Faculty Bibliography

Introduction/Background Niraparib improves progression-free survival (PFS) in patients (pts) with newly diagnosed advanced ovarian cancer after 1st-line (1L) platinum-based chemotherapy (CT). We report the efficacy of niraparib in pts by biomarker status. Methodology This double-blind, placebo (PBO)-controlled, phase 3 study randomized 733 pts with newly diagnosed advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete or partial response (CR or PR) to 1L platinum-based CT. Stratification factors were best response to the 1L CT (CR/PR), receipt of neoadjuvant CT (yes/no), and homologous recombination status (deficient/proficient/ not determined). Pts received niraparib or PBO once daily. The primary endpoint of PFS assessed by blinded independent central review was analyzed using a stratified Cox proportional hazards model and hierarchically tested in homologous recombination deficient pts, then the overall population. Results Of 733 randomized pts (niraparib, 487; PBO, 246), 373 (51%) were homologous recombination deficient (niraparib, 247; PBO, 126) and 249 (34%) were homologous recombination proficient (niraparib, 169; PBO, 80). Overall, 35% had stage IV disease, 67% received NACT, and 31% had a PR to 1L CT. Niraparib-treated pts in all the biomarkers groups had a statistically significant and clinically meaningful benefit in PFS (table 1). The most common grade >=3 adverse events were anemia (31%), thrombocytopenia (29%), and neutropenia (13%). Conclusion Niraparib improved PFS as evidenced by reduction in the risk of recurrence or death due to any cause in the overall population of advanced ovarian cancer. No new safety signals were identified

Background: Niraparib has shown progression-free survival (PFS) benefit in recurrent OC after platinum-based chemotherapy (CT) in all patients (pts) regardless of BRCA status. This study evaluated the efficacy of niraparib in pts with newly diagnosed advanced OC after completion of first-line (1L) CT regardless of BRCA status.
Method(s): This double-blind, placebo (PBO)-controlled phase III trial evaluated niraparib in pts with newly diagnosed advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer with a complete or partial response (CR or PR) to 1L platinum-based CT. Stratification factors were best response to the 1L CT regimen (CR/PR), receipt of neoadjuvant CT (NACT; yes/no), and homologous recombination deficiency (HRD) status (positive/negative/unknown) per the Myriad myChoice HRD test. Pts received niraparib or PBO once daily. PFS assessed by blinded independent central review was the primary end point, analyzed using a stratified Cox proportional hazards model and hierarchically tested in HRD-positive (HRDpos) pts and then the overall population.
Result(s): Of 733 randomized pts (niraparib, 487; PBO, 246), 373 (51%) were HRDpos (niraparib, 247; PBO, 126). Overall, 35% had stage IV disease, 67% received NACT, and 31% had a PR to 1L CT. Niraparib-treated pts in the HRDpos subgroup and overall population had a significant reduction in the risk of disease recurrence or death with a substantial improvement in PFS (Table). All subgroups showed a sustained and durable treatment effect. The most common grade >=3 adverse events were anemia (31%), thrombocytopenia (29%), and neutropenia (13%). No treatment-related deaths occurred.
Conclusion(s): Niraparib significantly improved PFS in pts with newly diagnosed advanced OC, including pts at high risk of progressive disease in the HRDpos subgroup and overall population. No new safety signals were identified. Niraparib should be considered as a treatment option for pts with advanced OC after completion of 1L CT. (Table Presented)

Objectives To describe the practice patterns and treatment of nonagenarians who initiated care with a gynecologic oncologist. Methods Retrospective chart review of women aged 90 or older who presented to a gynecologic oncologist between 10/09 and 12/18 at an urban academic medical center. Descriptive statistics utilized for variables of interest. Results We identified 34 nonagenarians (median age 92, range 90-98): 10 (29%) had benign disease, 8 (24%) pre-malignancy or suspected malignancy, and 16 (47%) malignancy. Of these, 79% had age and/or functional status discussed in the care plan. Of the 8 with suspected malignancy, 5 declined further workup. The cancer distribution revealed 5 (31%) vulvar, 5 (31%) uterine, 4 (25%) ovarian, 1 (6%) vaginal and 1 (6%) cervical cancers. Combined, 37% had stage I disease; 6% stage 3; 6% stage 4; 13% recurrent; and 25% unstaged. All received treatment plans: 7 (47%) with palliative intent and 8 (53%) with curative intent. In the curative group, 7 underwent surgery (1 adjuvant chemotherapy) and 1 chemotherapy/radiation. In the palliative group, 4 underwent radiation, 1 chemotherapy and 2 declined/unknown. Overall, 13 (87%) completed the proposed treatment. Treatment-related complications included 1 superficial skin infection and 1 thirty-day readmission. Conclusions Nonagenarians often presented with vulvar or endometrial cancer and 87% successfully completed treatment with minimal adverse effects or toxicity. Age and/or functional status were considered in the care plan for 79% of women, but it did not preclude treatments that had the potential to preserve meaningful quality of life and/or cure patients of their disease

Objectives To identify referral patterns and uptake of risk reducing surgery (RRS) in patients with non-BRCA genes associated with an increased risk of epithelial ovarian cancer. Methods A chart review of patients with mutations in MLH1, MSH2, EPCAM, MSH6, PMS2, RAD51C/D, BRIP1 was conducted from 2015-2018. Patients with BRCA1/2 and variants of uncertain significance were excluded; MSH6 and PMS2 were included (though recent change to insufficient evidence). Primary outcomes of interest were referral to a gynecologic oncologist and the uptake of RRS. Results Of 78 patients, 18 had undergone surgical management for treatment of cancer prior to genetic testing and were excluded. The majority of the patients (41 of 60, 68%) with non-BRCA actionable mutations were associated with Lynch Syndrome (LS). Of these patients, 23 of 60 (56%) were seen by gynecologic oncologists. Twenty of 41 (49%) underwent RRS. Excluding the MSH6 and PMS2 patients, 9 of 21 (43%) of patients with LS underwent RRS. Among patients with the non-BRCA and non-LS associated genes (RAD51C, RAD51D, BRIP1) the most common reason for testing was family history of cancer (10 of 19). Fifteen of 19 were referred to a gynecologic oncologist; all patients with BRIP1 mutation were referred, while 70% of those with RAD51/D were referred. Among this subset of patients, 9/19 (47%) patients underwent RRS; the remaining patients were screened with surveillance ultrasounds and/or CA-125. Conclusions Two-thirds of patients with non-BRCA genes associated with increased risk of ovarian cancer were referred to gynecologic oncologists, with a 48% of uptake or RRS

Objectives Platinum and taxane-based therapy is considered standard for patients with newly diagnosed advanced/recurrent EC. We sought to compare post-platinum treatment outcomes between published and real-world sources. Methods We searched PubMed (10 years) and Embase conference proceedings (3 years) for median OS (mOS), PFS (mPFS), ORR, and grade 3/4 adverse events (AEs) in advanced/recurrent EC, and compared to IBM Market-Scan real-world US claims data (1/2014-11/2018). For MarketScan, post-platinum therapy initiation (Index) represents the date of first EC drug claim after the end of platinum. Results Data were extracted from 28 studies, including 4 controlled studies (3 randomized). Across studies, mOS was 9.6 mo (range 5.5-14.5 mo) and mPFS 2.8 mo (1.4-7.4 mo). Among the 5 studies with highest ORR, mPFS was 3.4 mo (3.0-7.4 mo). Most commonly reported grade 3/4 AEs were diarrhea (in 9/28 studies=32%), fatigue (8/28=29%), and anemia (7/28=25%). 1,576 patients met the real-world inclusion criteria. Median follow-up was 9.3 mo post-Index, and median 29.6 mo pre-Index coverage. 76% of patients received initial platinum-taxane therapy, most commonly carboplatin-paclitaxel (63%). Post-Index, 48% of patients received monotherapy: 19% hormonal therapy, 9% liposomal doxorubicin, 5% bevacizumab, 3% taxane; 2% any other monotherapy. Besides carboplatin-paclitaxel (13%), 4% received any other combination regimen. Median duration of post-platinum treatment was 3.5 mo across regimens. Conclusions Although chemotherapy and hormonal therapy are used for EC post-platinum, efficacy is lacking among reported studies and real-world data, and no uniform standard of care exists. More effective and tolerable therapies are needed for advanced/recurrent EC

BACKGROUND:mutations. The efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy is unknown. METHODS:In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival. RESULTS:Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred. CONCLUSIONS:Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency. (Funded by GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov number, NCT02655016.).

Objective: TSR-042 is an investigational humanized antiprogrammed death (PD)-1 monoclonal antibody that binds with high affinity to the PD-1 receptor and effectively blocks interaction with the ligands PD-L1 and PD-L2. TSR-042 is being evaluated in patients with advanced solid tumors in the ongoing phase I/II GARNET trial (NCT02715284) (Sachdev JC et al. Ann Oncol. 2017(suppl 5):28:420;1185P). Here we present safety and efficacy data from the previously treated recurrent or advanced endometrial cancer (EC) cohorts, along with pharmacokinetics (PK) and receptor occupancy (RO) findings at the recommended phase II dose (RP2D).
Method(s): Patients with previously treated recurrent or advanced EC were evaluated. Patients received the RP2D of TSR-042: 500 mg Q3 weeks for the first 4 cycles and 1,000 mg Q6 weeks thereafter. Antitumor activity was assessed by investigators per immune related (ir) RECIST. Serum and peripheral blood mononuclear cells were collected for PK and RO measurements, respectively.
Result(s): A total of 110 EC patients received at least 1 dose of TSR-042 at the RP2D. The median age was 66.0 years. The median number of prior lines of therapy for advanced or metastatic disease was 1 (range 0-3). Overall, 94 patients had at least 1 tumor assessment (n = 79) or discontinued treatment prior to week 12 (n = 15); the overall response rate (including confirmed and unconfirmed responses per irRECIST) among these patients was 27.7% (50.0% in microsatellite instability-high [MSI-H] patients; 19.1% in microsatellite stable [MSS] patients). The disease control rate among these patients was 48.9%. At the time of data cutoff, responses were ongoing in 88.4% of responders. Detailed efficacy results based on microsatellite status will be presented at the meeting. Sixty-eight EC patients (61.8%) had at least 1 treatment-related adverse event (TRAE). Grade >=3 TRAEs were reported in 13 patients (11.8%), and the most common grade >=3 TRAE was aspartate aminotransferase increased (2.7%). TSR-042 PK was linear and dose-proportional. Maximal RO was observed at the RP2D consistent with previous results and was maintained through the course of treatment.
Conclusion(s): TSR-042 demonstrated robust clinical activity in patients with previously treated recurrent or advanced EC in both MSI-H and MSS subgroups and a safety profile similar to approved anti-PD-1 therapies.
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