PARP binds to DNA breaks, attracting DNA repair proteins to the site. BRCA facilitates homologous recombination, which can be used to repair single-strand DNA breaks that are not repaired by the PARP mechanism. Failure in both pathways simultaneously leads to damage being irreparable, which ultimately results in cell death. Cell death that occurs as a result of two simultaneous genetic/metabolic defects, as in this case, is referred to as synthetic lethality. Through this process, PARP inhibition has been shown to selectively kill cells deficient in BRCA, BRCA2, and to a lesser extent, other DNA-repair genes.1
There are 5 available small-molecule PARP inhibitors, olaparib, rucaparib, veliparib, talazoparib, and niraparib. These are already being used clinically to treat breast and ovarian cancers. Yet no PARP inhibitor has yet to be approved for use in metastatic prostate cancer despite the fact that BRCA2 alterations are the most common germline mutations associated with advanced prostate cancer and are also commonly found somatic mutations in non-familal prostate cancer.
The TOPARP A and B trials were the first clinical trials to investigate the use of PARP inhibitors in metastatic prostate cancer. In TOPARP A, men were given olaparib and their response rate was used to determine whether further trials with this molecule would be performed. Since the response was found to be “intermediate” (16/49 patients), tumor DNA from the tumors of the 50 participants were sequenced to determine predictors of response. BRCA2 was found to be the most predictive, however other DNA repair proteins such as ATM were also found to be mildly predictive.
Thus, the TOPARP B trial was initiated.2 It recruited 98 men with known DNA repair gene mutations who had been selected from a population of 711 HRPC patients in the UK who had their tumors sequenced. These recruited men were given olaparib. The results of this trial, which were published in Lancet Oncology showed good responses (~54%) especially among patients with BRCA-deficient tumors (70-80%) or, to a lesser extent, ATM deficient tumors.
(A notable secondary finding of the trial was a relatively high number of banked prostatectomy specimens that were not able to be evaluated genetically, suggesting a new for improvement in the test as well as in tissue handling/preservation.)
This finally led to the development of the PROfound study, which randomized men with metastatic hormone-resistant prostate cancer who had progressed on at least one therapy in addition to androgen deprivation and whose tumors were deficient in at least one gene involved in homologous recombination to olaparib 300mg bid or the clinicians choice of best alternative therapy. Those with BRCA or ATM mutations were followed as “cohort A” and those with other DNA damage repair mutations were followed as “cohort B”. The primary endpoint was radiographic progression-free survival.
In cohort A, olaparib was found to be superior (median PFS 7.39 vs 3.55 months with a HR of 0.34, 0.25-0.47). Even more strikingly, there was an overall survival benefit for olaparib in the combined cohorts despite the fact that crossover was allowed after progression in the control arm and 80% of patients in the control arm ultimately crossed over (17.5 vs 14.2 months, HR 0.67, 0.49-0.93). Hematologic toxicities were common, especially anemia which occurred in 50%. Thrombocytopenia occurred in 10.2% and neutropenia in <5%. Retrospective genetic analysis of data from this trial further identified multiple previously unrecognized genes, such as RADS1B, RADS54L, and PPP2R2A which seemed to correlate with better response to olaparib, although this finding is only exploratory at this point.
It is likely that better understanding of predictors of response to olaparib will allow further refinement in its use, however for now it seems PARP inhibition will soon become a new treatment for metastatic hormone-resistant prostate cancer in patients with tumors harboring BRCA2, BRCA1, ATM, and possibly other DNA-repair protein defects
Presented by: Joaquin Mateo, MD, PhD, Principal Investigator, Prostate Cancer Translational Research Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain
Written by: Marshall Strother, MD, Society for Urologic Oncology Fellow, Division of Urologic Oncology, Fox Chase Cancer Center, Philadelphia PA, @mcstroth, at the 20th Annual Meeting of the Society of Urologic Oncology (SUO), December 4 - 6, 2019, Washington, DC
1. Bryant, H., Schultz, N., Thomas, H., Parker, K., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N. and Helleday, T. (2005). Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature, 434(7035), pp.913-917.
2. Mateo J, Porta N, Bianchini D, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. The Lancet Oncology. December 2019. doi:10.1016/s1470-2045(19)30684-9