Olaparib Demonstrates High Response in mCRPC With DNA-Repair Defects

Emma Hall, PhD

The PARP inhibitor olaparib (Lynparza) had an overall response rate (ORR) of nearly 90% in a biomarker-defined subgroup of patients with metastatic castration-resistant prostate cancer (mCRPC) who had DNA-repair defects, according to findings from a study recently published in The New England Journal of Medicine.

“This phase II clinical trial combined a highly targeted cancer drug with cutting-edge genomic sequencing,” said study co-leader Emma Hall, PhD, deputy director, Cancer Research Clinical Trials and Statistics Unit at the Institute of Cancer Research (ICR), in a statement. “We showed that a subset of men whose tumors had mutations in their DNA repair machinery responded particularly well to treatment with olaparib. The next trial includes only men with these mutations in their tumors, with the aim of proving that olaparib is highly effective for them.”

The open-label, single-group, two-stage, multicenter phase II TOPARP-A trial 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 (Zytiga) or enzalutamide (Xtandi), 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.

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.

“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 ICR and The Royal Marsden, in a statement. “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.”

“Even though the number of men surviving prostate cancer is increasing, it’s still the second most common cause of cancer death in UK men. This is partly because the disease is so hard to treat once it has spread around the body,” added Aine McCarthy, MD, science information officer at Cancer Research UK, in a statement. “This trial is exciting because it could offer a new way to treat prostate cancer by targeting genetic mistakes in cancers that have spread. The hope is that this approach could help save many more lives in the future.”

Olaparib was approved for the treatment of patients with advanced BRCA1/2-mutated ovarian cancer in December 2014.

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.