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Hot Topic - Guest Editor Shahneen Sandhu
The Newsletter of ANZUP Cancer Trials Group Limited
AUTUMN 2016
HOT TOPIC Molecular stratification of prostate cancer and targeting DNA repair defects. MOLECULAR STRATIFIED TREATMENT BRCA1 BRCA2 ATM CHEK2POLY (ADP-RIBOSE) POLYMERASE (PARP) INHIBITORSGERMLINE OLAPARIBMCRPC DNA-REPAIRDEFECTS PERSONALISED THERAPY WITH A PARP INHIBITORMETASTATIC CRPC (MCRPC)
The treatment mutation carriers including patients with biopsies were obtained from all patients. of advanced PC. Recent sequencing data indicates that Next-generation sequencing revealed castration 25% of patients with CRPC have germline deletions and mutations in multiple resistant prostate and / or somatic loss of function in key DNA-repair genes including BRCA1, cancer (CRPC) DNA repair genes including BRCA1, BRCA2, ATM, CHEK2, etc. Sixteen out of remains critically BRCA2, PALB2, ATM, CHEK2, and FANCJ 49 patients with underlying DNA repair important despite etc. that are likely to confer susceptibility defects exhibited an 88% response rate
SHAHNEEN SANDHU recent treatment to PARP inhibition via synthetic lethality. to olaparib. Radiological-progressionadvances with docetaxel, cabazitaxel, abiraterone and enzalutamide. While these newer treatments are incrementally improving survival most men with metastatic CRPC (mCRPC) succumb to their disease, which is highly heterogeneous. Despite this, clinical trials in mCRPC remain focused on population-based approaches without molecular stratification. There is an unmet need for developing personalised treatments in this disease based on molecular drivers that offer durable clinical benefit. Poly (ADP-ribose) polymerase (PARP) We explored in an investigator-led phase II trial recently published in the New England Journal of Medicine the efficacy of olaparib in sporadic mCRPC with underlying DNA repair defects. In Part A of TOPARP (Trial of PARP Inhibition in Prostate Cancer) we enrolled 50 patients with mCRPC who had previously failed multiple lines of therapy including docetaxel, cabazitaxel, abiraterone and enzalutamide. Patients received 400 mg of olaparib twice daily until radiological progression, clinical progression, or unacceptable toxicity. Patients were mandated to have paired fresh tumour free survival was 9.8 months versus 2.7 months; P <0.001 and overall survival was 13.8 months versus 7.5 months; P = 0.05 in favour of the biomarker-positive group. The sensitivity and specificity of detection a DNA-repair alteration using the DNA repair panel was 88% and 94% respectively. Critically, we have shown 25–30% of all men with sporadic mCRPC have underlying defects in DNA repair, undertaking tumour biopsies and genomic studies for molecular stratification is feasible and that these patients benefit from a personalised therapy with a PARP inhibitor. inhibitors potentially offer the first biopsies, circulating tumour cell (CTC) A Phase III registration olaparib study will opportunity for molecular stratified and circulating tumour DNA collections commence in 2016. Additional efforts to treatment in prostate cancer (PC) patients for analyses of germline and somatic pre-screen patients for these underlying with underlying defects in DNA repair. DNA repair defects. The primary end DNA repair defects in also currently The PARP protein is implicated in multiple point of the trial was novel and included underway as part of a PCFA Grant. aspects of DNA repair, and the PARP response rate based on either RECIST inhibitor, olaparib results in significant response, a decline in PSA levels of ≥50%, and durable anti-tumour activity in or a confirmed decline in the CTC count homologous recombination (HR) defective from ≥5 cells per 7.5 ml of blood to <5 tumours arising in germline BRCA1/2 cells per 7.5 ml. Notably, fresh tumour SHAHNEEN SANDHU Medical Oncologist, John Mills Young Investigator (PCFA)