. The best response to therapy was complete response in 16 (55%) patients, partial response in 9 (31%) patients, and 3 (10%) patients with progression of disease. The median progression-free survival (PFS) was 13.2 months. Grade 3 and 4 toxicities occurred in 20% of patients. In all, 7 patients discontinued therapy due to adverse events. Quality-of-life scores remained high during therapy. Response to therapy did not correlate with PD-L1 tumor expression. Conclusions: Combination platinum-taxane therapy with pembrolizumab did not increase median progression-free survival in this cohort of patients. Key message: EOC is an immunogenic disease, but immune checkpoint inhibitor therapy has yet to impact outcomes. The current study utilized pembrolizumab in combination with standard chemotherapy followed by a maintenance treatment strategy in incompletely resected EOC. Progression-free survival was not extended in this poor prognostic group with combined chemotherapy and immunotherapy. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT 027766582.

Laparoscopic predictability of minimally invasive interval debulking in advanced ovarian cancer: The MIID-SOC trial.

BACKGROUND: We sought to create a laparoscopic-based model to predict the ability to perform a minimally invasive (MIS) cytoreductive surgery in advanced epithelial ovarian cancer patients who have received neoadjuvant chemotherapy (NACT). METHODS: Fifty women were enrolled in a multi-institutional prospective pilot study (NCT03378128). Each patient underwent laparoscopic evaluation of 43 abdominopelvic sites followed by surgeon dictated surgical approach, either continue MIS or laparotomically. However, if the procedure continued MIS, the placement of a hand-assist port for manual palpation was mandated to emulate a laparotomic approach and all 43 sites were re-evaluated. Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were calculated for each site to predict MIS resectability. Each parameter was assigned a numeric value based on the strength of statistical association and a total predictive index score (PIV) was assigned for each patient. Receiver operating characteristic curve analysis was used to assess the ability of the model to predict the MIS approach. RESULTS: Twenty-seven patients (61%) underwent MIS surgery. The following abdominopelvic sites were selected for inclusion in the model: gastrosplenic ligament, rectum, left mesocolon, transverse colon, right colon, cecum, appendix, liver capsule, intrahepatic fossa/gallbladder, ileum/jejunum. Using the PIV, a ROC was generated with an AUC = 0.695. In the final model, a PIV <2 identified patients able to undergo an optimal MIS cytoreductive surgery with an accuracy of 68.2%. The specificity, or the ability to identify patients who would not be able to undergo an optimal MIS interval cytoreductive surgery, was 66.7%. CONCLUSION: This predictive index model may help to guide future inclusion criteria in randomized studies evaluating the MIS approach in advanced epithelial ovarian cancer.

Activity of pembrolizumab and lenvatinib in mismatch repair deficient (dMMR) endometrial cancer patients who have failed pembrolizumab monotherapy: A case series.

To evaluate the efficacy of the combination of pembrolizumab and lenvatinib in MMR deficient (dMMR) endometrial cancer (EC) patients who previously failed to respond to single-agent pembrolizumab. A retrospective review of MMR deficient endometrial cancer patients was performed. Patients who failed to respond to pembrolizumab as a single-agent and subsequently received a combination of pembrolizumab and lenvatinib were analyzed. RECIST 1.1 criteria was used to establish clinical response (complete response, partial response, stable disease, and progression) based on CT and/or PET, comparing imaging before and after the addition of lenvatinib. Radiologic review was conducted by an independent radiologist. Eight patients with dMMR EC meeting treatment criteria were identified. The patients' ages ranged from 54 to 80 and all tumors identified were of endometrioid histology. Initial pathologic stage ranged from FIGO stage IB to IVB and recurrence confirmed via imaging or tissue biopsy. Patients received a median of 14 cycles of therapy with pembrolizumab and lenvatinib (range 1-39). All patients had decrease in measurable disease with an objective response of 75 % (PR 62.5 %, CR 12.5 %). Both patients who received the initial recommended dose of 20 mg daily required a dose reduction. Based on this retrospective study, patients with dMMR EC without significant benefit from pembrolizumab monotherapy have a significant clinical response after the addition of lenvatinib. Combination therapy should be considered for dMMR EC patients who fail pembrolizumab monotherapy.

Response of low HER2-expressing ovarian carcinosarcoma to trastuzumab deruxtecan, a case report.

•Treatment options are limited for recurrent ovarian carcinosarcoma (OCS).•A patient with HER2 1 + IHC and negative FISH amplification was treated with trastuzumab deruxtecan.•A durable partial response was achieved, suggesting a possible treatment option for OCS patients with HER2 expression.

A phase III, multicenter, randomized study of olvimulogene nanivacirepvec followed by platinum-doublet chemotherapy and bevacizumab compared with platinum-doublet chemotherapy and bevacizumab in women with platinum-resistant/refractory ovarian cancer.

BACKGROUND: Treatment options for patients with platinum-resistant/refractory ovarian cancers are limited and only marginally effective. The development of novel, more effective therapies addresses a critical unmet medical need. Olvimulogene nanivacirepvec (Olvi-Vec), with its strong immune modulating effect on the tumor microenvironment, may provide re-sensitization to platinum and clinically reverse platinum resistance or refractoriness in platinum-resistant/refractory ovarian cancer. PRIMARY OBJECTIVE: The primary objective is to evaluate the efficacy of intra-peritoneal Olvi-Vec followed by platinum-based chemotherapy and bevacizumab in patients with platinum-resistant/refractory ovarian cancer. STUDY HYPOTHESIS: This phase III study investigates Olvi-Vec oncolytic immunotherapy followed by platinum-based chemotherapy and bevacizumab as an immunochemotherapy evaluating the hypothesis that such sequential combination therapy will prolong progression-free survival (PFS) and bring other clinical benefits compared with treatment with platinum-based chemotherapy and bevacizumab. TRIAL DESIGN: This is a multicenter, prospective, randomized, and active-controlled phase III trial. Patients will be randomized 2:1 into the experimental arm treated with Olvi-Vec followed by platinum-doublet chemotherapy and bevacizumab or the control arm treated with platinum-doublet chemotherapy and bevacizumab. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients must have recurrent, platinum-resistant/refractory, non-resectable high-grade serous, endometrioid, or clear-cell ovarian, fallopian tube, or primary peritoneal cancer. Patients must have had ≥3 lines of prior chemotherapy. PRIMARY ENDPOINT: The primary endpoint is PFS in the intention-to-treat population. SAMPLE SIZE: Approximately 186 patients (approximately 124 patients randomized to the experimental arm and 62 to the control arm) will be enrolled to capture 127 PFS events. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Expected complete accrual in 2024 with presentation of primary endpoint results in 2025. TRIAL REGISTRATION: NCT05281471.

Association of Clinical Trial Participation With Improved Overall Survival for Recurrent, Platinum-Resistant Ovarian Cancer.

OBJECTIVE: To investigate whether clinical trial participation is associated with overall survival in patients with platinum-resistant ovarian cancer. METHODS: An IRB-approved, retrospective, single-institution cohort study was performed in patients with platinum-resistant ovarian cancer from January 1, 2009, to December 31, 2017. Platinum resistance was defined as progression within 6 months after completion of platinum chemotherapy. Patients were divided into two cohorts: 1) clinical trial participants for platinum-resistant ovarian cancer or 2) standard of care. The association of trial participation with overall survival from the date of platinum resistance was assessed with univariate and multivariable models. RESULTS: Of 305 eligible patients with recurrent platinum-resistant ovarian cancer, 46 (15.1%) were clinical trial participants. There were no significant differences in age (61.2 years vs 63.3 years, P =.21), body mass index (27.5 vs 27.6, P =.90), race ( P =.61), medical comorbidities ( P >.05), or performance status ( P =.07) for clinical trial participants compared with those receiving standard of care. The majority underwent primary cytoreduction (76.1% vs 69.1%, P =.34) with no differences in residual disease ( P =.43) for clinical trial participants compared with those receiving standard of care. There was no difference in poly-ADP-ribose polymerase inhibitor (21.7% vs 15.1%, P =.26) or bevacizumab (22.2% vs 32.1%, P =.31) use for clinical trial participants compared with those receiving standard of care. On multivariable analysis controlling for comorbidities, stage, and germline mutational status, clinical trial participation was associated with significantly improved overall survival from the date of platinum resistance compared with standard of care (13.8 months vs 10.5 months, adjusted hazard ratio 1.46, 95% CI 1.04-2.05, P =.028). CONCLUSIONS: In this retrospective cohort of patients with platinum-resistant ovarian cancer, clinical trial participation was associated with improved overall survival compared with standard of care therapies. Availability and participation in clinical trials should be prioritized in patients with recurrent, platinum-resistant ovarian cancer.

Targeting CD47-SIRPa axis shows potent preclinical anti-tumor activity as monotherapy and synergizes with PARP inhibition.

The objective was to correlate CD47 gene expression with resistance to immune checkpoint inhibitors (ICI) in tumor tissue of gynecological cancer (GC). Further, we sought to assess the efficacy of targeting CD47 pathway alone and in combination in pre-clinical ovarian cancer (OC) models. We performed transcriptomic analyses in GC treated with ICI. Signaling pathway enrichment analysis was performed using Ingenuity Pathway Analysis. Immune cell abundance was estimated. CD47 expression was correlated with other pathways, objective response, and progression-free survival (PFS). Anti-tumor efficacy of anti-CD47 therapy alone and in combination was investigated both in-vitro and in-vivo using cell-line derived xenograft (CDX) and patient-derived xenograft (PDX) models. High CD47 expression associated with lower response to ICI and trended toward lower PFS in GC patients. Higher CD47 associated negatively with PDL1 and CTLA4 expression, as well as cytotoxic T-cells and dendritic cells but positively with TGF-ß, BRD4 and CXCR4/CXCL12 expression. Anti-CD47 significantly enhanced macrophage-mediated phagocytosis of OC cells in-vitro and exhibited potent anti-tumor activity in-vivo in OC CDX and PDX models. In-vitro treatment with PARPi increased CD47 expression. Anti-CD47 led to significantly enhanced in-vitro phagocytosis, enhanced STING pathway and synergized in-vivo when combined with PARP inhibitors in BRCA-deficient OC models. This study provides insight on the potential role of CD47 in mediating immunotherapy resistance and its association with higher TGF-ß, BRD4 and CXCR4/CXCL12 expression. Anti-CD47 showed potent anti-tumor activity and synergized with PARPi in OC models. These data support clinical development of anti-CD47 therapy with PARPi in OC.

LCK facilitates DNA damage repair by stabilizing RAD51 and BRCA1 in the nucleus of chemoresistant ovarian cancer.

Poly-ADP Ribose Polymerase (PARP) targeted therapy is clinically approved for the treatment of homologous recombination (HR) repair deficient tumors. The remarkable success of this therapy in the treatment of HR repair deficient cancers has not translated to HR-proficient cancers. Our studies identify the novel role of non-receptor lymphocyte-specific protein tyrosine kinase (LCK) in the regulation of HR repair in endometrioid epithelial ovarian cancer (eEOC) model. We show that DNA damage leads to direct interaction of LCK with the HR repair proteins RAD51 and BRCA1 in a kinase dependent manner RAD51 and BRCA1 stabilization. LCK expression is induced and activated in the nucleus in response to DNA damage insult. Disruption of LCK expression attenuates RAD51, BRCA1, and BRCA2 protein expression by hampering there stability and results in inhibition of HR-mediated DNA repair including suppression of RAD51 foci formation, and augmentation of γH2AX foci formation. In contrast LCK overexpression leads to increased RAD51 and BRCA1 expression with a concomitant increase in HR DNA damage repair. Importantly, attenuation of LCK sensitizes HR-proficient eEOC cells to PARP inhibitor in cells and pre-clinical mouse studies. Collectively, our findings identify a novel therapeutic strategy to expand the utility of PARP targeted therapy in HR proficient ovarian cancer.

Prospective evaluation of the tolerability and efficacy of niraparib dosing based on baseline body weight and platelet count: Results from the PRIMA/ENGOT-OV26/GOG-3012 trial.

BACKGROUND: The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) trial was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen of niraparib for first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer. METHODS: In the phase 3 PRIMA trial, patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy (N = 733) were initially treated with a fixed starting dose (FSD) regimen of 300 mg once daily. Subsequently, the protocol was amended so newly enrolled patients received an ISD: 200 mg once daily in patients with baseline body weight < 77 kg or baseline platelet count < 150,000/µL, and 300 mg once daily in all other patients. Efficacy and safety outcomes were assessed by starting dose. RESULTS: Overall, 475 (64.8%) patients were assigned to an FSD (niraparib, n = 317; placebo, n = 158) and 258 (35.2%) were assigned to an ISD (niraparib, n = 170; placebo, n = 88). Efficacy in patients who received FSD or ISD was similar for the overall (FSD hazard ratio [HR], 0.59 [95% CI, 0.46-0.76] vs. ISD HR, 0.69 [95% CI, 0.48-0.98]) and the homologous recombination-deficient (FSD HR, 0.44 [95% CI, 0.30-0.64] vs. ISD HR, 0.39 [95% CI, 0.22-0.72]) populations. In patients with low body weight/platelet count, rates of grades ≥3 and 4 hematologic treatment-emergent adverse events, dose interruptions, and dose reductions were lower for those who received ISD than for those who received FSD. CONCLUSIONS: In PRIMA, similar dose intensity, similar efficacy, and improved safety were observed with the ISD compared with the FSD regimen.

Efficacy and toxicity of carboplatin and gemcitabine administered on day 1 and day 8 (day1&8) versus day 1-only for platinum-sensitive recurrent epithelial ovarian cancer.

OBJECTIVE: To compare response rate, progression-free survival, overall survival, and toxicity of carboplatin and gemcitabine administered on day 1 and day 8 (day1&8) versus a modified day 1-only regimen in recurrent platinum-sensitive ovarian cancer. METHODS: A retrospective single-institution cohort study was performed in women with recurrent platinum-sensitive ovarian cancer between January 2009 and December 2020 treated with carboplatin and gemcitabine on a 21-day cycle. The impact of dosing schedule on response rate, progression-free survival, overall survival, and toxicities was assessed with univariate and multivariate models. RESULTS: Of 200 patients, 26% (n=52) completed day 1&8, 21.5% (n=43) started day 1&8 but dropped day 8, and 52.5% (n=105) received day 1-only. There were no differences in demographics. Median starting carboplatin and gemcitabine doses were area under curve (AUC) 5 and 600 mg/m2 for day 1-only versus AUC4 and 750 mg/m2 among day 1&8, respectively (p<0.001). A total of 43 patients (45.3%) dropped day 8 primarily due to neutropenia (51.2%) or thrombocytopenia (30.2%). The response rates were 69.3% for day 1&8-completed, 67.5% for day 1&8-dropped, and 67.6% for day 1-only (p=0.92). Median progression-free survival was 13.1, 12.1, and 12.4 months for day 1&8-completed, day 1&8-dropped, and day 1-only, respectively (p=0.29). Median overall survival was 28.2, 33.5, and 34.3 months for the above groups (p=0.42). The rate of grade 3/4 hematologic toxicity (48.9% vs 31.4%, p=0.002), dose reductions (58.9% vs 33.7%, p<0.001), blood transfusions (22.1% vs 10.5%, p=0.025), and treatment with pegfilgrastim (64.2% vs 51%, p=0.059) were higher among day 1&8 versus day 1-only, respectively. CONCLUSIONS: There was no difference in response rate, progression-free survival, or overall survival for day 1&8 versus day 1-only, regardless of whether day 8 was dropped. Day 1&8 was associated with greater hematologic toxicity. A modified day 1-only regimen may represent an alternative to day 1&8 and warrants prospective study.

Ovarian cancer recurrence: is the definition of platinum sensitivity modified by PARPi, bevacizumab or other intervening treatments? : a clinical perspective.

In view of the high risk of recurrent disease in stage III and IV ovarian cancer following primary first-line chemotherapy, a variety of maintenance and consolidation treatment strategies have been developed. These have included: radiation, intravenous or intraperitoneal chemotherapy, targeted therapies, and immunotherapy. Popular at this time is the use of Poly-adenosine ribose polymerase (PARP) inhibitors and bevacizumab as maintenance therapy. What effect these maintenance or consolidation therapies have on subsequent response to therapy, specifically platinum-based chemotherapy, is only beginning to be studied. In this manuscript, we review the impact of PARP inhibitors and bevacizumab as well as radiation and maintenance chemotherapy on subsequent response to treatment. Prior use of bevacizumab does not appear to adversely affect subsequent response to platinum-based chemotherapy or platinum-based chemotherapy with bevacizumab. Prior therapy with PARP inhibitors induces platinum resistance to subsequent platinum-based therapy and negates classic predictors of response such as platinum-free interval and breast cancer susceptibility gene (BRCA) mutational status.

What proportion of patients with stage 3 ovarian cancer are potentially cured following intraperitoneal chemotherapy? Analysis of the long term (≥10 years) survivors in NRG/GOG randomized clinical trials of intraperitoneal and intravenous chemotherapy in stage III ovarian cancer.

OBJECTIVE: Patients with advanced epithelial ovarian cancer (EOC) alive without progression at a landmark time-point of 10 years from diagnosis are likely cured. We report the proportion of patients with Stage III EOC who were long-term disease-free survivors (LTDFS≥10 years) following either intraperitoneal (IP) or intravenous (IV) chemotherapy as well as the predictors of LTDFS. METHODS: Data from 3 mature NRG/GOG trials (104, 114, 172) were analyzed and included demographics, clinicopathologic details, route of administration, and survival outcomes of patients living ≥10 years assessed according to the Kaplan-Meier method. Cox regression survival analysis was performed to evaluate independent prognostic predictors of LTDFS. RESULTS: Of 1174 patients randomized, 10-year overall survival (OS) was 26% (95% CI, 23-28%) and LTDFS ≥10 years was 18% (95% CI, 16-20%). Patients with LTDFS ≥10 years had a median age of 54.6 years (p < 0.001). Younger age (p < 0.001) was the only independent prognostic factor for LTDFS≥10 years on multivariate Cox analysis. CONCLUSIONS: Approximately 18% of patients were LTDFS ≥10 years. They form the tail end of the survival curve and are likely cured. Our results provide a comparative benchmark to evaluate the impact of PARP inhibitors in 1st line maintenance trials on survival outcomes.

Assessment of travel distance for hyperthermic intraperitoneal chemotherapy in women with ovarian cancer.

Objective s: To evaluate travel distance in women with advanced or recurrent epithelial ovarian cancer (OC) undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) and the subsequent impact upon outcomes. Methods: An IRB-approved single-institution prospective registry was queried for women with OC who underwent HIPEC from 1/1/2009-12/1/2020. Demographic, oncologic, and surgical data were recorded. The patient's home zip code was compared to the institutional zip code to determine travel distance using Google Maps. Patients were divided into three strata for analysis: 1) local: ≤50 miles, 2) regional: 51-99 miles, and 3) distant: ≥100 miles and univariate analysis was performed. Results: Of 127 women, the median distance travelled was 57.0 miles (IQR: 20.6, 84.6). There were no significant differences in mild (28.3% vs. 26.3 vs. 24.1%), moderate (21.7% vs. 15.8% vs. 17.2%) or severe postoperative complications (11.7% vs. 5.3% vs. 17.2%) (p = 0.75) for local, regional and distant patients, respectively. There was no difference in progression-free survival (17.4 vs. 22.2 vs. 12.8 months, p > 0.05) or overall survival (57.3 vs. 61.6 vs. 29.2 months, p > 0.05) for local, regional or distant patients, respectively. Conclusions: This study demonstrates that women with OC are willing to travel for HIPEC, with over 50% traveling > 50 miles. Our results suggest that women who travel for HIPEC procedures are not at increased risk for perioperative complications or worse oncologic outcomes than those local to HIPEC centers.

Incidence and prognostic significance of inguinal lymph node metastasis in women with newly diagnosed epithelial ovarian cancer.

OBJECTIVE(S): To assess incidence and oncologic outcomes in women with advanced epithelial ovarian cancer (EOC) with inguinal lymph node metastasis (ILNM) at diagnosis. METHODS: An IRB-approved, retrospective single-institution cohort study was performed in women with stage III/IV EOC from 2009 to 2017. Patients with inguinal lymphadenopathy (defined as >1 cm in short axis) clinically or radiographically were identified. The impact of ILNM on progression-free survival (PFS) and overall survival (OS) were assessed. RESULTS: Of the 562 women with advanced EOC, 18 (3.2%) had ILNM at diagnosis, accounting for 25.7% of all patients with stage IVB disease (n = 70). Five patients (27.7%) had a known genetic predisposition for EOC, including BRCA1 (11.1%, n = 2), BRCA2 (11.1%, n = 2) and BRIP1 (5.6%, n = 1). The majority of patients underwent optimal primary cytoreductive surgery (CRS), including debulking of inguinal nodal metastasis (83.3%, n = 15), with 50% (n = 9) having no gross residual disease after surgery. There was no difference in PFS (19.9 vs. 19.9 vs. 17.2 months, p = 0.84) or OS (137.2 vs. 52.9 vs. 67.6 months, p = 0.29) in women with stage III/IV with ILNM, stage III/IV without ILNM, and stage IVB disease without ILNM, respectively. Progression-free survival was improved in women with ILNM who underwent an optimal resection to no macroscopic disease vs. non-optimal resection (27.4 vs. 14.3 months, p = 0.019). Median overall survival at the time of analysis did not reach statistical significance (137.2 vs. 57.3 months, p = 0.24). CONCLUSION(S): In this retrospective cohort study, 3.2% of women with advanced EOC presented with ILNM at diagnosis. Although ILNM did not portend worse clinical outcomes compared to all Stage III/IV and Stage IVB patients, respectively, resection to no gross residual disease was associated with improved PFS.

Effect of risk-reducing salpingo-oophorectomy on sex steroid hormone serum levels among postmenopausal women: an NRG Oncology/Gynecologic Oncology Group study.

BACKGROUND: Risk-reducing salpingo-oophorectomy is an effective ovarian cancer risk reduction strategy. However, bilateral oophorectomy has also been associated with increased long-term nonneoplastic sequelae, effects suggested to be mediated through reductions in systemic sex steroid hormone levels. Currently, it is unclear whether the postmenopausal ovary contributes to the systemic hormonal milieu or whether postmenopausal ovarian volume or other factors, such as body mass index and age, affect systemic hormone levels. OBJECTIVE: We examined the impact of oophorectomy on sex steroid hormone levels in postmenopausal women. Furthermore, we explored how well ovarian volume measured by transvaginal ultrasound correlated with direct ovarian measures obtained during surgical pathology evaluation and investigated the association between hormone levels and ovarian volumes. STUDY DESIGN: Postmenopausal women who underwent risk-reducing salpingo-oophorectomy (180 cases) or ovarian cancer screening (38 controls) enrolled in an international, prospective study of risk-reducing salpingo-oophorectomy and risk of ovarian cancer algorithm-based screening among women at increased risk of ovarian cancer (Gynecologic Oncology Group-0199) were included in this analysis. Controls were frequency matched to the cases on age at menopause, age at study entry, and time interval between blood draws. Ovarian volume was calculated using measurements obtained from transvaginal ultrasound in both cases and controls and measurements recorded in surgical pathology reports from cases. Serum hormone levels of testosterone, androstenedione, androstenediol, dihydrotestosterone, androsterone, dehydroepiandrosterone, estrone, estradiol, and sex hormone-binding globulin were measured at baseline and follow-up. Spearman correlation coefficients were used to compare ovarian volumes as measured on transvaginal ultrasound and pathology examinations. Correlations between ovarian volumes by transvaginal ultrasound and measured hormone levels were examined using linear regression models. All models were adjusted for age. Paired t tests were performed to evaluate individual differences in hormone levels before and after risk-reducing salpingo-oophorectomy. RESULTS: Ovarian volumes measured by transvaginal ultrasound were only moderately correlated with those reported on pathology reports (Spearman rho [ρ]=0.42). The median time interval between risk-reducing salpingo-oophorectomy and follow-up for the cases was 13.3 months (range, 6.0-19.3), and the median time interval between baseline and follow-up for the controls was 12.7 months (range, 8.7-13.4). Sex steroid levels decreased with age but were not correlated with transvaginal ultrasound ovarian volume, body mass index, or time since menopause. Estradiol levels were significantly lower after risk-reducing salpingo-oophorectomy (percentage change, -61.9 post-risk-reducing salpingo-oophorectomy vs +15.2 in controls; P=.02), but no significant differences were seen for the other hormones. CONCLUSION: Ovarian volumes measured by transvaginal ultrasound were moderately correlated with volumes directly measured on pathology specimens and were not correlated with sex steroid hormone levels in postmenopausal women. Estradiol was the only hormone that declined significantly after risk-reducing salpingo-oophorectomy. Thus, it remains unclear whether the limited post-risk-reducing salpingo-oophorectomy changes in sex steroid hormones among postmenopausal women impact long-term adverse outcomes.

The Overtreatment and Cost Effectiveness of Primary versus Secondary Maintenance Therapy with Poly-Adenosine Ribose Phosphate Inhibitors (PARPi) for Epithelial Ovarian Cancer (EOC).

BACKGROUND: No data exist to suggest PARP inhibitor (PARPi) therapy as first-line maintenance is superior to PARPi therapy as second-line maintenance. OBJECTIVE: To determine the efficacy and cost of primary versus secondary olaparib or niraparib maintenance in Epithelial Ovarian Cancer (EOC). METHODS: A retrospective cohort study was performed in women with EOC to determine the survival following primary or secondary PARPi maintenance. We modeled the costs of olaparib and niraparib based on previously published costs and duration of therapy based on the Solo 1/Solo 2 and Prima and Nova trials, respectively. RESULTS: Among 40 patients treated with PARPi as primary or secondary maintenance there was no difference in overall survival (p=0.97). Among 166 women with stage III/IV germ-line BRCA mutated EOC, 28.8% were disease free for >3 years (18.6% never recurred and 10.2% recurred >3 years after chemotherapy). Since 29% of the BRCA mutated patients did not recur within 3 years, primary olaparib maintenance therapy was significantly more expensive than secondary olaparib maintenance therapy by 260%. Primary niraparib maintenance therapy was slightly more expensive than secondary niraparib maintenance therapy by 4%, 51%, and 15% for BRCA mutated, HR deficient, and HR proficient patients, respectively. By eliminating the overtreatment of patients with primary PARPi therapy, the cost savings for 100 women with EOC with BRCA mutations would be $37,335,360 for olaparib and $8,197,592 for niraparib. CONCLUSION: Up to 29% of BRCA mutated patients may be overtreated with primary PARPi maintenance with significantly increased treatment costs.