Preliminary experience with the use of chemotherapy (CT) following treatment with olaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi), in patients with <i>BRCA1/2</i>-deficient ovarian cancer (BDOC).

Abstract

5041 Background: A synthetic lethal approach by PARP inhibition has clinical activity in BDOC (NEJM 2009; 361: 123-34). Proposed mechanisms of PARPi resistance include the restoration of BRCA1/2 function, with theoretical impact both on platinum (PL) and taxane (TX) sensitivities (Nature 2008; 451: 1111-5, CCR 2007; 13: 7413-20). The aim of this study was to provide clinical data on the use of CT following olaparib therapy. Methods: Patients (p) with advanced BDOC who received CT following disease progression on olaparib (Apr 06-Nov 09; doses ≥200mg bd) were included. Demographic and clinicopathologic factors, treatment details, and responses were documented. Results: Twenty-six p (confirmed BRCA1/2 mutations [n=22]; strong family history of BRCA1/2-associated cancers [n=4]) were treated with CT following progression on olaparib. These p previously received a median of 3 lines of CT (range 1-10), a median of 2 with PL (range 1-7) and 1 with TX (range 1-2); 58% and 38% of these p had previous progression-free survival (PFS) of <6 months (m) following PL and TX-based CT, respectively. Response rate (RR) by RECIST/GCIG criteria to olaparib was 54% (95% CI 35-73). Following olaparib, most p received carboplatin (Cb) and/or TX-based CT. The median interval between the start of olaparib and CT was 8.7 m (range 1.2-26.6). Of 23 evaluable p (Table), overall RR was 43% (95% CI 23-64); these responses occurred independently of responses to olaparib. Overall median PFS and overall survival were 3.8 m (95% CI 2.1-5.6) and 7.6 m (95% CI 6.2-8.9). RRs to Cb and TX-based CT were 64% (95% CI 35–92) and 70% (95% CI 42-98), respectively. Seven p who received other regimens had no response. Conclusions: This study provides preliminary evidence that chemoresponsiveness is maintained, particularly with Cb and TX, in this group of heavily pretreated p following treatment with olaparib. Further correlative work with additional follow-up will be conducted. Regimen n (evaluable p) n (responses) Cb/liposomal doxorubicin (LD) 3 2 Cb/gemcitabine 3 1 Weekly Cb/paclitaxel (P) 5 4 Weekly P 4 3 Docetaxel 1 0 LD 4 0 Topotecan 2 0 5-FU/doxorubicin 1 0 Total 23 10 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca AstraZeneca AstraZeneca