1. In this phase II trial, use of the poly(adenosine diphosphate[ADP]-ribose) polymerase (PARP) inhibitor olaparib showed a positive response in a subset of metastatic castration-resistant prostate cancer patients with DNA repair defects.
2. While olaparib treatment showed evidence of anti-tumour growth through PSA and circulating tumour-cell decrease, and radiologic response on CT/MRI, impact on overall survival remains unknown.
Evidence Rating Level: 2 (Good)
Study Rundown: Few treatment options are available to metastatic, castration-resistant prostate cancer patients, such cancers have a high degree of genetic heterogeneity, and can have abnormalities interfering with DNA repair. Some of these abnormalities are sensitive to PARP inhibitors. This phase II prospective cohort trial assessed the anti-tumour activity of the PARP inhibitor olaparib. Through next-generation sequencing assays using biopsied prostate tissue, genetic abnormalities were identified and in turn, targeted with olaparib. Anti-tumour activity was observed by decreases prostate specific antigen (PSA) levels and circulating tumour-cells, as well as radiologically (CT and MRI). The study found that in patients that were not responding to standard treatment and had defects in DNA-repair genes the PARP inhibitor olaparib led to a high response.
In-Depth [prospective cohort]: This prospective cohort study aimed to demonstrate the anti-tumour activity of olaparib, PARP inhibitor, on metastatic castration-resistant prostate cancer with DNA-defects. Treatment response was indicated by either: Response Evaluation Criteria in Solid Tumours (RECIST, version 1.1), reduction in prostate specific antigen (PSA) by at least 50%, or reduction in circulating tumour-cell count from >5 cells/7.5 mL to <5 cells/7.5 mL.
A total of 50 patients were enrolled in the phase II study, and were treated with olaparib 400 mg tablets twice per day. All patients received some form of prior chemotherapy (docetaxal, abiraterone, enzalutamide, cabazitaxel). A total of 16/49 patients could be evaluated (33%) had a response [95% [CI] 28-48], with 12 patients having a response lasting >6 months. Next-generation sequencing using tissue from prostate biopsies, revealed 16/49 (33%) having deleterious DNA-repair genes (ex. BRCA1/2, CHEK2, ATM, Fanconi’s anemia genes). Of these 16 patients, 14 had a response to olaparib.
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