Olaparib in Patients with BRCA-Related Cancers
Promising results in phase II study in patients with advanced ovarian, breast, pancreatic, and prostate cancers with a BRCA1/2 mutation
Olaparib produced a tumour response rate of 26.2% in several advanced cancer types associated with BRCA1 and BRCA2 mutations. The response rate provides new hope for patients with ovarian, breast, pancreatic and prostate cancers whose disease has not responded to standard therapies. Results of the phase II study are published online in the Journal of Clinical Oncology.
In this multicentre phase II study, eligibility included ovarian cancer resistant to prior platinum; breast cancer with at least three chemotherapy regimens for metastatic disease; pancreatic cancer with prior gemcitabine treatment; or prostate cancer with progression on hormonal and one systemic therapy.
Olaparib was administered orally at 400 mg twice per day. The primary efficacy endpoint was tumour response rate. Based on the data, the authors consider olaparib warrants further investigations. The response in metastatic pancreatic cancer patients who had received an average of two prior lines of chemotherapy is an especially noteworthy finding since therapeutic options for these patients are limited.
The research team studied 298 patients with inherited BRCA1 and BRCA2 mutations who had advanced cancers that were progressing on standard treatments. Patients were enrolled and treated at 13 centres around the world. In addition to the 26.2% overall response rate, researchers also found stable disease for at least eight weeks in 42% of patients.
Overall survival at one year following treatment with olaparib was 64% among ovarian cancer patients (with a median progression-free survival of 7 months), 45% among breast cancer patients (with a median progression-free survival of nearly 4 months), 41% among pancreatic cancer patients (with a median progression-free survival of nearly 5 months), and 50% among prostate cancer patients (with a median progression-free survival of more than 7 months).
"By building on previous research, our study offers new hope for patients suffering from cancers caused by inherited BRCA1 and BRCA2 gene mutations," said Dr Susan Domchek, executive director of the Basser Research Center for BRCA at the University of Pennsylvania's Abramson Cancer Center, and senior author on the study. "Olaparib was reasonably well tolerated in the current study, even in such a heavily pre-treated population, showing that PARP inhibitors such as olaparib potentially represent a much-needed advanced treatment option."
Side effects were reported for 54% of participants, the most common of which was anaemia (17%). Authors suggest the increased incidence of anaemia compared to other studies may be due to the study population's longer history of cancer and higher number of prior chemotherapy treatments. Other side effects included fatigue, nausea, and vomiting. Most toxicity could be managed by dose interruption and dose reduction.
Olaparib is an oral poly (ADP-ribose) polymerase inhibitor with activity in germline BRCA1/2–associated tumours. BRCA1 and BRCA2 mutations in women increase the risk of several cancers, including breast and ovarian, while in males the BRCA2 mutation in particular has been tied to breast, prostate, and pancreatic cancer. About 5% of breast cancers and 10% of ovarian cancers are associated with an inherited mutation in BRCA1 or BRCA2.
The study was presented at the 2013 Annual Meeting of the American Society of Clinical Oncology.
The study was sponsored by AstraZeneca.
Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation. JCO 2014; Published online before print November 3. doi: 10.1200/JCO.2014.56.2728