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.
Joaquin Mateo, MD, and colleagues
In the TOPARP-A phase II trial reported in The New England Journal of Medicine, Joaquin Mateo, MD, of the Institute of Cancer Research and The Royal Marsden in London, and colleagues, found that the PARP inhibitor olaparib (Lynparza) produced a high response rate in patients with previously treated metastatic castration-resistant prostate cancer with tumors exhibiting defects in DNA-repair genes.1
In the trial, 50 patients enrolled from 7 sites between July 2012 and September 2014 received oral olaparib at 400 mg twice daily until radiologic progression, unequivocal clinical progression, unacceptable side effects, withdrawal of consent, or death. The primary endpoint was response rate, defined as objective response, reduction in prostate-specific antigen (PSA) level of ≥ 50%, or confirmed reduction in circulating tumor cell count from ≥ 5 per 7.5 mL of blood to < 5 per 7.5 mL. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase chain reaction testing were performed on mandatory tumor biopsies from all patients.
Patients had a median age of 67.5 years (range = 41–79 years), median time from diagnosis of prostate cancer was 5 years, 46% had metastatic disease at initial diagnosis, median time since confirmation of castration-resistant disease was 2.2 years, Eastern Cooperative Oncology Group performance status was 0 or 1 in 88%, median PSA level was 349.5 ng/mL, and median circulating tumor cell count was 37 per 7.5 mL. The number of prior regimens for castration-resistant disease was two for 6%, three for 14%, and at least four for 80%. Prior treatment included docetaxel in 100%, abiraterone (Zytiga) in 96%, cabazitaxel (Jevtana) in 58%, and enzalutamide (Xtandi) in 28%. All patients had undergone chemical or surgical castration, and 50% had had radical prostatectomy or radiotherapy.
Overall, response was observed in 16 of 49 evaluable patients (response rate = 33%, 95% confidence interval = 20%–48%). Reductions in PSA level of ≥ 50% occurred in 11 patients (22%), and reduction in circulating tumor cell count to < 5 per 7.5 mL occurred in 14 patients (29%). Confirmed radiologic partial response was observed in 6 (19%) of 32 patients with measureable disease at baseline.
Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes, including BRCA1/2, ATM, Fanconi anemia genes, and CHEK2, in 16 patients (33%). Aberrations consisted of BRCA2 aberrations in seven patients (four with biallelic somatic loss, three with germline mutations), ATM aberrations in five patients, homozygous somatic deletions of BRCA1 or CHEK2 with FANCA deletion in three patients, a somatic frameshift mutation in PALB2 (localizer of BRCA2) in one patient with a heterozygous PALB2 deletion, and biallelic somatic aberrations in HDAC (which has a role in ATM function) in one patient. Among these 16 patients, 14 (88%) responded to olaparib, compared with 2 (6%) of 33 biomarker-negative patients (P < .001). Response was observed in each of seven patients with BRCA2 loss and in four of five with ATM aberrations. Response was also observed in one patient with somatic homozygous deletion of BRCA1 and FANCA, the one patient with biallelic PALB2 aberrations, and the one patient with biallelic somatic aberrations in HDAC2.
Median radiologic progression-free survival was 9.8 months in biomarker-positive patients vs 2.7 months in biomarker-negative patients (P < .001). Median overall survival was 13.8 vs 7.5 months (P = .05).
The most common adverse events of any grade were anemia (76%), fatigue (58%), nausea (36%), and arthralgia (30%). The most common grade ≥ 3 adverse events were anemia (20%), fatigue (12%), and leukopenia (6%). A reduction in olaparib dose to 300 mg twice daily was required in 26% of patients, with the most common reason being anemia (14%). Adverse events led to discontinuation of treatment in 6% of patients.
The investigators concluded: “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.”■
Disclosure: The study was supported by Cancer Research UK, AstraZeneca, and others. For full disclosures of the study authors, visit www.nejm.org.
1. Mateo J, Carreira S, Sandhu S, et al: DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 373:1697-1708, 2015.
New data on molecular biomarkers in advanced prostate cancer are accumulating at a fast pace. The studies in this area can now be broadly grouped in two distinct areas—those that broadly relate to androgen signaling and those that relate to DNA-repair pathways.
The Androgen-Signaling Pathway