Matulonis, Ursula A.

Abstract Background: The combination of cediranib (ced) and olaparib (olap) improves progression-free survival and overall response rates (ORR) in women with recurrent plat sensitive high-grade serous (HGS) ovarian cancer compared to olap alone. In this Phase 2 study of ced/olap in women with relapsed ovarian cancer (NCT02345265), we observed an ORR of 74% with ced/olap in plat sensitive relapsed patients (pts) and an ORR of 20% in plat resistant pts. BROCA-HR was performed to characterize tumor HRD status and to correlate this with the activity of ced/olap in the plat sensitive and resistant settings. Methods: Pts with relapsed ovarian cancer across 11 centers were enrolled to 2 cohorts, either plat sensitive or resistant. All pts received ced 30mg daily and olap tablets 200mg BID. Archival, pre-treatment, and on-treatment biopsies were collected on all pts where safely feasible; pts also had the option of undergoing a post-progression biopsy. A baseline blood sample was collected for germline testing and matched control. Available samples were sequenced with BROCA-HR, and HRD status was determined by (1) presence of an HR-related mutation or (2) an increase in loss of heterozygosity (LOH) score. Results: 72 pts were enrolled, with 70 pts receiving study treatment (35 plat sensitive and 35 plat resistant). BROCA-HR analysis is complete on 60 samples, with 10 samples in final analysis. The concordance of HRD status by presence of an HR-related mutation or by LOH score was relatively low (agreement=36/60=60%, Cohen's Kappa=0.28). In 19 pts with a germline BRCA mutation, 16 were HRD+ by LOH (LOH high), 2 were HRD- by LOH (LOH low), and 1 not quantifiable. 3 pts had a somatic BRCA mutation; 1 was LOH high, 1 LOH low, and 1 not quantifiable. 4 pts had non-BRCA somatic HR-related mutations (3 CDK12; 1 ATR); 3 were LOH high and 1 LOH low. Of the 34 pts without HR-related mutations, 15 were LOH high, 16 were LOH low, and 3 not quantifiable. In 29 plat sensitive pts with BROCA-HR results, 18 were HRD+ by mutation (12 germline BRCA, 3 somatic BRCA, 3 somatic other), and 16 were HRD+ by LOH (LOH high). The ORR in plat sensitive pts by HRD status with available HRD results was: 22/29=75.9% (13/18=72% HRDmut+; 9/11=82% HRDmut-); (12/16=75% LOH high; 6/9= 67% LOH low). In 31 plat resistant pts with BROCA-HR results, 8 were HRD+ by mutation (7 germline BRCA, 0 somatic BRCA, 1 somatic other), and 19 were HRD+ by LOH. The ORR in plat resistant pts by HRD status with available HRD results was: 7/31=22.6% (4/8=50% HRDmut+; 3/23=13% HRDmut-, P=0.05); (7/19=37% LOH high; 0/11= 0% LOH low, P=0.03). Updated results with the full data set are pending. Conclusion: Ced/olap has clinical activity in women with relapsed ovarian cancer, both in the plat sensitive and plat resistant settings. In women with plat sensitive disease, where response rates are high, HRD status by presence of an HR-related mutation or LOH status does not appear to provide significant additional information regarding likelihood of response. In women with plat resistant disease, the presence of HRD by an HR-related mutation or LOH status is correlated with a higher likelihood of response. Citation Format: Joyce F Liu, Su-Chun Cheng, Robert M Wenham, Andrea E Wahner Hendrickson, Deborah K Armstrong, Nancy Chan, David E Cohn, Jung-Min Lee, Richard T Penson, Mihaela Cristea, James Abbruzzese, Koji Matsuo, Alexander B Olawaiye, Jennifer Curtis, Geoffrey Shapiro, Ursula A Matulonis, Elise Kohn, Percy Ivy, Elizabeth M Swisher. Correlation of homologous recombination deficiency (HRD) status by BROCA-HR sequencing with response to combination cediranib and olaparib in relapsed ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A074. doi:10.1158/1535-7163.TARG-19-A074

5012 Background: VEGF receptor-mediated-signaling contributes to ovarian cancer pathogenesis. Elevated VEGF expression and serum levels are associated with poor clinical outcomes. We investigated RAM, a fully human VEGFR-2 antagonist antibody, in patients (pts) with persistent or recurrent EOC/FTC/PPC. Methods: Adult women with EOC/FTC/PPC who had completed ≥1 platinum (P)-based chemotherapeutic (ct) regimen and had a P-free interval (PFI) of <12 months (m), progression on, or persistent disease after P-based therapy were eligible. Any number of prior ct regimens was allowed. ECOG PS 0-1 and adequate organ function were required. Pts received 8 mg/kg RAM IV every 2 weeks. Primary endpoints were progression-free survival at 6m (PFS-6) and confirmed objective response rate (ORR) by RECIST 1.0. Results: 60 pts were treated; 1 remains on study as of Dec 2011. Median age was 62 years (range 27-80). Median number of prior regimens was 3 (range 1– 14). 51 pts (85%) received ≥ 2 prior regimens; 25 pts (42%) received >3 prior regimens. 45 pts (75%) were P resistant or refractory, with 65% (39 pts) serous tumors. PFS-6: 34.2% (95% CI: 21.7% – 47%). Best overall response: 3 PR (5%), 34 SD (57%), 20 PD (33%) and 3 not evaluable (5%). Median duration of PR: 5.6m (3.7, 5.6, 17.5); median PFS: 3.5m (95% CI: 2.3 – 5.3). Median OS: 11.1m (95% CI: 8.3 – 17.0). No unexpected toxicities were observed. Grade (G) 3 adverse events (AEs) observed in >5% of pts were: headache (10%) and fatigue (8%). No G4 AEs were observed in >5% of pts. 5 deaths occurred on RAM or within 30 days of discontinuation; 4 due to PD, and 1 due to intestinal perforation. 1 G4 bowel perforation and one G4 colo-vaginal fistula were noted. All 3 cases of perforation/fistula occurred in the setting of progressive, large-volume disease. Correlative biomarker studies are ongoing to identify patients most likely to benefit. Conclusions: Ramucirumab was reasonably tolerated and demonstrated single-agent activity in persistent or recurrent ovarian carcinoma, with approximately one-third of patients progression free at 6 months.

Abstract Background: In vivo synergy with concurrent PI3-Kinase inhibition and PARP inhibition has been observed in BRCA-deficient and BRCA-proficient preclinical models of triple negative breast cancer (TNBC) and ovarian cancer (OC). A phase I trial of the oral pan-class I PI3-Kinase inhibitor BKM120 and the PARP inhibitor olaparib demonstrated anti-cancer activity in TNBC and OC, both in patients with and without germline BRCA1 and BRCA2 (BRCA) mutations. However, CNS toxicity (depression) and liver function test abnormalities limited dose escalation of BKM120 prompting evaluation of the alpha specific PI3-Kinase inhibitor BYL719 (which has no CNS toxicity) in combination with olaparib. Methods: Olaparib was administered twice daily (tablet formulation) and BYL719 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with primary objectives of defining the maximum tolerated dose (MTD) and recommended phase 2 dose of the combination of BYL719 and olaparib, and secondary objectives of defining toxicity, activity, and pharmacokinetic profiles of both agents. Eligibility included recurrent TNBC or high grade serous (HGS) OC, or any histology OC or breast cancer (BC) with presence of a known germline BRCA mutation, performance status of 0-1 and measurable/evaluable cancer. Patients with platinum sensitive or resistant or refractory OC were eligible and prior PARP inhibitor use was allowed. Dose-expansion cohorts at the MTD were enrolled for both BC and OC. Results: 46 patients (16 BC and 30 OC) have been enrolled in the study; 28 patients participated in the dose escalation portion of the study (4 BC and 24 OC). Two patients with OC did not receive study drugs because of ineligibility. MTD was defined as BYL719 200mg once daily and olaparib 200mg twice daily. Dose limiting toxicities included hyperglycemia, rash and fever with decreased neutrophil count. Four patients (3 OC and 1 BC) discontinued protocol therapy because of toxicity (2 for hyperglycemia, 1 for nausea and 1 for allergic reaction). Most common toxicities included nausea, hyperglycemia, fatigue, diarrhea and vomiting. At the MTD, 6 patients with OC and 12 patients with BC were enrolled into a dose expansion cohort. The OC expansion cohort has completed enrollment, while the BC cohort is still enrolling. Among patients with OC who received study drugs (28 patients, 26 (93%) with platinum resistant disease), objective response rate (ORR) by RECIST 1.1 was 36% (10/28 patients, all partial responses (PRs)). Median duration of response was 167 days (range 16-398 days); 5 of 10 patients with PR remain on treatment. ORR was 33% for patients with germline BRCA mutations and 31% for patients without germline BRCA mutations. Among patients without germline BRCA mutations with platinum resistant OC, ORR was 29%. Conclusions: Combined BYL719 and olaparib is feasible, and similar clinical benefit was observed in patients with and without germline BRCA mutations. The activity of this combination in OC patients without germline BRCA mutations and with platinum resistant disease was higher than expected from olaparib monotherapy and warrants further investigation. This work was funded in part by the Stand Up To Cancer Ovarian Dream Team. Clinical trial: NCT01623349. Citation Format: Panagiotis A. Konstantinopoulos, William T. Barry, Michael Birrer, Shannon N. Westin, Sarah Farooq, Karen Cadoo, Christin Whalen, Weixiu Luo, Hui Liu, Carol Aghajanian, David B. Solit, Gordon B. Mills, Barry S. Taylor, Helen Won, Michael F. Berger, Sangeetha Palakurthi, Joyce F. Liu, Lew Cantley, Scott H. Kaufmann, Elizabeth M. Swisher, Alan D. D'Andrea, Eric Winer, Gerburg M. Wulf, Ursula A. Matulonis. Phase I study of the alpha specific PI3-Kinase inhibitor BYL719 and the poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib in recurrent ovarian and breast cancer: Analysis of the dose escalation and ovarian cancer expansion cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT008. doi:10.1158/1538-7445.AM2017-CT008