Arun Azad: Thanks, Neeraj. It's always a pleasure.
Neeraj Agarwal: So tell us about the Phase I-II PETRANHA study on the combination of saruparib, a new PARP inhibitor, with androgen receptor pathway inhibitors you presented at the ASCO GU meeting.
Arun Azad: Yeah. So, this is the updated data from the PETRANHA trial, a Phase I-II trial of saruparib, which is, as you said, a novel selective PARP1 inhibitor, which we hope will have less hematological toxicity than non-selective PARP inhibitors. We presented some data from this study at the ESMO meeting last year. And this is an update now focusing only on the patients with metastatic hormone-sensitive prostate cancer, mHSPC. And so, actually the data we present is really looking at the safety of this combination, which is the primary endpoint, but also some preliminary efficacy data as well.
Neeraj Agarwal: So, what ARPIs were used in combination with saruparib in this study?
Arun Azad: Yeah. So, all the patients received ADT, of course, and saruparib at 60 milligrams daily. And then there were three different ARPIs used, darolutamide, abiraterone, and enzalutamide. And they were run as three separate cohorts, and it was really an investigator choice of which one the patient went into. These were not randomized comparisons. It was a Phase I-II study, but there were three different ARPIs available. Apalutamide was also subsequently made available, but because it was later in the trial course, we didn't have mature data to present with apalutamide as well, but there will be data from apalutamide in the future.
Neeraj Agarwal: Please tell us more about the findings of the study.
Arun Azad: Yeah. So first, as I said, the primary endpoint of the study is safety. And so really there were no new safety signals that we saw compared to what was presented last year. Overall, the treatment with ADT plus an ARPI plus saruparib was well-tolerated. Only 7% of patients discontinued saruparib due to toxicity, and only 3% discontinued their ARPI due to toxicity. So, generally well tolerated. We did see some hematological toxicity. Even though it is a selective PARP1 inhibitor, there is still some heme toxicity. And the most common thing was anemia. Grade-3 anemia was seen in 17%. We saw some neutropenia and thrombocytopenia, but very low rates of Grade-3 events, also some fatigue. But pleasingly, we saw very little gastrointestinal toxicity, which, as you know, in non-selective PARP inhibitors can be a problem, things like nausea and decreased oral intake. So, from a safety perspective, really what we saw was confirming the findings from ESMO with no new safety signals. In terms of efficacy, we saw really impressive efficacy. And what's really notable is that we saw activity in patients with and without HRR mutations, which I think is a really important point.
As you know, it's been a topic of some controversy about whether PARP inhibitors have activity outside of those mutations. So, we looked at a couple of different efficacy measures. One was objective responses, which were seen in over 80% of patients on the study. And as I said, there was really no difference between patients with and without HRR mutations. And so, that was obviously pleasing to see. The other efficacy data we presented was undetectable PSA rate at 12 months, which as you know, is a surrogate for overall survival. And again, we saw around three quarters of patients had an undetectable PSA in the overall cohort at 12 months, which is very encouraging about the activity of the combination. But again, there was virtually no difference or very little difference between patients with and without HRR mutations. And so, we think that supports further development of this combination in patients with and without HRR mutations.
Neeraj Agarwal: It's quite intriguing and encouraging to have 75% of patients achieving an undetectable PSA level. I don't think we have that data from any Phase III trial of ADT plus ARPI.
Arun Azad: Yeah, that efficacy was very impressive on its own. Even if we put aside the mutation status of patients, I think just that level of undetectable PSA rate at 12 months further reinforces to us that this combination is active. And again, this is not a randomized study. It's a Phase I-II study, single arm, so we don't have the comparison, but it wasn't as though all the activity was being driven by patients with HRR mutations. They were only a minority of the patients enrolled, around 15%. Most patients actually either had no HRR mutation or unknown HRR mutation status. And in those patients, we're still seeing high undetectable PSA rates. So, that's very encouraging. I think that this combination works well in a broad population.
Neeraj Agarwal: I agree 100%. And I think this is a very nice segue to the discussion of Phase III EvoPAR-Prostate01, which is ongoing globally and you are leading the trial. So, congratulations on that. Please tell us more about this EvoPAR-Prostate01 trial and what should we expect from this trial based on the data from the PETRANHA study.
Arun Azad: Yeah. So, thanks Neeraj. I mean, EvoPAR-Prostate01 is a Phase III registrational study, global study that's looking at an all-comer population of mHSPC patients who are receiving ADT plus ARPI. Everyone is receiving that and then with saruparib versus placebo. And so, this is a large study. An important thing here is that at baseline prior to enrollment, all patients will have a defined HRR status, either positive or negative based on combination of tumor tissue and ctDNA. No one can enroll in this study with an unknown status. So everyone will have a defined state, defined HRR status so that we can really evaluate this combination in the HRR-positive patients and in the HRR-negative patients to really test our hypothesis from PETRANHA that this drug or this combination can work in patients with and without mutations. Now, we still believe, of course, that it's going to work best in patients with HRR mutations and particularly BRCA mutations. But our data from PETRANHA suggests that there will be activity in the patients without mutations, which we need to test.
The one thing I will say there is that obviously, we've seen results from AMPLITUDE already with niraparib in mHSPC, and we will see at some point soon data from TALAPRO-3 with talazoparib as well in mHSPC. Those are both studies with HRR-positive patients only, and so we're eagerly awaiting the further results from AMPLITUDE but also from TALAPRO-3. This EvoPAR-Prostate01 is different because we also have an HRR-negative cohort. So hopefully we will see activity of the combination in that and we can expand the use of PARP inhibitors in a meaningful way for patients.
Neeraj Agarwal: That's very exciting news and really hope the trials are positive to provide newer and more treatment options for our patients. Thank you, Arun, for taking the time to discuss the results of the Phase I-II PETRANHA study, and also to talk about ongoing Phase III EvoPAR-Prostate01 trial.
Arun Azad: Thanks so much, Neeraj.