Olaparib Nears 90% Response in Molecular Subgroup of mCRPC

Joaquin Mateo, MD

Treatment with the PARP inhibitor olaparib (Lynparza) demonstrated a durable overall response rate (ORR) of 87.5% in a biomarker-defined subgroup of men with pretreated sporadic metastatic castration-resistant prostate cancer (mCRPC) in a phase II multi-step adaptive trial. In the full population of the study, the ORR was 32.7%.

Results from the study, labeled TOPARP, were presented at the 2015 AACR Annual Meeting. In the first stage of the trial, labeled TOPARP-A, olaparib was administered to patients with unselected mCRPC, followed by preplanned genomic analysis using next-generation sequencing (NGS) to identify a biomarker-defined subgroup based on those who responded. Overall, the study found that patients with somatic or germline defects in DNA repair genes, such as BRCA2 and ATM, were more likely to respond to olaparib than those without the alterations, representing a unique molecularly-defined treatment population.

“The data from TOPARP-A show that single-agent PARP inhibition with olaparib has durable antitumor activity in men with metastatic castration-resistant prostate cancer and identified a molecularly distinct subgroup of patients that respond to the drug,” study author Joaquin Mateo, MD, clinical research fellow 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 (UK), said in a statement. “These are potentially the first clinical data supporting molecular stratification of treatment in prostate cancer, and we are testing this idea in the second stage of the TOPARP trial, TOPARP-B.”

The first stage of the study enrolled 50 patients across 7 UK centers. All the patients had received prior treatment with docetaxel, 48 had received abiraterone (96%), and 29 had received cabazitaxel (58%). Patients received olaparib at a dose of 400mg twice daily continuously in a 28-day cycle. The primary endpoint of the study was ORR. The secondary endpoints for the study included safety, tolerability, progression-free survival (PFS), and overall survival (OS).

In the full population of evaluable patients (n = 49), 16 (32.7%) responded to olaparib (95% CI: 20.0-47.5), six patients had radiological responses, as assessed by RECIST, and 11 patients had a biochemical response defined as a ≥50% decrease in PSA levels.

NGS was conducted on fresh CRPC biopsies, taken before and during treatment with olaparib. Overall, deleterious mutations were identified in the tumor samples for 16 of 49 evaluable patients (32.7%). Of these, 14 patients experienced a response to olaparib (87.5%).

All patients with a BRCA2 alteration responded to treatment with olaparib. Defects in ATM were indicative of response to olaparib, although, 1 patient with a type of ATM alteration did not respond to therapy. In addition to these alterations, biallelic losses in other relevant genes were seen in FANCA and CHEK2. In patients without DNA repair defects (n = 28), a response to olaparib was not observed.

Researchers reported that the gene panel had a 94% specificity rate. According to Mateo, this means that 94% of patients without these mutations will be correctly identified, which will help clinicians select the correct treatment for a patient because they can be reasonably certain that olaparib will not benefit a patient who does not have these mutations. The sensitivity for the test was 87.5%.

As with previous studies involving olaparib, the most common grade >3 adverse events were anemia (20%) and fatigue (12%), with 26% of patients requiring a dose reduction.

The next stage of the study will seek to validate the molecular signature by enrolling only participants who test positive (NCT01682772). “For TOPARP-B, we are enrolling only patients who screen positive for the DNA repair mutations linked to response in TOPARP-A,” Mateo confirmed.

The FDA approved olaparib as a treatment for women with BRCA-positive advanced ovarian cancer following treatment with three or more prior lines of chemotherapy in December 2014. The drug was approved along with a companion diagnostic to identify patients with this alteration, labeled BRACAnalysis CDx.

Mateo J, Sandhu S, Miranda S, et al. Phase II trial of the PARP inhibitor olaparib in sporadic and unselected metastatic castration resistant prostate cancer (mCRPC). Presented at: 2015 AACR Annual Meeting; April 18-22; Philadelphia, PA. Abstract CT322.

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