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BACKGROUND: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. DESIGN: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts' consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. CONCLUSION: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer. ispartof: ANNALS OF ONCOLOGY vol:33 issue:3 pages:276-287 ispartof: location:England status: published

Background Prognosis and OS are poor in patients with advanced or recurrent endometrial cancer (EC). First-line standard of care for these patients is paclitaxel-carboplatin chemotherapy; however, more effective and tolerable therapies are needed. In the phase 1b/2 trial KEYNOTE-146, which assessed the PD-1 inhibitor pembrolizumab combined with the multikinase inhibitor lenvatinib, an ORR of 38% was observed in patients with previously treated advanced EC. ENGOT-en9/LEAP-001 (NCT03884101) is a randomized, open-label, active-controlled, phase 3 study investigating pembrolizumab + lenvatinib vs chemotherapy in patients with EC. Trial design Patients with newly diagnosed advanced (stage III-IV) or recurrent EC not previously treated with antiangiogenic agents; systemic chemotherapy (unless within a chemoradiation regimen); PD-1, PD-L1, or PD-L2 inhibitors; or other T-cell receptor–targeted therapies will be eligible. Patients will be randomized 1:1 to receive pembrolizumab 200 mg Q3W + lenvatinib 20 mg daily or paclitaxel 175 mg/m2 Q3W + carboplatin AUC 6 Q3W. Randomization will be stratified by proficient vs deficient mismatch repair (pMMR vs dMMR) status. The pMMR population will be further stratified by prior chemoradiation (yes/no), measurable disease (yes/no), and ECOG performance status (0/1). Patients will receive treatment for ≤35 cycles of pembrolizumab vs 7 cycles of chemotherapy or until initiation of a new anticancer treatment, unacceptable AEs, or withdrawal of consent. Primary endpoints are PFS (per RECIST v1.1 by blinded independent central review) and OS. Secondary endpoints are ORR, health-related QOL, safety/tolerability, and lenvatinib pharmacokinetics. Exploratory endpoints are disease control rate, clinical benefit rate, and duration of response. Enrollment is ongoing.

Introduction/Background Maintenance therapy with PARP inhibitor, olaparib, showed its efficacy in term of prolonged progression-free survival (PFS) and some others endpoints in platinum-sensitive, BRCA1/2-dependent, recurrent ovarian cancer (BRCA1/2-PSROC) in phase 2 and 3 clinical trials. The aim of the study was to analyze real-world effect of olaparib treatment in BRCA1/2-PSROC patients in Poland. Methodology Olaparib therapy was funded by Polish Ministry of Health for patients with deleterious BRCA1/2 mutations. Inclusion and exclusion criteria consistent with, ‘Study 19’ ones were strictly kept and noted in medical records. Follow-up included monthly visits with basic lab tests, Ca125 level and computer tomography (CT) performed three-monthly or if progression was suspected. Treatment was stopped when progression by RECIST criteria was seen, in case of allergy to the drug or long-term grade ≥3 NCI CTC toxicity. No treatment beyond progression was allowed. Date of progression consistent with CT scan date was noted in medical records. Patients were followed until progression or treatment discontinuation. Time to olaparib discontinuation (TTD) as a surrogate of PFS were plotted using Kaplan-Meier survival curves. Results Between 19/09/2016 and 30/07/2018, 311 patients with BRCA1/2-PSROC started maintenance therapy with olaparib, 400 mg twice daily (capsules). Finally, data on follow-up time and TTD from 301 patients were available for the analysis. The end of therapy in analyzed period was noted in 63 (21%) of patients. Median follow up time was 245 days (range 29–668; SD=152,6). Median of TTD was not reached at 22 months. Conclusion The effect of olaparib maintenance therapy in platinum-sensitive recurrent ovarian cancer patients in Poland confirms its effectiveness in term of TTD, calculated as a surogat of PFS, when strict inclusion and exclusion criteria are kept. Disclosure Authors received honoraries and travel grants from Astra-Zeneca Polska SA.

Background Data from a randomized Phase II trial (NCT00628251) of olaparib (capsules, 200 or 400 mg bid, n=32 per arm) vs pegylated liposomal doxorubicin (PLD, n=33) in gBRCAm OC pts with recurrence ≤12 months after prior platinum therapy indicated efficacy for olaparib (Kaye et al. JCO 2012). However, the efficacy of PLD was higher than previously reported in this setting. We led a confirmatory Phase III, open-label study of olaparib vs non-platinum chemotherapy in gBRCAm PSR OC pts (NCT02282020). Methods Pts were randomized (2:1) to olaparib tablets (300 mg bid) or chemotherapy treatment of physician’s choice (TPC) (paclitaxel [P; 80 mg/m2 on day 1 (D1), D8, D15, D22 every 4 weeks (q4w)], topotecan [T; 4 mg/m2 D1, D8, D15 q4w], gemcitabine [G; 1000 mg/m2 D1, D8, D15 q4w] or PLD [50 mg/m2 D1 q4w]) until progression, stratified by: TPC, prior lines of chemotherapy (2–3 vs ≥4) and platinum-free interval (6–12 vs >12 months). Primary endpoint: ORR (blinded independent central review [BICR]). Secondary endpoints included PFS and safety. Results 266 gBRCAm PSR OC pts were randomized (olaparib, n=178; TPC, n=88 [PLD, n=47; P, n=20; G, n=13; T, n=8]); 12 in the TPC arm withdrew before receiving study treatment. 223 pts (84%) had baseline BICR measurable disease (olaparib, n=151; TPC, n=72). ORR was 72% with olaparib vs 51% with TPC (OR 2.53, 95% CI 1.40–4.58; P=0.002). HR for PFS by BICR was 0.62 (95% CI 0.43–0.91; P=0.013; median 13.4 vs 9.2 months [olaparib vs TPC]) and by investigator assessment was 0.49 (95% CI 0.35–0.70; P Conclusions Pts with gBRCAm PSR OC receiving olaparib monotherapy had a significant, clinically relevant improvement in ORR and PFS vs TPC, with no new safety signals.

22191 Among women with BRCA1 mutation the risk of developing breast cancer is 50 - 80%, ovarian cancer 40% and about 10% for Fallopian tube and peritoneal cancer. One of the possibilities to reduce...