DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer

Abstract

Background: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.

Methods: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.

Results: Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.

Conclusions: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).

Figure 1. Genomic Aberrations in DNA Repair in Patients with Metastatic, Castration-Resistant Prostate Cancer

Data are shown for the 49 patients who could be evaluated for a response. Mutations and deletions in DNA-repair genes were identified through next-generation sequencing studies. Green shading indicates patients who were classified as having a response to olaparib in the clinical trial. Patients were considered to be biomarker-positive if homozygous deletions, deleterious mutations, or both were detected in DNA-repair genes (but not single copy deletions without events detected in the second allele). A star indicates that a particular genomic event was detected in germline DNA. Archival tumor samples were used for the sequencing studies in Patients 13, 18, 21, 40, 41, and 49 because the biopsy samples obtained during the trial were negative for tumor content.

Figure 2. Antitumor Activity of Olaparib and Association with Defects in DNA-Repair Genes, According to Biomarker Status

Panels A and B show radiologic progression–free survival and overall survival curves, respectively, for patients with genomic defects in DNA-repair genes (biomarker-positive group) and patients without such defects (biomarker-negative group). The hazard ratio for radiologic progression in the biomarker-positive group as compared with the biomarker-negative group was 0.24 (95% confidence interval [CI], 0.11 to 0.50), and the hazard ratio for death was 0.47 (95% CI, 0.22 to 1.02). Panels C and D show mean percentage changes in prostate-specific antigen (PSA) levels and circulating tumor-cell (CTC) counts, respectively, over the course of treatment in the biomarker-positive and biomarker-negative groups.

Figure 3. Radiologic Evidence of Tumor Responses to Olaparib at Week 12

Panel A shows CT scans of the chest, obtained in the lung and soft-tissue window settings, from a 61-year-old man with metastatic, castration-resistant prostate cancer (Patient 39) who had a response to olaparib; there was shrinkage of the lung and nodal (arrows) metastatic deposits after 12 weeks of therapy (right), as compared with baseline (left). Whole-exome sequencing showed a somatic homozygous deletion of BRCA2. Panel B shows CT scans with coronal reconstruction in a 70-year-old man with a somatic BRCA2 frameshift insertion (p.Y2154fs*21) and somatic deletion of the second allele (Patient 20). The scans show the response in the mediastinal and abdominal lymph nodes (arrows). The patient received treatment for a total of 48 weeks. Panel C shows multiparametric whole-body MRI scans, including diffusion-weighted imaging, with coronal three-dimensional reconstruction and selected axial images in a 79-year-old man (Patient 1) who had a response to olaparib, with an 85% reduction in the PSA level. The patient received treatment for a total of 73 weeks. The images show reduction in the water content within the skeletal metastasis, which in conjunction with other findings on imaging would be consistent with tumor regression during therapy (right), as compared with baseline (left). Next-generation sequencing of the baseline bone marrow–biopsy specimen revealed a somatic missense mutation within the ATM phosphoinositide 3-kinase catalytic domain (p.N2875S), with no evidence of genomic loss of the second allele and with maintenance of ATM expression on immunohistochemical assessment.