NEW YORK (GenomeWeb) – A clinical trial led by researchers at the Institute of Cancer Research in London has found that prostate cancers with certain mutational profiles have a high response rate to a drug previously approved for the treatment of ovarian cancer in patients with germline BRCA mutations who have been treated with three or more prior lines of therapy.
The team published the results of the trial this week in the New England Journal of Medicine.
The US Food and Drug Administration approved olaparib, marketed as Lynparza by AstraZeneca, in December 2014 in conjunction with Myriad Genetics' BRACAnalysis CDx companion diagnostic test for patients with advanced ovarian cancer. According to AstraZeneca's pipeline, it is also investigating the use of the drug in prostate cancer.
Olaparib is a poly ADP-ribose polymerase (PARP) inhibitor and blocks enzymes involved in DNA repair.
Researchers at the ICR theorized that the drug might be effective in prostate cancer patients who also had mutations in DNA repair genes.
In a phase II trial, 50 patients with metastatic castrate-resistant prostate cancer were treated with olaparib, 49 of whom could be evaluated. Of those, 16 responded, with 12 receiving the drug for more than six months.
Researchers at the University of Michigan next performed exome and transcriptome sequencing on biopsied samples of the patients' tumors prior to treatment, as well as exome sequencing on normal saliva samples. Researchers at the ICR performed targeted sequencing on the samples, using Qiagen's GeneRead DNA-seq panel and Illumina's MiSeq instrument. Copy number data was validated with PCR, and circulating tumor cell counts were done.
Patients were considered "biomarker positive" if they had a homozygous deletion or deleterious mutation in a gene involved with DNA repair or DNA damage or in a gene known to be sensitive to PARP inhibition.
Of the 49 patients who could be evaluated, 43 had tumor biopsy material suitable for NGS, and for the six other patients, the researchers evaluated archival samples taken at diagnosis.
Sixteen patients, or 33 percent, had aberrations in DNA repair genes. Seven patients had multiple alterations to BRCA2, including three patients who had germline frameshift mutations. One patient with BRCA2 alterations also had a somatic CHEK2/FANCA deletion. Two other patients also had somatic deletions of either BRCA1 or CHEK2, along with a FANCA deletion. Five patients had aberrations to ATM, three of which were in the germline. One patient had a somatic frameshift mutation in PALB2, and one had somatic mutations in HDAC2.
While the overall response rate was 33 percent, patients with alterations to DNA repair genes had a higher response rate than those without. Of the sixteen biomarker-positive patients, 14, or 88 percent, responded to olaparib, while only two out of the 33 patients without a biomarker, or 6 percent, responded to olaparib, for a sensitivity of 88 percent and specificity of 94 percent. In addition, the biomarker-positive group had longer progression-free survival, amedian of 9.8 months compared to 2.7 months in the biomarker-negative group.
One responder who was classified as biomarker-negative did have deletions in BRCA2 and PALB2, however those deletions were only on one allele of each gene. This patient nonetheless had "clear radiologic response," as well as an 86 percent reduction in prostate specific antigen, according to the authors. In addition, the researchers reported that the second patient without a biomarker who initially responded in fact "had little evidence of a true response," since he progressed after 12 weeks.
The researchers noted that while patients' responses to treatment typically lasted more than six months, and were "associated with prolonged radiologic progression– free survival and impressive falls in circulating tumor-cell counts," they cannot yet determine whether olaparib improves overall survival among patients with metastatic, castration-resistant prostate cancer and DNA-repair defects.
Nonetheless, the findings do suggest that "next-generation sequencing analyses of tumor biopsy samples can increase our understanding of treatment responses," the authors wrote.
The study also suggests 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," the authors concluded.
The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust co-sponsored the investigator-iniatied study. AstraZeneca provided olaparib free of cost and some funding in collaboration with the National Institute for Health Research Cancer Research Network but had no other role in the study.