FDA Grants Olaparib Breakthrough Designation in mCRPC

Gina Columbus @ginacolumbusonc
Published Online: Thursday, Jan 28, 2016

Antoine Yver

Antoine Yver

Olaparib (Lynparza) has received an FDA breakthrough therapy designation as a treatment for patients with BRCA1/2 or ATM-mutated metastatic castration-resistant prostate cancer (mCRPC) in those who have received a prior taxane-based chemotherapy and at least either hormonal agent enzalutamide (Xtandi) or abiraterone acetate (Zytiga).

The designation, which will accelerate the development and review of the first-in-class oral PARP inhibitor, is based on data from the phase II TOPARP-A trial that demonstrated that olaparib monotherapy had an overall response rate (ORR) of nearly 90% in a biomarker-defined subgroup of patients who had DNA-repair defects.1

“More than 27,000 men died of prostate cancer last year in the US alone,” said Antoine Yver, head of Oncology, Global Medicines Department, AstraZeneca, in a statement. “The Breakthrough Therapy designation for Lynparza is encouraging news for patients, and their families, as there are currently very limited treatment options for metastatic castration-resistant prostate cancer. We will work closely with the FDA to introduce Lynparza as a new treatment option as soon as possible.”

Results from the TOPARP-A trial were presented at the 2015 American Association for Cancer Research Annual Meeting.

The open-label, single-group, two-stage, multicenter study examined olaparib in 50 patients with mCRPC whose disease had progressed following 1 or 2 chemotherapy regimens. Patients had an ECOG performance status of 0 to 2 and all had received prior docetaxel. Ninety-eight percent (n = 49) of patients received prior abiraterone acetate or enzalutamide, and 58% (n = 29) had received cabazitaxel (Jevtana).

Olaparib was administered at a dose of 400 mg twice daily until radiologic progression, unequivocal clinical progression, unacceptable side effects, withdrawal of consent, or death. Next-generation sequencing (NGS) was conducted on biopsied tumor specimens. The primary endpoint was ORR, while secondary endpoints included radiologic progression–free survival (rPFS), progression-free survival, overall survival (OS), time to PSA progression, proportion of patients with conversion of circulating tumor cell count, and adverse events.

In the 49 evaluable patients who received at least one dose of olaparib, ORR was 33% (n = 16). At a median follow-up of 14.4 months, median OS was 10.1 months. The median duration of treatment was 40 weeks, with 12 patients receiving olaparib for >6 months and 4 patients receiving the agent for >12 months. Twenty-two percent of patients had reductions in PSA of 50% or more.

Using NGS, the researchers discovered that 16 of 49 (33%) patients had homozygous deletions, deleterious mutations, or both in DNA-repair genes. Fourteen of these 16 (88%) patients (labeled as “biomarker-positive”) responded to olaparib.

Of these 14 patients, 7 harbored BRCA2 mutations, 5 had ATM aberrations, and 2 had ATM mutations with no germline events. Homozygous somatic deletions of BRCA1 or CHEK2 occurred with FANCA deletion in 3 patients, while a somatic frameshift mutation in PALB2 was also detected in a patient with a heterozygous PALB2 deletion. Moreover, biallelic somatic aberrations in histone deacetylase 2 (HDAC2) were identified in 1 patient.

Radiographic progression-free survival (rPFS) was significantly longer in the biomarker-positive group than in those who were biomarker negative (median, 9.8 vs 2.7 months; P <.001). OS was also prolonged in the biomarker-positive group (median, 13.8 months, vs 7.5 months in the biomarker-negative group; P = .05). Established prognostic factors were balanced between the two groups.

Grade 3/4 treatment-related adverse events included anemia (20%), fatigue (12%), leukopenia (6%), thrombocytopenia (4%), and neutropenia (4%). Twenty-six percent of patients required a dose reduction to 300 mg twice daily. Of these 13 patients, 3 required a second dose reduction to 200 mg twice daily. Treatment was permanently discontinued in 6% of patients due to adverse events.

Under the breakthrough therapy designation, the FDA will expedite review of submission data within 60 days of receiving it.

“Our trial marks a significant step forward in the treatment of prostate cancer, showing that olaparib is highly effective at treating men with DNA repair defects in their tumors. It also proves the principle that we can detect prostate cancers with specific targetable mutations using genomic sequencing to deliver more precise cancer care by matching treatment to those men most likely to benefit,” said Johann de Bono, MD, professor, head of Drug Development at the Institute of Cancer Research and The Royal Marsden, in a statement following publication of the phase II data. “I hope it won’t be long before we are using olaparib in the clinic to treat prostate cancer, or before genomic stratification of cancers becomes a standard in this and other cancers.”

Olaparib is currently approved as a maintenance therapy for patients with BRCA-mutated ovarian cancer. AstraZeneca is currently examining the PARP inhibitor’s potential in other PARP-dependent tumors, including gastric cancer, pancreatic cancer, and adjuvant and metastatic BRCA-mutated breast cancer.


1. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Eng J Med. 2015;373:1697-1708.




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