In the quest to establish more potent treatment strategies that target vulnerabilities in BRCA1/2-associated cancers, PARP inhibitor olaparib continues to drive more precise and personalized treatment approaches. By extending survival and reducing risk of disease progression, this powerful anti-cancer therapy has been approved for the treatment of both BRCA1/2 mutated advanced breast and ovarian cancers, and is also licensed as maintenance therapy after response to platinum-based chemotherapy for the latter. The body of research pointing to the benefit of PARP inhibition beyond tumors with BRCA1/2 mutations also continues to mount.

Published as an online first and open access Article in The Lancet Oncology*, first authored by Joaquin Mateo, Principal Investigator of VHIO’s Prostate Cancer Translational Research Group, results from the TOPARP-B multi-center phase II trial have now confirmed the anti-tumor activity of single agent PARP inhibitor, olaparib, against metastatic castration-resistant prostate cancer (mCRPC). Designed as an open-label single arm study, the second in this two part adaptive trial sought to establish the efficacy of treating mCRPC patients with DNA-damage repair (DDR) alterations, who had previously received chemotherapy and were no longer responding to standard treatments.

Led by Corresponding Author Johann S. de Bono, the Institute of Cancer Research – Royal Marsden NHS Foundation Trust (UK), the B-half of this academic study drew on the promising results reported from TOPARP-A where the association between DNA repair defects and response to olaparib in 49 molecularly unselected patients was first described. These initial findings suggested that those patients whose tumors had mutations in a range of genes implicated in DNA damage repair would be most likely to benefit from this treatment. The research also indicated that whileBRCA1/2 tumors were the most sensitive to therapy, confirmed responses were also observed in patients with other DDR alterations.

Commenting for VHIO Communications Joaquin Mateo said,“TOPARP-B is a pioneering, prospective study in a genomically defined population of patients with mCRPC aimed at establishing defects in DNA-repair genes as a predictive biomarker for treating this disease. Not only did we assess different doses of olaparib and correlated several genomic aberrations and anti-tumor activity, we also confirmed the anti-tumor activity of this agent against advanced prostate cancer with defective DNA repair secondary to either germline or somatic gene inactivation.”

Having performed targeted screening and identified those patients whose prostate cancers had faulty DNA repair genes, 98 patients from across a total of 17 UK hospitals were randomly assigned and treated in this study. The investigators found that overall, 47 per cent of patients with these DNA repair defects responded to olaparib, putting the brakes on disease progression for an average of 5.5 months. The most common defects were BRCA mutations, although various others were also identified in other genes including PALB2 and ATM, among others.

Importantly, those men with BRCA1/2 mutated disease responded the best, with 80 per cent responding and 40 per cent free of cancer progression for over a year. “The high and durable responses observed in our subpopulation of patients with mCRPC support the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice based on tumor sequencing. Based on our findings, this gene-targeted approach could help guide treatment decisions as well as match more effective therapies to the molecular make up of individual patients’ tumors,” added Joaquin.

Encouraging responses were also observed in patients carrying PALB2 mutations, ATM mutations, and other DNA repair gene alterations – totaling at 50, 37, and 20% respectively. These findings might also point to PARPi having a role as monotherapy or in combination to more effectively tackle other subtypes of metastatic prostate cancer.

TOPARP is an investigator-initiated clinical trial funded by Cancer Research UK, ECMC and Prostate Cancer UK; Joaquin Mateo was the lead clinician scientist of the trial, funded by the Prostate Cancer Foundation and Movember, who now generously support him and his new group at VHIO.

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*Joaquin Mateo, Nuria Porta, Diletta Bianchini, Ursula McGovern, Tony Elliott, Robert Jones, Isabel Syndikus, Christy Ralph, Suneil Jain, Mohini Varughese, Omi Parikh, Simon Crabb, Angus Robinson, Duncan McLaren, Alison Birtle, Jacob Tanguay, Susana Miranda, Ines Figueiredo, George Seed, Claudia Bertan, Penny Flohr, Berni Ebbs, Pasquale Rescigno, Gemma Fowler, Ana Ferreira, Ruth Riisnaes, Rita Pereira, Andra Curcean, Robert Chandler, Matthew Clarke, Bora Gurel, Mateus Crespo, Daniel Nava Rodrigues, Shahneen Sandhu, Aude Espinasse, Peter Chatfield, Nina Tunariu, Wei Yuan, Emma Hall†, Suzanne Carreira, Johann S de Bono. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. 2019. Lancet Oncol. DOI: https://doi.org/10.1016/S1470-2045(19)30684-9