Phase I/Ib Study of Olaparib and Carboplatin in BRCA1 or BRCA2 Mutation-Associated Breast or Ovarian Cancer With Biomarker Analyses

DNA repair is essential for cells to survive damage caused by ambient environmental toxins, chemotherapy, and other treatments (1,2). Homologous recombination (HR) is a predominantly error-free mechanism to repair double-strand DNA break (DSB). Key components of DSB repair are the tumor-suppressor proteins BRCA1 and BRCA2. Dysfunctional HR leads to activation of the base excision repair pathway, a single-strand DNA break repair pathway requiring polyADPribose polymerase (PARP) (3). Increased PARP-1 expression and/or activity in tumor cells has been demonstrated in many tumor types (4–6). Active base excision repair stalls replication to allow single-strand DNA break repair. The absence of single-strand DNA break repair causes DNA helix strain at transcription forks and leads to DSBs requiring HR and, therefore, BRCA1 and BRCA2 (7). Development of DSBs in the absence of HR activates nonhomologous end joining, a poor-fidelity DSB repair pathway. PARP inhibition has been shown to induce phosphorylation of DNA-dependent protein kinase and permit error-prone nonhomologous end joining in HR-deficient cells (8). Thus, HR dysfunction sensitizes cells to PARP inhibition, leading to further chromosomal instability, cell cycle arrest, and apoptosis (9). Germline HR deficiency improves the therapeutic window for PARP inhibition (10–12). The interrelationship between DNA repair pathways led to the development of PARP inhibitors (PARPis) as therapeutic agents. Olaparib, an oral PARP1/2 inhibitor, is tolerated at single-agent continuous doses up to 400mg twice daily (capsules) (13). It has been active as monotherapy in tumors with defective HR, specifically germline BRCA1 or BRCA2 mutations (gBRCAm). Clinical activity with prolonged disease stabilization and tumor burden reduction has been reported in gBRCAm-associated breast and/or ovarian cancer (gBRCAm BrCa/OvCa) (14–18). Phase II studies have confirmed the activity of olaparib monotherapy with response rates of 41% in gBRCAm patients with advanced BrCa (17) and 31% to 40% in those with OvCa (13,15). The optimal application of PARPis in treatment of gBRCAm BrCa/OvCa has not yet been determined. gBRCAm carriers with OvCa have increased susceptibility to platinums (19) and often receive multiple lines of platinum-based chemotherapy and can have longer overall survival than nonmutation carriers (20,21). It has been demonstrated preclinically that concomitant use of olaparib increases cytotoxic activity of cisplatin in cisplatin-resistant OvCa cell lines (22), and an intermittent schedule of olaparib with carboplatin yields antitumor activity in a BRCA2-mutated human ovarian cancer xenograft model (23). Thus, we hypothesized addition of olaparib to carboplatin as a stress to the DNA repair machinery would improve clinical benefit of carboplatin and could be safely given to women with gBRCAm-associated cancers. We conducted a phase I/Ib study to evaluate the safety, tolerability, and activity of olaparib administered with carboplatin. Our translational aim was to discover potential predictive biomarkers of response to the carboplatin/PARPi combination.