AZD2281 (KU-0059436), a PARP (poly ADP-ribose polymerase) inhibitor with single agent anticancer activity in patients with BRCA deficient ovarian cancer: Results from a phase I study

5510 Background: AZD2281 is a novel, potent orally active PARP inhibitor. It induces cancer specific synthetic lethality in homologous recombination repair defective cells, including BRCA-deficient tumors. We previously reported a first-in-human Phase I trial, with dose escalation guided by toxicity, pharmacokinetic and pharmacodynamic (PD) data (Yap et al, ASCO 2007 Abstr 3529). Method: Initial dose escalation phase included patients (p) with a wide range of drug-resistant cancers. Once a PD active dose was identified, enrichment of the population with p with BRCA-deficient tumors was encouraged. Doses started from 10mg daily for 2 of 3 weeks, escalating to 600mg bd continuously. After the maximum tolerated dose (400mg bd) was identified, an expansion phase in BRCA-deficient ovarian cancer (BDOC) at 200mg bd was opened. Results: Of the total 92 p treated, 44 p had BDOC (includes 1 p with compelling family history). Doses received were 40mg daily (1 p), 100mg bd (3 p), 200mg bd (34 p), 400mg bd (5 p) and 600mg bd (1 p). Toxicities were mainly gastrointestinal and mild, with little myelosuppression seen. 1 p at 400mg bd had a dose limiting neurocognitive toxicity. 32 p with BDOC, the majority of whom were platinum resistant/refractory are so far evaluable for response. All evaluable p had either received treatment for at least 8 weeks (2 cycles) or progressed prior to completion of 2 cycles. 14 p have achieved partial response, 13 meeting GCIG- CA125 criteria and 10 meeting RECIST criteria. Of the responders, 1 p has been on drug > 56 weeks whilst 7 p have maintained responses for ≥ 24 weeks. Stable disease (SD) was seen in an additional 8 p, 7 of whom continue on drug and 3 p had SD ≥ 16 weeks. Responses were seen at all dose levels from 100mg bd and above. Conclusion: AZD2281 is well tolerated and has demonstrated compelling activity in patients with BDOC. Responses were seen in all p groups including platinum resistant disease. Updated efficacy data, together with a correlation of potential predictive factors including platinum free interval will be presented on a total planned cohort of 46 p with BDOC. A randomised study in BRCA-deficient ovarian cancer has been planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Kudos Kudos Kudos Kudos AstraZeneca Oncology AstraZeneca Oncology