Neeraj, congratulations. Thank you for joining us to break this all down.
Neeraj Agarwal: Thank you, Zach, for having me. Always my pleasure.
Zachary Klaassen: Always good chatting with you.
Neeraj Agarwal: Yep.
Zachary Klaassen: The talazoparib, enzalutamide story has an interesting and important story to sort of build up to TALAPRO-3. So maybe just go through some of those earlier studies, earlier trials that led up to it.
Neeraj Agarwal: So I think preclinical data started emerging in about 10 years, 15 years ago that there could be cooperative interaction between AR pathway and PARP. And it led to a study, study eight, about seven, eight years ago, maybe 10 years ago published in Lancet Oncology showing that abiraterone plus olaparib had activity more than abiraterone. And ultimately three phase three trials were reported, MAGNITUDE trial and the PROpel trial and the TALAPRO-2 trial, testing the combination of ARPI plus PARP inhibitor versus ARPI alone. And these trials led to variable approvals. For example, combination of talazoparib plus enzalutamide is approved for patients with mCRPC with HRR mutations and a combination of abiraterone plus PARP inhibitors are approved for BRCA1 and BRCA2 mutations in the US. And they have different types of approval in various countries, I won't get into that.
Zachary Klaassen: Sure.
Neeraj Agarwal: There was evidence emerging that talazoparib plus enzalutamide may have some cooperative interaction enhancing the anti-tumor effect efficacy of the combination versus individual drugs. And then on the side, BRCAAway trial was going on under Dr. Maha Hussain's leadership. And in that trial, first-line mCRPC patients were treated with ARPI plus PARP inhibitor combination. So abiraterone plus olaparib combination versus olaparib versus abiraterone. This trial asks the question which other big phase three trials did not ask, which was combination of RP plus PARP is better than PARP alone or not, in patients with mCRPC with BRCA1, BRCA2, ATM mutations.
One caveat, all these trials were designed in the era where ARPIs were not used in the pre-mCRPC setting. So they have different indications. But the signal was quite strong from all those trials that there is, first of all, from BRCAAway, we learned that it is likely better to give them upfront together rather than sequencing for not only efficacy perspective because half of the patients do not get subsequent lines of therapies in prostate cancer. We have published, other people have published. So those were the reasons we decided to go into the metastatic hormone-sensitive, now called as metastatic androgen pathway modulation sensitive prostate cancer and with HRR mutations. So all this rationale from TALAPRO, from BRCAAway, from other preclinical rationale, I thought it was a good idea to intervene early on.
We also know from all these big studies upfront intensification studies that patients where we used mCRPC medications early on. So docetaxel was used early on in CHAARTED trial. All these ARPIs which were available or approved in mCRPC setting, when you move them to mHSPC or MAPMS setting, all of them were pretty much amplifying. All of the efficacy were amplified. So I think if you put together all these data, we decided to conduct TALAPRO-3 trial, combination of enzalutamide plus ADT versus ADT plus enzalutamide plus talazoparib.
Zachary Klaassen: Right. So there's a perfect background for setting up the design of TALAPRO-3. And I think it's important for the listeners to understand really who these patients were, what their mutation assessment was, randomization, and the outcomes you guys assessed.
Neeraj Agarwal: Metastatic APMS population or hormone-sensitive metastatic prostate cancer population. I think we have to keep repeating these two different terms together for at least a year for everyone to get used to MAPMS term. So newly diagnosed metastatic hormone-sensitive prostate cancer patients with homologous recombination repaired gene alterations. The panel was quite broad, BRCA1, BRCA2 also included ATM, CDK12, CHEK2, pretty much all standard HRM gene mutation, which are present in a standard NGS panel.
So that was the first thing. And patients were randomized to one-to-one. So there were 599 patients. They were newly diagnosed. They could have received ADT for three months to allow them to undergo sequencing and all that. And they were randomized to ADT plus enzalutamide plus talazoparib versus ADT plus enzalutamide plus placebo. So blinded placebo control trial, strictly done. Radiographic progression-free survival was the primary endpoint by investigator assessment. Overall survival was a key alpha-protected secondary endpoint.
The stratification factors are very standard de novo versus relapsed mHSPC, high-volume versus low-volume and BRCA versus non-BRCA HRR gene alterations because we really wanted to show if non BRCA gene alterations are experiencing benefit or not.
Zachary Klaassen: Sure. And really some impressive results. So take your time, go through the results.
Neeraj Agarwal: Yeah. So we were also very pleased with the efficacy. In fact, if you look at our statistical considerations, we were hoping for a rPFS of 0.63, hazard ratio of 0.63. So the sample size was actually assessed based on the expected hazard ratio of 0.63.
Zachary Klaassen: Aggressive trial.
Neeraj Agarwal: Yeah. But coming to the results, we were pleasantly surprised when we saw the results. Hazard ratio was 0.48 for radiographic progression-free survival as assessed by the investigators, which basically results in a 52% reduction in risk of progression or death. In the active control arm, enzalutamide arm, the median rPFS was 45.8 months, which is very close to what you have seen with RJ trial or other trials. And that was a surprising part that to beat such an active control with a hazard ratio of 0.48, we thought it was quite remarkable. In fact, most patients have not progressed yet, so we don't even have a median rPFS in the experiment alarm. It is non-reached. If you look at the overall survival, it is again, immature, thankfully. It means patients are doing well.
Zachary Klaassen: That's right.
Neeraj Agarwal: But hazard ratio is 0.767. So again, very few events have been met overall, but it's still trending, the combination arm. So we are pretty excited about the results. If you look at other clinically meaningful endpoints, for example, if you look at time to PSA progression, time to next treatment, which is mostly chemotherapy. And in my experience in our patients, delaying time to chemotherapy is a very meaningful endpoint for them and both were quite improved remarkably with the combination arm versus enzalutamide plus placebo on. So if you look at the enza-tala versus enza-placebo, there was almost 50%, 49% to be precise, decrease in the risk of PSA progression. If you look at time to subsequent neoplastic therapy, again, very exactly the same figure, 49% reduction in risk of receiving next therapy.
If you look at next treatments as expected, docetaxel was the most common next treatment among patients who received next treatment. Again, most patients are still undergoing protocol treatment. They have not received experienced progression. But among those who have progressed, docetaxel is the most common treatment in both arms and olaparib is a next most common treatment in the controller. Of course, quality of life always comes up when we talk about efficacy. So we look at standard quality of life EORTC measures. And if you look at different domains, the quality of life was not adversely affected. So it was similar in both arms in different domains. I won't get into different domains given the time constraints. But other than appetite loss, the quality of life was maintained.
So to summarize the efficacy data, a quite meaningful improvement in radiographic progression free survival with a 52% reduction in risk of radiographic progression. OS trends are favoring the talazoparib enzalutamide right now, a strength. So we'll see in the future. PSA progression, time to PSA progression, time to subsequent neoplastic therapy, there's a decrease, 49% reduction risk and quality of life is maintained.
Zachary Klaassen: Outstanding summary. It's just fantastic results. Congratulations to you and the team.
Neeraj Agarwal: And I'd like to talk about the safety.
Zachary Klaassen: Yeah, absolutely. Yep. Go for it.
Neeraj Agarwal: Yeah. So safety wise, again, no surprises here. We had seen from the TALAPRO-2 trial and what we saw in the TALAPRO-3 trial was very similar, very expected. Anemia was the most common toxicity. Before I go to anemia, if you look at overall Grade 3/4 toxicity by CTCAE, and by the way, CTCAE capture one toxicity one time. So if a toxicity is happening multiple times, it's still considered presence or absence. So I think from that perspective, we have to keep that in mind.
So 79% of patients in the combination arm, talazoparib plus enzalutamide had Grade 3/4 adverse events, which were treatment emergent, meaning after starting treatment, and 41% of patients in the enzalutamide plus placebo arm had treatment emergent, adverse event, which was Grade 3 and 4. Despite all of that, if you look ... And those modifications were quite common, mostly driven by talazoparib, despite frequent dose modifications, more than 80% of patients did not have to discontinue talazoparib because of side effects. So that's a good news.
Now, if you come to the type of toxicity, anemia was the most common toxicity as expected. 51% had Grade 3/4 anemia. And so I like to delve deeper into anemia for now for a minute. 43% of these patients had grade one, two anemia before starting protocol treatment, which tells us that metastatic hormone-sensitive prostate cancer with HRR alterations may have aggressive features. When you start them on protocol treatment, the median time to onset of Grade 3/4 anemia was three months, 3.2 months really precise. So anemia occurs early and the good news is after 13 weeks of treatment, the incidence of anemia goes down. Why? Because protocol mandated dose reduction of talazoparib after onset of Grade 3/4 anemia. So once Grade 3/4 anemia happened, you had to reduce the dose of talazoparib.
And that was the key thing to understand and for me to talk about during my talk, because once you reduce the dose of talazoparib for Grade 3/4 anemia, then patients are able to tolerate talazoparib as evidenced by similar duration of talazoparib treatment in patients who developed Grade 3/4 anemia or who did not develop Grade 3/4 anemia. So 34 months in those patients who had Grade 3/4 anemia versus 36 months in patients who did not develop Grade 3/4 anemia and only 5% of patients had to discontinue talazoparib due to anemia.
To be complete, I have to mention the blood transfusion. Protocol required Grade 3/4 anemia to resolve within eight weeks of onset. I think this is something which can avoid in future protocols. It is not necessary because what really happened was you cannot really fix Grade 3/4 anemia in eight weeks without blood transfusion because of the life of blood cells and you just look at the calculation, do the calculations. So 40% of these patients receive blood transfusion so that they didn't have to discontinue talazoparib. So if you could not resolve Grade 3/4 anemia without by eight weeks, they were required to stop, discontinue treatment with talazoparib.
So I think that pressured investigators who use blood transfusion. So initially after they got blood transfusion, they also required dose reduction of talazoparib and mandated by the protocol. So if you look at total number of blood transfusions during entire three year duration of talazoparib, median is two. And if you look at dose intensity of talazoparib, that's pretty high. It's a median equivalent of 0.37, which is one level lower. So to summarize the side effect, anemia is the main side effect. Key is to monitor our patients in the real-world. You don't have to follow the protocol treatment. So monitor the patients maybe every 15 days or every one month for first three, four months, you will know who is on track to develop Grade 3/4 anemia. And in my practice, I would reduce the dose before they develop Grade 3/4 anemia. I rarely do blood transfusions.
I don't have to do blood transfusions in my regular real-world patients. So that would be the approach I will have just talking about clinical implications in this video. But otherwise, we were quite pleased to have a pretty good quality of life, no compromise, I would say, in quality of life and literally 50% reduction in risk of progression or death.
Zachary Klaassen: I think too, Neeraj, if you look at the dose reduction, you still had this rPFS benefit that you had. So it tells you that you can treat these patients, the ones that need dose reduction can get it, but that rPFS benefit is still there, which is great.
Neeraj Agarwal: And most importantly, I won't reduce the dose at baseline because 50% of this was a question asked, why shouldn't you decrease the dose upfront? It means we will be under-dosing half of the patients. This anemia is likely happening because the interaction of enzalutamide with talazoparib leading to increased plasma exposure of talazoparib. So really what is really happening is by reducing the dose, we are actually leveling them to where they should be. So it's okay to reduce the dose after they develop anemia, not before. And that's the key reason we did not want to decrease the dose upfront and I think that strategy worked out. I think we saw the results and I was so pleased to see the overall results.
Zachary Klaassen: Yeah, absolutely. My last question is the context. I mean, this is getting to be a busy space, a very exciting space. We have AMPLITUDE has been approved December 2025. We have now TALAPRO-3 coming into the scene. How do we operationalize all this as we sit in the real-world, as you mentioned?
Neeraj Agarwal: First of all, it's great news for our patients.
Zachary Klaassen: Absolutely.
Neeraj Agarwal: So metastatic APMS treatment is going to be more and more personalized. We are talking about hopefully approval of capivasertib in PTEN loss space, PTEN deficient space, and then HRR mutations, and then PSMA. PSMA is targeting strategy. For now we have PLUVICTO, or lutetium, but I'm sure we'll have more type of radioligand therapies and we have AMPLITUDE trial data, niraparib plus PARP inhibitor and we already have docetaxel chemotherapy in that space.
So how do I look at these data? I think currently my approach is do CT scans, bone scans, PSMA PET scans. I order NGS testing. I will start ordering immunohistochemistry testing once capivasertib is approved and patient would have started androgen deprivation therapy during this time. So that has to be started so we start controlling the disease right away. Then I get the results, overall results. Patients who have HRR mutations, we can look at whether what ARPI they need. Again, the approval of talazoparib has not happened yet. We don't know the label yet. I'm really hoping for an HRR-mutation-positive approval rather than BRCA1 and BRCA2 approval based on the history with the TALAPRO-2 trial. So if it is BRCA1, BRCA2 mutation cohort, then we have two options, abiraterone plus niraparib and enzalutamide plus talazoparib. And that can be personalized based on patient's comorbidities, copay and other conditions, other concurrent drugs they are on.
If they have PTEN deficiency, high level of PTEN deficiency, once capivasertib is approved, I'll think about capivasertib because these patients have really poor rPFS. And based on our experience, these two mutations are not overlapping. They seem to be exclusive, not 100% maybe, but they seem to be exclusive. The other group of patients who are not biomarker positive and who have high volume disease, then they definitely have ADT plus ARPI. It has not been beaten by ADT plus ARPI plus docetaxel chemotherapy triplet. So ADT plus ARPI or high PSMA PET positive patients where PSMA PET expression is high, then definitely I'll think about lutetium therapy.
So I think it is going to be more and more personalized and we are always, we have PSA response biomarker. So six months after starting treatment, if PSA doesn't go down to less than 0.2, then we have the option of adding docetaxel at the time in those patients who started ADT plus ARPI, or there's a P6 trial going on where you are adding lutetium at that point. So I think this is going to be very exciting for our patients.
Zachary Klaassen: Absolutely. Neeraj, this has been a fantastic discussion. This is going to be so helpful for our listeners putting into context TALAPRO-3. Congratulations again and thank you for joining us on UroToday.
Neeraj Agarwal: Thank you for having me.