Alan Bryce: My pleasure. Thanks for having me, Pedro. Good to see you, my friend.
Pedro Barata: Thank you so much. So we'll talk a little bit about your important presentation TRITON-3. So for context, TRITON-3 is a trial that you and others put together, really establishing the role of a PARP inhibitor, rucaparib, against what was considered standard of care of a ARPI switch, abiraterone enzalutamide, or docetaxel compared to rucaparib for patients who progress on a prior RPI. I mean, using the old designation mCRPC patients, we're now calling that APMR, so androgen pathway modulation resistant disease, but post-ARPI setting. So Alan, tell us, you did focus this time doing AUA, you did focus on safety. So tell us why that was an important angle that you want to present and highlight and tell us the summary of those observations.
Alan Bryce: Thank you, Pedro. So as we get into the follow-up sub-studies out of TRITON-3, we're going through the normal deeper dive into smaller details of the studies so that investigators and clinicians have that data at their fingertips. One of the things that becomes a real issue with PARP inhibitors is the management of the toxicities. And there's really class effects across all the various PARP inhibitors. The biggest which are going to be the myelosuppression and then some GI toxicity and fatigue, but especially the anemia, the transfusion rate. I think these are major issues with PARP inhibitors. So across all the studies, we've seen transfusion rates from 20% to up over 40%, or 20s to 40s.
And I think these are key issues that physicians have to manage and really be aware of because we're used to using ARPIs in prostate cancer where management of anemia is not a very big issue. And so depending upon the comfort level of the treating clinician with anemia and transfusion needs, the PARP inhibitors sometimes represent a more complicated drug to use than the ARPIs. And we hear this from some community physicians who say, "Look, I'm not used to ordering transfusions in my practice. How am I supposed to do this?" I think, in reality, the med-oncs are fairly comfortable, but the urologists generally less so. So that was really the focus of the AUA presentation to talk about what are the toxicities we see with rucaparib? How does it compare to the control arm, which of course on this study was physician's choice of docetaxel or an RP switch.
And in terms of findings, so top line, the rate of Grade 3 or greater adverse events was fairly comparable between the physician's choice arm and the rucaparib arm, 59% on rucaparib, 50% on the physician's choice arm. But the drug discontinuation due to adverse events with rucaparib was only 14%. On the physician's choice arm, it was 22% driven much more by the docetaxel than by the ARPIs. But even on the ARPI-treated patients, the drug discontinuation rate was 8%. So ARPI is 8% versus 14% rucaparib, not that much different. And then adverse events of special interest with rucaparib, the rate of transfusions was 28%. The rate of MDS only 1%. And importantly, the median dose intensity, which is to say what proportion of total doses given were full dose versus less than full dose. And counted day by day and across the entire conduct of the study, the median dose intensity for patients was 98%. So 98% of the days a patient was getting drug, it was at full dose more for the median.
So really for most patients, they do fairly well with it. The rate of transfusions at 28% is really on the lower side for the PARP inhibitors as we've seen across various studies. I think what that really speaks to is it's the therapeutic index, this key concept we talk about in oncology and drug development. What's the window between the dose that's effective for tumor suppression versus the dose at which you're going to get toxicity? And we need a wide window there. If those lines are reversed, you can't use the drug. And I think what we see here is that with rucaparib, you get to an effective dose at a very reasonable level with a very reasonable window. And I think with proper management, proper attention paid to the hemoglobin, it's a very manageable drug in most scenarios.
Pedro Barata: Alan, that's a beautiful summary. And just for the community team out there and their experience, with other PARP inhibitors, we've seen that usually we take around two to three months of time for us to understand and appreciate what is the dose patient is going to be on moving forward? In other words, most discontinuations, those interruptions, dose reductions happen within that time period, 20 weeks, maybe 24 weeks. Is that what you saw in TRITON-3? In other words, you see people getting what we call often "get on cruise control". Once you find out your right dose, you stick to it, which also allows us with thinking about how often we see the patients. I tend to see my patients more often in the first few months and then space things out. Is that what you observe in the TRITON-3?
Alan Bryce: Yeah. So one of the data sets we presented at AUA, we showed the median time of onset of various toxicities to your point. And for anemia, the median time of onset was a little more than two months. It was around day 70 or so. For thrombocytopenia, it was more like day 110. So in the first say two months, month one, month two, you tend to see more of the GI toxicity as the early onset, diarrhea, nausea, also fatigue. And then the clinically significant anemia is going out more towards, like I say, day 70 or so.
So what that means, as you suggest, is you can really tailor the intensity of your follow-up to that. I think if you get beyond two to three months and you haven't had GI toxicity, at that point you feel good you're not going to. I think the point about the anemia being day 70, what it tells you is... Median, right? It tells you is it doesn't tend to come on after a week. It's not explosive, which makes sense. The lifespan of a new erythrocyte is about 90 days. So if you shut off all marrow production, think you lose 1% a day essentially. So it takes several weeks to get into trouble.
Now you don't shut it off completely with a PARP inhibitor. But what this means is that you can track the patient over the first two months and I think, as a clinician, really get a strong sense of how your patient's marrow is doing. And I think as a clinician, and this goes beyond the presentation, but just as we speak to clinicians, you can exercise a lot of clinical judgment. Obviously the older the man, the softer the marrow, the more you have to pay attention to this. A 50-year-old is different than an 80-year-old. The man who comes in with a baseline hemoglobin of 10 because of age, because of prior pelvic radiation, whatever that is, you're going to approach that man differently than the man who starts with a hemoglobin of 14.
And so I think one of the problems with the clinical trials is, of course, the dose adjustments are limited by what's written into the protocol. And there are times when you're sitting there watching the hemoglobin fall saying, "All right, I know this man is going to need a dose adjustment, but per protocol, I can't do it yet." In clinic, you don't have to wait. So for the man who's got a more fragile marrow, I'd watch the hemoglobin every two weeks in the beginning and I'd make adjustments. Just really jump on top of it for the first two months, you keep track, you make adjustments. And I think if you do that in clinical practice, your transfusion rate does not have to be 20-something percent. It can be less than 10% because you can manage in an anticipatory way.
Pedro Barata: That's a wonderful message, Alan. It's sometimes how we write the protocols and we want physicians to understand and providers to understand the benefit of being on protocol. Therefore, they're going to be maybe more aggressive. Sometimes some persistent anemia despite transfusions may require either dose reduction further or dose discontinuation. And so some of us, as an attempt to keep the patient on an active regimen, become more aggressive and that can include more transfusions that we end up seeing in real life. As to your point, we proactively address those. And quite frankly, I think our colleagues that treat many cancers where PARP inhibitors are approved beyond prostate cancer may have more experience than we do because they're dealing with this in ovarian, in breast, in pancreas, and therefore they might have learned that already about the management piece, which is super critical. I couldn't agree with you more.
Alan, before I let you go, I have one last question. We've seen this big important discussion around control arms on the Phase 3 trials for patients who end up with mCRPC or APMR post-RPI exposure and what to do. In the U.S., people do a lot of RPI switch. Outside U.S., docetaxel is the preferred regimen and docetaxel works, is an active regimen. And we got the approval of lutetium-177-PSMA-617 in this setting as well recently or more recently. And we just saw data comparing the two. A Canadian study by Dr. Xi et al, basically put things into perspective and looking at how chemo does. So this is not an old comer population. We're talking about specifically BRCA ATM, which is different from all HR, but not surprisingly I would say PARP inhibitors, rucaparib was shown to be superior to docetaxel.
So I would like your thoughts around when we see a patient like this we may not have tested, we think of chemotherapy, not as much maybe in U.S., and outside U.S. Then we have a PARP showing superiority. I'm not aware of a lot of data like yours to show that. So tell me a little bit about, give me the message around out there saying, "You know what? Chemo works, why don't I do that and do the test later on?" If you will. And another additional, I know a lot of thoughts for you, but would that be different if I were to think of a platinum-containing regimen instead of docetaxel? So anyway, a loaded question for you, but I'm wondering your insights on this.
Alan Bryce: Great points and great question. So absolutely one of the things we're very proud about in this study is the fact that we had docetaxel in the control arm, and that's rare. And if you look at the rest of the drug approvals that we've seen over the past six, seven years, almost every drug approval is based upon comparison to ARPI switch. In fact, this study, TRITON-3, is the only clinical trial in mCRPC, APMR, where the experimental drug has beaten docetaxel. This is it. There's dozens of clinical trials we've done in prostate cancer randomizing events, docetaxel. This is the only drug that's beaten docetaxel. And of the PARP inhibitors, this is the only PARP inhibitor where we can definitively say this PARP inhibitor, rucaparib, is better than doce because we designed the study that way.
And just for the listeners, so we really don't overlook the details, in the physician's choice arm, which was doce or ARPI switch, a majority of patients got docetaxel. So 75 patients were placed on docetaxel, 60 on ARPI switch. So docetaxel was the most common treatment in the control arm. And docetaxel is more effective than ARPI switch. And that's the other point. ARPI switch, we know it doesn't work. So what happens in clinical trials, other clinical trials will show maybe better hazard ratios, but they show better hazard ratios because the control arm is basically placebo. We have a more active control arm. That means it's harder to show a positive study because the control arm is more effective. So the fact that rucaparib was positive versus docetaxel, again, the only positive study randomized against docetaxel in prostate cancer registration study, I mean, it really shows to me a couple of things. One, I believe we should be having docetaxel in the control arms of our registration trials. I think the days of just doing ARPI switch should be in the past.
But two, when you're thinking about rucaparib versus docetaxel in this setting, you can be absolutely confident that rucaparib is more effective and leads to a higher response rate than docetaxel. The data is clear, and you can't say that about any other PARP inhibitor. Now you asked the secondary question of, well, what about platinum? And the answer is we don't know versus platinum. Of course, that is something that we use commonly in prostate cancer, but it's not per guideline by NCCN and it's not an FDA-approved option. So it's not part of the trial design, but it is something we use, especially in the other part malignancies, pancreas cancer, ovarian, breast, platinum use is much more common. So we don't really know. How would rucaparib compare to say a platinum doublet, doce carbo, something like that? The answer is, we don't know. And it's another future study for someone to consider is in resource-constrained environments, if carboplatin would be a lot less expensive, should that be considered an alternative regimen? I think that would be a great clinical trial.
Pedro Barata: I definitely agree with you. And again, merits to the design because you designed with, I believe, the Alliance team many, many years ago. And it's always easier to go back and think what else could we have asked and designed? And you guys were able to design this at that time and saw that docetaxel needed to be included in the control arm, which I do think it speaks up to the thoughtful process that was put into the trial design. And just a reminder for the listeners, the FDA recognized that with the expanded label TRITON-2 and then TRITON-3 and is now available for patients harboring BRCA ATM in that setting.
So Alan, it was awesome as always. Thank you so much. Super helpful. I learned a lot, and congratulations on the presentation again. And we'll talk again soon. Thank you so much.
Alan Bryce: Thank you, Pedro.