Research sheds light on PARP inhibitor use in mCRPC
The future of poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors in the treatment of metastatic castration-resistant prostate cancer (mCRPC) is promising in light of encouraging results from recent clinical studies.
“Treatment of mCRPC remains a considerable challenge,” said Professor Gerhardt Attard of the University College London Cancer Institute, London, UK. “Mortality rate of mCRPC patients remains high as responses to current standard treatments are short-lived due to tumour resistance. There is also a lack of evidence to support treatment selection that can help optimize outcomes of mCRPC patients.”
“The good news is that around 90 percent of mCRPC have actionable genomic aberrations,” he added. “For example, homologous recombination repair [HRR] mutations [eg, BRCA2, BRCA1, ATM] are found in around a quarter of mCRPC.” [Cell 2015;161:1215-1228]
“In the mCRPC setting, BRCA mutations are associated with poor survival,” Attard noted. [J Clin Oncol 2013;31:1748-1757] “This suggests a need for novel treatments, such as PARP inhibitors, to improve outcomes of mCRPC patients whose tumours harbour HRR mutations.”
The phase II TOPARP-A study investigated the use of the PARP inhibitor olaparib (400 mg BID capsule formulation) in the treatment of mCRPC. In this study in 50 mCRPC patients who had received prior treatment, 16 had HRR mutations such as BRCA1/2, ATM and CHEK2. Of these 16 patients, 88 percent had a response to olaparib. “Compared with patients with no HRR mutations, those with HRR mutations had significantly longer median radiologic progression-free survival [rPFS] [9.8 months vs 2.7 months; p<0.001],” said Attard. “In this study, olaparib demonstrated antitumour activity in mCRPC patients who harboured defects in DNA repair genes and failed to respond to standard treatment.” [N Engl J Med 2015;373:1697-1708]
The ongoing phase III PROfound study will compare olaparib with enzalutamide or abiraterone in HRR mutation-positive mCRPC patients who have failed prior treatment with a new hormonal agent (eg, abiraterone, enzalutamide). [https://clinicaltrials.gov/ct2/show/NCT02987543]
“Apart from HRR mutation-positive mCRPC, PARP inhibitors can also potentially be used in combination with androgen deprivation therapy [ADT],” said Attard.
In an in vivo study, androgen receptor inhibition impaired double-strand DNA repair, causing upregulation of PARP-mediated repair pathways. Therefore, dual inhibition of androgen receptor and PARP may confer a synergistic effect, leading to improved antitumour activity. [Nat Commun 2017;8:374]
The ADT/PARP inhibitor combination strategy was tested in a phase II trial. In the trial, 171 patients with mCRPC previously treated with docetaxel were randomized to receive the ADT abiraterone alone or in combination with olaparib. “Median investigator-assessed rPFS was significantly longer with olaparib plus abiraterone vs abiraterone alone [13.8 months vs 8.2 months; hazard ratio, 0.65; p=0.034],” noted Attard. “However, no significant difference was observed in terms of objective response rate and circulating tumour cell conversion rate.” [Lancet Oncol 2018;19:975-986]
“In a post-hoc analysis, the benefits of olaparib plus abiraterone were observed across HRR mutation statuses,” he continued. “However, the combination was associated with an increased incidence of adverse events [AEs], including higher rates of anaemia and serious cardiovascular AEs.” [Lancet Oncol 2018;19:975-986]
“A phase III study is planned based on the promising results observed from this phase II trial,” Attard added.