These are potentially the first clinical data supporting molecular stratification of treatment for prostate cancer.
—Joaquin Mateo, MD
Olaparib (Lynparza) achieved encouraging response rates in men with metastatic prostate cancer, particularly those with mutations in genes involved in DNA repair (BRCA2 and ATM, most commonly).1 If validated, these results of the TOPARP-A trial will usher in the first drug targeted to somatic or germline mutations for prostate cancer.
Olaparib is approved for the treatment of ovarian cancer and inherited BRCA mutations. This is the first trial to suggest this drug can benefit men with similar genomic abnormalities and prostate cancer.
“TOPARP-A was initiated to show the anticancer effect of the PARP (poly ADP-ribose polymerase) inhibitor olaparib in men with metastatic castration-resistant prostate cancer and identify a molecularly distinct subgroup of patients that responds to the drug. These are potentially the first clinical data supporting molecular stratification of treatment for prostate cancer, and we are testing this idea in the second stage of this trial, TOPARP‑B. For TOPARP-B, we are enrolling only patients who screen positive for the DNA repair mutations linked to response in TOPARP‑A,” said presenting author Joaquin Mateo, MD, Clinical Research Fellow at the Institute of Cancer Research and The Royal Marsden NHS Foundation Trust in London, speaking at the Annual Meeting of the American Association for Cancer Research (AACR).
TOPARP was designed as a multi-step trial with an adaptive design based on response rate and correlative biomarker studies. TOPARP-A enrolled 50 men with metastatic, castration-resistant prostate cancer, all of whom progressed after treatment with previous lines of therapy, including taxanes. No patient was previously exposed to platinum chemotherapy or a PARP inhibitor. These patients were unselected for genetic abnormalities.
Patients were biopsied and underwent repeat biopsy after treatment. Whole-exome sequencing was performed after the response rate was determined.
Among 49 patients with evaluable data, 16 had a response to olaparib, for an overall response rate of 32.7%. Six patients had confirmed radiologic responses, according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria, and 11 patients had biochemical responses (ie, > 50% decline in prostate-specific antigen [PSA]). The majority of patients had responses for more than 6 months; four patients responded for more than a year; and five patients are still on therapy, Dr. Mateo said.
Next-generation sequencing identified mutations in genes associated with DNA repair in biopsies from bone marrow and metastases, including BRCA2 and ATM genes, in tumor tissue from 16 of the 49 evaluable patients. Of these 16 mutation-positive patients, 14 (88%) responded to olaparib.
Most of the mutations were somatic, developing in the tumor. BRCA2 was the most common gene, found in seven patients (three with germline and four with somatic mutations); all seven of these patients responded to olaparib. ATM was the second most common abnormal gene, found in five patients (three germline, two somatic mutations); four responded to olaparib, and one had progressive disease.
Losses in other genes that sensitize patients to olaparib were identified, including PALB2 and HDAC2.
The specificity of the DNA gene repair panel was 94%. Dr. Mateo said this means that 94% of patients not responding to olaparib did not have mutations in these genes, and this will help clinicians select the right treatment, because they can be reasonably certain that olaparib will not benefit a patient who tests negative for these mutations.
“There were no surprises regarding safety,” Dr. Mateo said. “The main toxicities with olaparib were anemia and fatigue, and some myelotoxicity was observed. Compared with tolerability in ovarian cancer, olaparib was better tolerated. We did not see major gastrointestinal toxicities.”
“We worked with our U.S. colleagues on behalf of the Stand Up To Cancer-Prostate Cancer Foundation Dream Team to identify biomarkers of response to olaparib,” Dr. Mateo said. ■
Disclosure: Dr. Mateo reported no potential conflicts of interest.
1. Mateo J, Sandhu S, Miranda S, et al: DNA repair defects and antitumor activity with PARP inhibitors: TOPARP, a phase II trial of olaparib in metastatic castration resistant prostate cancer. 2015 AACR Annual Meeting. Abstract CT322. Presented April 21, 2015.