What this means for patients: A Phase II clinical trial found that up to one-third of metastatic prostate cancer patients have mutations in genes that control DNA repair in their tumors, causing them to selectively respond to treatment with olaparib. This therapy was recently approved for ovarian cancer patients who have tumors with similar mutations and is likely to gain approval for prostate cancer patients. This study is the first breakthrough in precision medicine for prostate cancer patients– where the unique biology of a patient’s tumor is used to select the therapies most likely to benefit him.
May 26, 2015 — Hereditary mutations in the BRCA1 and BRCA2 genes are infamous for their role in significantly increasing a woman’s risk for developing ovarian and breast cancer, prompting women who have inherited these mutations to take extreme and debilitating preventative measures. BRCA1 and BRCA2 participate in one of multiple molecular pathways that repair damaged DNA, and the inability to properly repair DNA can lead to the development of mutations that cause cancer. However, because cancer cells have highly unstable DNA, some amount of DNA repair ability is required for their survival. Thus, while loss of one DNA damage repair pathway causes an increased risk for developing cancer, if additional pathways are blocked, cancer cells become unable to maintain DNA integrity sufficient to survive. This phenomenon, called “synthetic lethality,” underlies the efficacy of olaparib (Lynparza®), an inhibitor of another DNA-repair gene, PARP1, in breast and ovarian cancer patients with BRCA1/2 alterations. In 2014, the FDA-approved olaparib for advanced ovarian cancer patients previously treated with three or more lines of chemotherapy and with demonstrated BRCA1/2 tumor alterations. Previous studies have found that 15-35% of metastatic castrate-resistant prostate cancers (mCRPC) contain such DNA repair defects including BRCA gene loss of function, generating the hypothesis that these patients may also be sensitive to PARP-inhibitors including olaparib.
At the 2015 Annual AACR meeting, Dr. Joaquin Mateo, of the Institute of Cancer Research in London, presented results from a Phase II clinical trial, “TO-PARP,” which is testing the efficacy of olaparib in prostate cancer patients. Fifty mCRPC patients previously treated with docetaxel, most of whom had also been previously treated with abiraterone (Zytiga®) or enzalutamide (Xtandi®), received oral olaparib twice-per day in 28 day-cycles until disease progression. Of the cohort, 49 patients could be evaluated, and 16 (32.7%) exhibited a response to olaparib. Tumor biopsies were obtained both prior to and following the initiation of olaparib treatment. Their genomes were assessed for the presence of any genomic alterations by the “International Prostate Cancer Dream Team” – a $10M multi-institutional collaborative prostate cancer precision medicine effort sponsored largely by the Prostate Cancer Foundation.
The goal of the Dream Team is to develop more precise and effective ways to treat patients by matching tumor mutations with drugs that specifically target those mutations. Of the 16 patients who responded to olaparib, 14 were found to have mutations in known DNA damage-repair genes, while only 2 of the 33 non-responders had mutations in any of these genes. Altered DNA damage-repair genes identified in the tumors of responders included BRCA2, BRCA1, ATM, FANCA, CHEK2 PALB2, HDAC2, MRE11, and NBN. Deletion of both copies of the BRCA2 or ATM genes were the most common alterations observed. The mutational statuses of the ERG oncogene, which is overexpressed in ~50% of prostate cancer patients, and the PTEN tumor suppressor gene which is commonly lost as prostate tumors progress, were not associated with olaparib responses.
Not only were olaparib responses highly specific to patients with tumors harboring DNA damage-repair gene alterations (14/16 responders vs. 2/33 non-responders), but responding patients also exhibited significantly longer progression-free survival (PFS) times than patients of similar status treated with abiraterone or enzalutamide in other trials. The median time on treatment was 38 weeks for olaparib responders vs. 12 weeks for patients treated with abiraterone or enzalutamide. Olaparib therapy was also considered to be well-tolerated. The most common grade 3-4 adverse events observed were anemia (20%) and fatigue (12%). Phase III clinical trials are being planned to confirm these results and if they do, will set the stage for FDA approval for olaparib in prostate cancer. Olaparib may very well be the first precision medicine approved for prostate cancer patients and validates the extensive efforts being made by the Dream Team and others to develop precision medicine strategies for the treatment of prostate cancer patients.
The 2015 AACR Annual Meeting was held from April 18-22, in Philadelphia, PA.