Prostate Cancer Nexus
Transcript: Arun Azad on the PETRANHA trial
Arun Azad, MBBS, FRACP, PhD
Interview recorded November 2025. All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
- Yeah, the rationale for the PETRANHA trial is that we know from previous studies the combination of a non-selective PARP inhibitor and androgen receptor pathway inhibitor is efficacious. But toxicity has been an issue with non-selective PARP inhibitors. So we're hoping to address in this study by using a selective PARP inhibitor being saruparib in combination with androgen receptor pathway inhibitors, we're hoping to find a more tolerable combination that retains activity in patients with metastatic prostate cancer. Yeah, so the advantage of saruparib is that the selective PARP1 inhibitor, so non-selective PARP inhibitors target both PARP1 and PARP2 enzymes. And PARP2 is the enzyme that leads to the toxicity of PARP inhibitors, particularly haematological toxicity, principally anaemia.
So by only targeting PARP1, we still get the efficacy of PARP inhibition with saruparib but we hopefully get less toxicity, particularly the haematological toxicity. So the PETRANHA trial looked at the combination of saruparib with androgen receptor pathway inhibitors in metastatic prostate cancer. We included patients with both metastatic castration resistant prostate cancer and metastatic castration sensitive prostate cancer. The primary endpoint was looking at adverse events, so safety, and the combination did appear safe overall. We also had key secondary endpoints looking at objective response rate and PSA response. In terms of the safety, we saw that discontinuation of saruparib and androgen receptor pathway inhibitors was uncommon, occurring in 10% and 4% of patients respectively. Also of note, grade three or higher anaemia occurred in less than 20% of patients, which actually compares quite favourably to many, to at least a couple of other non-selective PARP inhibitors. And grade three or higher GI toxicity was also uncommon, only occurring in, you know, in about 3% of patients. We also saw encouraging activity, and importantly we saw the anti-tumor activity occurred in patients both with and without homologous recombination repair gene mutations. So we saw objective response rates in the order of 73% in patients with metastatic castration resistant prostate cancer and undetectable PSA rates of 83% in patients with metastatic castration sensitive prostate cancer with a combination of saruparib plus androgen receptor pathway inhibitors. And again, the really important thing there is that we saw activity in patients with and without homologous recombination repair gene mutations. Yeah, so this combination does look promising.
Saruparib plus androgen receptor pathway inhibitors and the PETRANHA trial, which is a phase 1/2 trial, obviously a single arm study, there is no comparator arm, but the results do look promising. And this trial directly led to an ongoing phase three trial, which is called EvoPAR-Prostate01, which is a global randomised phase three trial that is evaluated in metastatic castration sensitive prostate cancer. And that's looking at the combination of all patients getting androgen deprivation therapy plus an androgen receptor pathway inhibitor, and then patients have randomised to receive saruparib or a placebo. So really what this study has done is laid a fantastic groundwork and platform for the phase three EvoPAR-Prostate01 trial, and that will really help us answer the question of whether this combination is effective in metastatic prostate cancer. And importantly, the design of the trial includes patients with both homologous recombination repair mutations as well as patients without mutations. So we'll be able to answer the question of the efficacy of this combination in patients with and without homologous recombination repair mutations, which is obviously very important for us to address as well. Yeah, so we definitely, in terms of the patient population who are likely to benefit the most from this combination, we certainly expect it would be patients with homologous recombination repair gene mutations, particularly patients with mutations in the BRCA1/2 genes and probably also genes like PALB2 and CDK12 based on prior studies. So we certainly expect those patients to do the best.
In terms of patients without homologous recombination repair gene mutations, whether the PARP inhibitors plus androgen receptor pathway inhibitors are efficacious in those patients without homologous recombination repair gene mutations is still a point of contention. There were a couple of previous trials that suggested there was benefit and at least one other trial that suggested there wasn't. So I think we're trying to address that question in the most, you know, in a definitive way in this trial. So I think that we need to be mindful that those patients are still, even if the, you know, the combination is effective in those patients, it will be less effective than in, you know, we would expect than in patients with homologous recombination repair gene mutations and particularly BRCA mutations. I think we also have to be mindful of the fact that even though rates of severe anaemia were quite low, really in the PETRANHA trial, that still is the major number one side effect that we see with saruparib.
So obviously patients who either have low haemoglobin or, you know, potentially at risk from complications of anaemia, like if they have significant cardiovascular disease, these are the sort of patients that we have to be very mindful of not, you know, not putting on saruparib or even other PARP inhibitors. And those patients are excluded from the, you know, largely from the EvoPAR-Prostate01 study. So that's another group of patients who we have to be cautious about using this combination in.
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