Hi, I’m Professor Phil Cornford of Liverpool University Hospitals in the UK and Vice Chair of the EAU Prostate Cancer Guidelines Panel. This series of videos has been co-created in association with ecancer. We will discuss the current role of PARP inhibitor use in prostate cancer and what we might expect in the future.
Although these four drugs are all PARP inhibitors, they have distinct chemical structures, causing differences in their pharmacodynamic and pharmacokinetic properties. These differences underlie their different efficacy and safety profiles.
In May 2020 the FDA approved rucaparib for patients with deleterious BRCA mutation (germline and/or somatic) and associated metastatic castration-resistant prostate cancer who had already been treated with both androgen receptor targeted therapy and taxane-based chemotherapy. The recent TRITON2 and TRITON3 trials were key to this approval.
TRITON2 is an ongoing phase II trial evaluating 600mg doses of rucaparib in patients with metastatic castration-resistant prostate cancer and an alteration in BRCA1, BRCA2, ATM, CKD12, or another pre-specified DNA damage response, or DDR, gene.
Results so far indicate that among patients with a BRCA mutation, 43.5% had confirmed objective response rates and 54.8% had confirmed decrease in PSA levels. The objective response rate and PSA response to treatment were less substantial for patients with other genetic mutations.
TRITON3 is a phase III trial that aims to evaluate the effectiveness of rucaparib as compared to second-line androgen receptor directed therapy and docetaxel in patients with metastatic castration-resistant prostate cancer. All patients in this study have a BRCA1, BRCA2 or ATM mutation and have previously progressed on first-line androgen receptor targeted therapy. They have not received chemotherapy.
Primary results indicate that radiographic progression-free survival was significantly improved in those patients treated with rucaparib monotherapy, versus physician’s choice.
The phase III PROfound study was a randomised trial evaluating olaparib 300 mg twice daily versus physician’s choice of abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer and progression on at least one novel hormonal agent and up to one prior taxane agent.
Patients had to have a somatic or germline HRR mutation and were allocated to one of two cohorts: Cohort A comprised patients with BRCA1, BRCA2 or ATM mutations and cohort B comprised patients with a mutation in at least one of twelve other HRR genes.
The primary endpoint of improving radiographic progression free survival with olaparib versus abiraterone and enzalutamide was met in Cohort A, and was also superior in the entire study population, comprising Cohort A and Cohort B. In addition, final overall survival analysis of PROfound showed an improvement with olaparib versus abiraterone or enzalutamide in Cohort A despite the fact that 86 of 131 patients crossed over to olaparib after disease progression in the control arm.
As a result of the favourable efficacy data from the PROfound trial, the FDA approved 300mg twice daily olaparib in May 2020 for use in patients with metastatic castration-resistant prostate cancer and deleterious or suspected deleterious germline or somatic HRR gene mutations in at least one of 14 genes and who had previously received treatment with enzalutamide or abiraterone.
The ongoing phase III PROpel trial is evaluating the efficacy and safety of olaparib in combination with abiraterone in treating patients with metastatic castration-resistant prostate cancer. This study builds on positive results from an earlier phase II trial.
Results presented at ASCO GU 2022 showed the combination significantly improved radiographic progression-free survival versus abiraterone alone as a first-line treatment. The patients underwent testing for the presence of homologous recombination repair gene mutations. Interestingly, the study showed clinically meaningful activity for all patients although the effect appeared greatest for those with mutations in an HRR gene. Results showed the combination reduced the risk of disease progression or death by 34% versus abiraterone alone.
Data presented at ASCO GU 2023 showed a final overall survival of 42.1 months vs 34.7 months for abiraterone alone, for a 19% reduction in the risk of death. Though not statistically significant, the results maintained a trend toward improved efficacy.
A further subgroup analysis of the secondary overall survival end point also showed trends in improvements across selected groups, with the largest improvement seen in HRR-mutated mCRPC.
Although not yet EMA or FDA approved, niraparib is the other notable PARP inhibitor showing potential in prostate cancer.
The phase two GALAHAD trial, in progress since 2016, aims to assess niraparib in metastatic castration-resistant prostate cancer. These results suggest that PARP inhibition through niraparib may soon play an important role in the treatment of metastatic castration-resistant prostate cancer in patients with DNA repair mutations.
The study authors recently concluded that niraparib is tolerable and shows anti-tumour activity in heavily pre-treated patients with metastatic castration-resistant prostate cancer and DNA damage repair defect status, particularly in those with BRCA alterations.
Similarly, the phase III MAGNITUDE trial assessed the safety and efficacy of niraparib plus abiraterone and prednisolone compared with abiraterone acetate and prednisolone plus placebo in patients with metastatic prostate cancer.
In patients with metastatic prostate cancer harbouring BRCA1 and BRCA2 mutations, the addition of niraparib to abiraterone acetate and prednisolone elicited efficacy benefits in patients with PALB2, CHEK2, and HDAC2 alterations. In this study there was no apparent benefit for men without HRR gene mutations. It is not clear why combination of abiraterone and olaparib appears to have clinical benefit whilst niraparib plus abiraterone was not effective in patients without HRR gene mutations although it is possibly because a reduced dose of niraparib was used in this study.
Lastly, talazoparib is also being investigated in mCRPC in the TALAPRO 1, 2 and 3 studies. The phase three TALAPRO-2 study looked at talazoparib in combination with enzalutamide, compared to placebo plus enzalutimide in men with or without HRR gene mutations.
Data presented at ASCO GU 2023 showed that the median radiographic progression-free survival was 37% better in the talazoparib vs the placebo arm, with this PFS appearing to be the longest observed in a randomised mCRPC clinical trial to date. Results also showed a trend toward improved overall survival at the time of analysis, but the data are not yet mature.
It should be noted there are currently no data comparing different PARP inhibitors for prostate cancer in a head-to-head study.
Moving on to the safety profiles, a recent real-world analysis of ovarian data presented at ASCO 2022, found that patients treated with FDA-approved PARP inhibitors had significant differences in the incidence of clinically relevant adverse events.
The findings highlighted differences in tolerability, use, and dose modifications associated with olaparib, rucaparib and niraparib. The analysis found that the risk of any clinical event of interest, as well as time to PARP dose decrease and PARP dose discontinuation, was significantly different with niraparib compared with olaparib and with niraparib compared with rucaparib.
Overall, the number of patients impacted by a clinical event of interest was significantly fewer in the olaparib treatment group, compared with patients receiving niraparib or rucaparib when they receive the full treatment dose.