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DNA-repair defects influence response to PARP inhibition in metastatic prostate cancer
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Treatment with the PARP inhibitor olaparib induced a high response rate among patients with metastatic prostate cancers harboring DNA-repair gene defects, according to phase 2 study results published in The New England Journal of Medicine.
“Prostate cancer is the most common cancer in men and the sixth leading cause of death from cancer among men throughout the world,” Joaquin Mateo, MD, a research fellow and doctoral candidate in the prostate targeted therapy group and drug development unit at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust in the United Kingdom, and colleagues wrote. “The interpatient molecular heterogeneity of this disease is well-recognized; however, treatment to date has not been molecularly stratified. It would be useful to identify predictive biomarkers in order to provide more precise treatment for this disease.”
Thus, Mateo and colleagues surmised that patients with metastatic, castration-resistant prostate cancer with DNA-repair defects may respond to poly(adenosine diphosphate–ribose) polymerase (PARP) inhibition. Researchers assigned 50 patients (median age, 67.5 years; median time from diagnosis, 5 years) to 400 mg twice-daily olaparib (Lynparza, AstraZeneca).
Response rate — defined as an objective response, a reduction of at least 50% in PSA 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 of blood — served as the primary endpoint.
The researchers performed targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase–chain-reaction testing on tumor biopsy samples.
Study participants — all of whom no longer responded to standard treatment options — had previously been treated with docetaxel (100%), abiraterone (Zytiga, Janssen) or enzalutamide (Xtandi; Astellas, Medivation; 98%), and/or cabazitaxel (Jevtana, Sanofi-Aventis; 58%).
The median duration of olaparib treatment was 12 weeks (interquartile range, 11-24). Sixteen patients responded to treatment (33%; 95% CI, 20-48), 12 of whom remained on treatment for more than 6 months.
The researchers identified homozygous deletions, deleterious mutations or both in DNA-repair genes — including BRCA1/2, ATM, Fanconi’s anemia genes and CHEK2 — in 16 (33%) of the 49 evaluable patients. Of those 16 men, 88% (n = 12) responded to olaparib, including all patients (n = 7) with a BRCA2 deletion and four of the five men with ATM aberrations.
The biomarker suite had a sensitivity of 88% and a specificity of 94%. Biomarker-positive men achieved significantly prolonged PFS (median, 9.8 months vs. 2.7 months; P < .001) and OS (median, 13.8 months vs. 7.5 months; P = .05).
Anemia (20%; n = 10) and fatigue (6%; n = 12) were the most common grade 3 or worse adverse events. However, the researchers noted that the adverse event profiles observed were consistent with previous studies of olaparib.
“The results of this clinical trial suggest that a common subset of metastatic prostate cancers can be molecularly stratified for treatment,” Mateo and colleagues wrote. “This subset, characterized by defects in DNA repair, accounts for approximately 25% to 30% of all sporadic, castration-resistant prostate cancers. … In conclusion, we report that PARP inhibition has antitumor activity in sporadic cases of metastatic, castration-resistant prostate cancer and that these responses are associated with DNA-repair defects in tumor cells that can be identified through next-generation sequencing assays.” – by Cameron Kelsall
Disclosure: Mateo reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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