Medical Research: What is the background for this study? What are the main findings?
Dr. Yap: This is a novel phase I trial assessing for the first time if the PARP inhibitor olaparib can be combined with the AKT inhibitor AZD5363. The study was undertaken at the Royal Marsden and The Institute of Cancer Research in London, England. This targeted combination was based on strong preclinical rationale demonstrating synergy between both drugs in BRCA positive tumors and also antitumor activity in non-BRCA positive tumors. Although olaparib was recently approved by the FDA for treating advanced ovarian cancer associated with defective BRCA genes, antitumor efficacy in different non-BRCA tumors is yet to be established.
The key finding for this study was that it was indeed possible to combine both drugs safely, with multiple patients with different cancers responding, including patients with and without BRCA1/2 mutations. We also assessed a new intrapatient dose escalation phase I trial design in this study, and demonstrated that the novel design could be successfully implemented, with completion of the dose escalation phase in 2 schedules of the combination with just 20 patients in 7.5 months.
Medical Research: What should clinicians and patients take away from your report?
Dr. Yap: The combination of olaparib and AZD5363 was well tolerated, with side effects including gastrointestinal symptoms, such as nausea, vomiting, diarrhea, as well as rash and fatigue. Out of 20 patients with advanced solid tumors, seven patients had either RECIST partial responses or prolonged disease stabilization. There were four confirmed RECIST partial responses, including in a patient with BRCA wild-type ovarian cancer, two patients with BRCA mutant breast cancer, and a patient with BRCA1-mutant ovarian cancer; two patients had ongoing prolonged RECIST disease stabilization, including a patient with BRCA unknown breast cancer at six months and a patient with peritoneal mesothelioma at one year, who had previously responded before progressing on treatment with a PI3K/mTOR inhibitor. One patient with BRCA-mutant advanced prostate cancer also continues to have a sustained radiological response on MRI and by PSA tumor marker response criteria at 11 months.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Yap: We have now established safe doses for this novel targeted combination and observed anticancer responses in patients with both BRCA positive and BRCA negative cancers. We are currently assessing this promising targeted combination of olaparib and AZD5363 in a larger cohort of patients with both BRCA and non-BRCA mutations. We believe that such PARP inhibitor based treatments have the potential to extend the use of PARP inhibitors to include patients with different types of non-BRCA positive cancers, such as breast, ovarian, prostate, small cell and pancreatic cancers. We also believe that other phase I trials of targeted combinations should incorporate the novel intrapatient dose escalation design assessed in this study to validate it independently.
New PARP Inhibitor Combo Shows Early Promise for Cancer Patients With and Without BRCA Mutation
MedicalResearch.com Interview with: Timothy Yap, MD, PhD, NIHR BRC (2015). PARP Inhibitor Combo For Cancer Patients With and Without BRCA Mutation