The designation is based on data from the phase 2 TOPARP-A trial that demonstrated that Lynparza monotherapy had an overall response rate of nearly 90 percent in a biomarker-defined subgroup of patients who had DNA-repair defects.
Lynparza (olaparib) received an FDA breakthrough therapy designation as a treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) on January 28. The designation applies to the treatment of patients with BRCA1/2 or ATM-mutated disease who have received a prior taxane-based chemotherapy and at least either hormonal agent Xtandi (enzalutamide) or Zytiga (abiraterone acetate).
The breakthrough therapy program is designed to streamline drug development for therapies to treat serious and life-threatening illnesses.
“More than 27,000 men died of prostate cancer last year in the U.S. 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.”
This designation is based on data from the phase 2 TOPARP-A trial that demonstrated that Lynparza monotherapy had an overall response rate (ORR) of nearly 90 percent in a biomarker-defined subgroup of patients who had DNA-repair defects.1 Results were presented at the 2015 American Association for Cancer Research Annual Meeting.
The open-label, single-group, two-stage, multicenter study examined Lynparza in 50 patients with mCRPC whose disease had progressed following one or two chemotherapy regimens. Patients had an ECOG performance status of 0 to 2 and all had received prior docetaxel. Ninety-eight percent of patients (49 patients in total) received prior Zytiga or Xtandi, and 58 percent (29 patients) had received cabazitaxel (Jevtana).
Lynparza 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 Lynparza, ORR was 33 percent (16 patients). 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 Lynparza for greater than six months and four patients receiving the agent for greater than 12 months. Twenty-two percent of patients had reductions in PSA of 50 percent or more.
Using NGS, the researchers discovered that 16 of 49 patients (33 percent) had homozygous deletions, deleterious mutations, or both in DNA-repair genes. Fourteen of these 16 patients (88 percent; labeled as “biomarker-positive”) responded to Lynparza. Of these 14 patients, seven harbored BRCA2 mutations, five had ATM aberrations, and two had ATM mutations with no germline events. Homozygous somatic deletions of BRCA1 or CHEK2 occurred with FANCA deletion in three 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 one patient.
Radiographic progression-free survival (rPFS) was significantly longer in the biomarker-positive group than in those who were biomarker negative (a median 9.8 versus 2.7 months). OS was also prolonged in the biomarker-positive group (a median of 13.8 months versus 7.5 months in the biomarker-negative group). Established prognostic factors were balanced between the two groups.
Grade 3/4 treatment-related adverse events included anemia (20 percent), fatigue (12 percent), leukopenia (6 percent), thrombocytopenia (4 percent) and neutropenia (4 percent). Twenty-six percent of patients required a dose reduction to 300 mg twice daily. Of these 13 patients, three required a second dose reduction to 200 mg twice daily. Treatment was permanently discontinued in 6 percent 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 Lynparza 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, professor, head of Drug Development at the Institute of Cancer Research and The Royal Marsden, in a statement following publication of the phase 2 data. “I hope it won’t be long before we are using [Lynparza] in the clinic to treat prostate cancer, or before genomic stratification of cancers becomes a standard in this and other cancers.”
Lynparza 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.