Treatment for advanced ovarian cancer is rarely curative; three quarters of patients with advanced disease relapse and ultimately die with resistant disease. Improving patient outcomes will require the introduction of new treatments and better patient selection. Abrogations in the DNA damage response (DDR) may allow such stratifications.A defective DNA-damage response (DDR) is a defining hallmark of high grade serous ovarian cancer (HGSOC). Indeed, current evidence indicates that all HGSOCs harbour a defect in at least one major DDR pathway. However, defective DDR is not mediated through a single mechanism but rather results from a variety of (epi)genetic lesions affecting one or more of the five major DNA repair pathways. Understanding the relationship between these pathways and how these are abrogated will be necessary in order to facilitate appropriate selection of both existing and novel agents.Here we review the current understanding of the DDR with regard to ovarian, and particularly high grade serous, cancer, with reference to existing and emerging treatments as appropriate.

8508 Background: Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) effective in treating advanced EGFR-mutated non-small cell lung cancer (NSCLC). Adjuvant osimertinib significantly decreases disease recurrence in stage IB-IIIA EGFR-mutated NSCLC. However, the benefit of neoadjuvant osimertinib prior to surgical resection remains unknown. Methods: This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (AJCC V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (NCT03433469). Patients received osimertinib 80 mg orally daily for up to two 28-day cycles prior to surgical resection. The primary endpoint was major pathological response (mPR) rate (≤10% residual viable tumor). 27 evaluable patients provide 87% power to detect a mPR rate of 50% with α = 0.05. Secondary endpoints included pathological response (PR) rate (≤50% residual viable tumor), pathological complete response (pCR) rate, unconfirmed objective response rate (ORR), rate of lymph node downstaging, unanticipated delays to surgery, surgical complication rate, disease-free survival (DFS), overall survival (OS), safety, and tumor mutational profile. Results: A total of 27 patients with early-stage (8 stage IA/B, 10 stage IIA/B, 9 stage IIIA) EGFR-mutated (11 exon 19 del, 16 L858R) NSCLC were treated with neoadjuvant osimertinib for a median 56 days prior to surgical resection. 24 (89%) patients underwent subsequent surgery; 3 (11%) patients were converted to definitive chemoradiotherapy. The mPR rate was 15% (4/27 patients) by intention-to-treat analysis. The PR rate was 48% (13/27). No pCR’s were observed. Partial responses by radiography were observed in 52% (14/27) of patients and stable disease in 44% (12/27) of patients. Lymph node downstaging was achieved in 44% (4/9) of patients with positive lymph nodes. Median DFS after surgical resection was 32 months (95% CI 26-not reached) with a median follow-up of 11 months. OS data are immature. Significant adverse events occurred in 3 patients with grade 2 (G2) dyspnea, grade 3 (G3) pulmonary embolism, and G3 atrial fibrillation. One patient developed G2 treatment-related pneumonitis that resolved without steroids. Perioperative complications occurred in 38% (9/24) of patients; most involved rapidly reversible postoperative G2 atrial fibrillation (6/9) unrelated to study drug. Tumors were evaluable for genetic alterations from 16 patients. 4/6 patients who did not achieve a PR had tumors that harbored loss of function mutations in RBM10 as compared to 0/10 patients who achieved a PR (p < 0.01). Conclusions: Neoadjuvant osimertinib in surgically resectable EGFR-mutated NSCLC achieved a 15% mPR, which did not meet the primary endpoint. Treatment was safe and may induce pathological responses and lymph node-downstaging of disease. Co-mutations in RBM10 may limit response. Clinical trial information: NCT03433469 .