The Uromigos Episode 110: PEACE-1—Triplet Therapy in Prostate Cancer

The Uromigos discuss an intriguing abstract that explores triplet therapy in metastatic hormone-sensitive prostate cancer. An improvement in progression-free survival was demonstrated with LHRH + androgen receptor inhibitor + docetaxel, although OS immature, and this approach will be debated until more data is available. View the ASCO abstract.

Episode Transcript

Tom:
Karim, welcome. Thanks for joining us. I’m here with Brian. Karim Fizazi, Institut Gustave Roussy, prostate cancer, one of the world’s leading prostate cancer doctors. Karim, thank you for joining us. It’s an honor. You’ve not been with us before. I don’t know how you’ve managed to avoid us. We’ve invited you many times, I’m sure. It’s terrific you’re here with us, and you’ve got this wonderful abstract.

It’s a two-by-two study in hormone-sensitive prostate cancer. Do you want to just talk a little bit about it, why you did it? And then I guess there is also this [inaudible 00:01:00] around the change that took place in the study. So, fire away, Karim.

Karim Fizazi:
Right. And again, thanks Tom, and you, Brian, for the invitation. PEACE-1 is a phase three trial, testing new treatments on top of standard of care for men with metastatic prostate cancer. This is the general philosophy. As I guess you both well know, until 2015, we’re using conventional hormonal therapy, it typically worked for a year or so, and then, a year ago you had CRPC to face.

So, starting five to six years ago, we’ve seen really a surge, a number of fantastic phase three trials releasing great data for the patients, with docetaxel first, and then second-generation hormonal therapies, such as abiraterone, apalutamide, enzalutamide, and then radiation therapy to the prostate for men with oligometastatic disease.

But really, the key question now is how best to combine this treatment, if ever we should combine. For example, the two or three different systemic treatments, but also for radiation therapy. This is exactly what PEACE-1 is trying to address as a question.

PEACE-1 uses a two-by-two design, patients are randomly allocated into four groups: standard of care alone, and this consists mostly in ADT plus docetaxel in the trial, or standard of care plus abiraterone, standard of care plus radiation, or everything, so standard of care plus abiraterone and radiation.

And again, what we are reporting here at ASCO 2021 are the very first data from the trial, namely that of the abiraterone equation, again, mainly on top of ADT plus docetaxel. So, in other words, should we use three different systemic treatments, or just two as we’ve been doing in the last years?

Brian:
And so, Karim, take us through the primary results. What did you find?

Karim Fizazi:
So, we looked for first analysis at the radiographic progression-free survival co-primary endpoint. The data are good, I think. The difference is highly significant favoring the abiraterone arm, again on top of ADT plus docetaxel.

Median RPFS rates were two years as expected in the control arm with ADT plus docetaxel versus 4.5 years in the experimental arm with abiraterone with a triplet treatment. And this obviously leads to an absolute difference of two years and a half in medians in favor of a triplet systemic treatment, which I think is impressive.

This was actually supported by other analysis of PFS. For example, when we looked at time to castration resistance, we found pretty much the same delta, more than two years of benefit and same when you can see their symptomatic progression as an event. Again, it’s more than two more years on top of the original two years shift by ADT plus docetaxel.

So, it really seems that the triplet treatment does much better as compared to ADT plus docetaxel. Having said that, of course the trial is currently immature for overall survival. We are collecting OS events and hopefully we’ll be able to report data on OS after the summer.

Tom:
Karim, the trial’s got a two-by-two type design and is quite complicated. What are the hazard ratios for the triplet versus the doublet?

Karim Fizazi:
It’s 0.5. So, 0.50, if you will. And when we looked at the subgroup analysis, this was true across the board. So, with or without radiation, with or without docetaxel, in high burden disease versus low burden disease. The benefit of abiraterone stands pretty much in all these subgroups. We also looked, for example, at the various means at castrating men, agonist or antagonist, and actually this was a stratification factor. And again, the benefit of abiraterone is there.

Tom:
Karim, there’s so much in this because of the four arms, but first question, I guess, is the [inaudible 00:06:00] or the control arm switched in 2005? What change did that have on the conduct of the trial?

Karim Fizazi:
Right. To protect. So, yes, indeed. We moved to ADT plus docetaxel as a standard of care to remain ethical towards patients, obviously, because we knew there was no overall survival benefit from adding docetaxel.

So yes, we changed the standard of care during the course of the trial to protect for any impact of this on the analysis. The use of docetaxel was added as a stratification factor. So, all the results I just reported to you, for example, are for patients receiving ADT plus docetaxel so they really had a half of a chance to receive abiraterone or not.

And the men who were treated before, if you will, receiving ADT as a standard of care, did not really count in the analysis I just reported to you. So, we feel really confident about the data. There’s no arming, if you will, from the methodology that we use in the trial.

Tom:
Karim, talk to me about the role of radiotherapy and what impact that’s had on this trial in terms of the PFS outcome.

Karim Fizazi:
Right. So, the first thing that we did by all the statistical analytical was to check there was no interaction between radiation and abiraterone. And fortunately, enough, there was not. And

I’m saying fortunately, because otherwise we would have to test all arms one by one versus the control arm. And of course, we would lose a lot of power doing this. Given this was not the case, you can then pull together the two abiraterone arms and compare them versus the control arm without abiraterone. And so, this was really good.

Now regarding the radiation for therapy effect, what we can safely say for now is that, for example, in terms of safety, we haven’t seen any arming within the first six months after randomization of combining radiation, ADT, abiraterone, and docetaxel. And obviously, of course, we did that partially sequentially. So, ADT plus docetaxel and abiraterone were given concomitantly, but then the radiation was given after docetaxel was completed. So, this is the first thing we can say regarding the radiation equation.

Now regarding the efficacy of radiation, we need to be patient because we, again, by our initial hypothesis and statistical analytical plan, were aiming to look first at whether patients with oligometastatic disease benefit from the radiation treatment in a context of, obviously, intensified systemic treatments. And to look at this question for both RPFS and OS, we need more events for the oligometastatic patients. So, I suspect that we should be able to do this maybe in a year or two from now, of course, depending on [inaudible 00:09:33].

Brian:
Karim, the patient population, was it just oligometastatic disease, or all-comers, or what was the breakdown?

Karim Fizazi:
So, all these patients had de novo metastatic disease, but it could be any bulk of the disease besides this. So, some men, approximately 45%, if I recall well, had low burden or low volume or low [inaudible 00:09:57], whatever you call it disease while the rest, approximately 55% had high burden disease.

Brian:
So where do you think we stand with the role of radiation in this setting? Because it’s debated. There are many trials that you know better than I do. And I know we debated in our tumor boards all the time. Where exactly do we stand in regard to that?

Karim Fizazi:
Well, I think that, thanks to the STAMPEDE data on radiation therapy, I feel confident recommending local radiation therapy to men with oligometastatic disease. So those with less than three [inaudible 00:10:34] metastases. I think the STAMPEDE data regarding these questions are extremely robust. And the number of patients who were randomized for this question in STAMPEDE was just great. So, it’s very unlikely to be a false positive, if you will.

So, yeah. And this isn’t directly supported by a subgroup analysis of the other randomized trials, the HORRAD trial, which actually included mostly high burden men or men with high burden disease. And for these men, obviously there’s no real benefit, but for the subgroup of men with low burden disease in HORRAD, the same trend that was in STAMPEDE was also reported.

So, I think that this is a true finding, and actually it makes sense. If you have, say 90% of your cancer in your prostate and you’re killing these cells, you’ll likely impact on overall survival. While if, say 80% of your cancer is outside of your prostate because you have many mets, it’s probably unlikely to be so.

Brian:
Yeah, so not dissimilar from debulking nephrectomy in kidney cancer, right? If you’re removing most of the tumor burden, that’s likely a benefit, but not otherwise. So that biologically makes sense.

Tom:
Karim, did you get the chance to look at OS? I know it’s immature, was that in your statistical analysis plan to have some alpha spend there?

Karim Fizazi:
Yes, we decided of course, to protect most of the alpha to the OS. So actually, for the RPFS to be a significant, which actually is the case, you had to have a p-value of several zero and then a one. For OS, it’s almost all of the alpha, which is capped, again, to protect it. So almost 0.05, if you will.

Tom:
Yeah. I think it’s 4.9. And so, you’ve still got that stored for OS, and you haven’t looked at OS as it currently stands, or you have?

Karim Fizazi:
Oh, no. I have zero data on OS.

Tom:
It’s completely protected, and we don’t know. So, without OS in the prostate field, what do the results of your trial mean? Before we get there, can I ask another question? I’m sorry, Karim. We haven’t talked about …

Brian:
He’s interrupting himself.

Tom:
I apologize. Karim, just talk to me about toxicity and what you have.

Karim Fizazi:
Sure. So actually, I think the news we have from the toxicity side are also good and reassuring. For example, of course, we are hearing about the febrile neutropenia incidence with drug-drug interaction, these things. And actually, this was reassuring, what we saw was 5% with or without abiraterone for the rate of neutropenia. So, this is no new issue. And the same applies to other hematological toxicities. So, this is really good.

Now regarding some either typical docetaxel related side effects, such as fatigue or GI toxicity, actually, we saw a lower incidence in the abiraterone arm, perhaps thanks to the prednisone or perhaps thanks to abiraterone, of course, I don’t know. This is obviously, again, used for patients.

Regarding the typical abiraterone related toxicity, what we saw was what we expected from what we know the drug. Namely, an excess in hypertension, hyperkalemia, and transamine is increased, but honestly, nothing bad. The incidence for hypertension, for example, was 12% in the abiraterone arm versus 8% in the control arm, nothing really bad.

What I’m describing here are the data during the first six months of therapy. We are currently collecting longer term toxicity data. And of course, we always need to be cautious sometimes, as we all know toxicity can happen in the longer term. But hopefully, again, we will this after the summer.

Tom:
Karim, treatment-related deaths, treatment-related discontinuations, what were they like?

Karim Fizazi:
So, with the current analysis, the current data, the toxicity related deaths was obviously very minimal. I think we had two deaths due to docetaxel in both arms if I recall well, and obviously a balance between the two arms.

And the discontinuation data, currently we … Well, for docetaxel we know, and it’s very similar between the median number of cycles was six. So that’s cool. For abiraterone, it’s too early to say. We are actually currently analyzing the discontinuing because this is more longer-term data.

Brian:
And so, Karim, for overall survival, you think end of the summer is when you might start to have the initial data? Because obviously it’s very impressive RPFS data, but do you think there has to be an OS benefit for this to be adopted?

Karim Fizazi:
I hope so, of course. Now, we need at least 250 death events to start the analysis for the ADT docetaxel group. Regarding the abiraterone question, if I were to bet, and again, as I’m speaking, I don’t know what the findings were, but I would say yeah. I would expect an OS benefit. Two years and a half of RPFS difference is really big. You don’t see that very often in oncology unfortunately, so I think-

Tom:
It’s funny. Brian’s never seen it in any of his trials.

Karim Fizazi:
Exactly. So it should be that early is better and that where we should be on OS benefit, but of course data will tell. Now if at the end of the day we are unfortunate and OS is similar, let’s say, I still think that for patients, denying two years and a half of additional good time, if you will, doesn’t really make sense.

Even if at the end of the day they leave the same time, I would be in favor of using the strategy of a triplet systemic treatment upfront. Of course, assuming we don’t see some more toxicity in the longer term.

Tom:
So, Karim, you’re saying that you think [inaudible 00:17:29] with no OS, in your opinion, it’s currently practice changing.

Karim Fizazi:
I think it is. Yes. I’d love to actually to hear you your opinion as well. So please tell me what you think. And beyond all of your opinions, what our colleagues will say.

Tom:
Just before we get there, Karim, because … When we put drugs together in cancer, we combine, we get sort of additive or some additivity, not synergy, very, very rarely, and sometimes antagonism and sometimes nothing at all. With this type of approach, it seems that you’re actually getting [inaudible 00:18:10] with this approach. Do you think that’s the case?

Karim Fizazi:
It’s really hard to say. It’s hard to say because first we don’t have so many clinical data regarding, for example, docetaxel versus abiraterone. [inaudible 00:18:34] to say the real comparative arm. The preclinical data are scarce, and it’s not that easy to use abiraterone in preclinical trials in prostate cancer.

[inaudible 00:18:51] metabolites of abiraterone are of importance. So, if you’re using the drug by its own, on self, for example, you don’t necessarily see the whole story. So, I think it’s really hard to say. I guess I would buy [inaudible 00:19:10] even if it’s not synergy, I would buy that. What I think we should be fearing more in the future is perhaps drug-drug interactions.

I’m not sure we’re paying enough attention to that. Some of the drugs [inaudible 00:19:30] of course, we are always fearing toxicity regarding that. It could be also the other way around. The drug can actually decrease the efficacy of another drug.

Tom:
Sure. So, Karim, what about the people who will come back and say, well, without the OS data, how do you know that if you just sequence them, you’re not going to get [inaudible 00:19:55] results? So, what you win on the swings you lose on the roundabouts.

Karim Fizazi:
Well, I guess you would not find the same results in terms of RPFS. Because by definition, RPFS is …

Tom:
Yeah, no, I agree with that. But with OS you might say, well, listen, we’ll keep the chemotherapy in the closet. And when the cancer comes back, we can zoom it in then, and we’ll have great results.

Inevitably, because people will say when these patients’ tumors grow after the triplet, obviously there are some new options for them. And we saw Mike Morris’s great data at ASCO this year with other bits and pieces, but you haven’t got that much maybe left in the cupboard once you’ve failed this triplet, or once the cancer has grown in this triplet.

Karim Fizazi:
I agree. Having said that, as I said, if ever at the end of the day, for OS, sequential or concomitant is similar, but concomitant, if I may call it this way. So, starting upfront with three treatments is associated with a much better time to progression, including actually clinical progression in symptoms. If it’s two years in a half of additional time.

Brian:
So, Karim, on that front, do you have quality of life data? Do you have data about symptoms?

Karim Fizazi:
Yes. We’ve collected our quality of life. We haven’t done live data for ASCO, obviously, but eventually we will report them. Indeed. Yes. I don’t have them as I’m speaking.

Tom:
Karim, are there other trials testing the same thing? Because clearly this is potentially a big deal in prostate cancer because upfront triplet therapy with or without radiation, which is discussion which I think we’ve had, would be a different approach. Are there other confirmatory trials for a meta-analysis? Are there other approaches that can support your findings?

Karim Fizazi:
Right. Yes, indeed. There are two other phase three trials regarding whether we should use triplet or a doublet. So, ADT docetaxel plus or minus a next-generation hormonal therapy.

One is of course from our great friend Chris Sweeney, which is ENZAMET. In his trial, a subgroup of men, 500 in total, actually were exactly randomized to get ADT docetaxel plus or minus enzalutamide. And I think Chris will report the OS data for this trial, hopefully in the soon future. So that is a second together with PEACE-1.

And finally, we have also the ARAMIS phase three trial, which is an industry sponsored trial, very large one testing exactly this hypothesis of doublet versus triplet with darolutamide. Hopefully there will be able to report data either later on this year or next year.

So eventually I think that we will have enough data to make all our minds clear about this question. Now regarding the integration of radiation therapy in all of this, I think PEACE-1 is the only phase three trial we’re having. So, I guess we’ll have to rely on the data.

Tom:
Karim, my last question. Brian I’m sure has got one or two. Because of the two-by-two design and the multiple arms and the change in the control arm, how much uncertainty did that create with the results?

Karim Fizazi:
I actually don’t think it creates most uncertainty. Because again, we made sure from the statistical plan that we would protect each analysis. And again, each analysis has to start by interaction test between radiation and abiraterone, which are the two compounds of the actual design.

So, if ever the interaction test is positive, you basically need to test only one arm to the control arm. So, you’re losing half of [inaudible 00:24:21]. It’s part of a game, and that’s okay. Here for the abiraterone question it was not the case. So, we could actually analyze the entire trial.

And again, the interaction test is really protecting you from doing mistakes. And actually, the same applies to the standard of care. We moved from ADT alone to ADT docetaxel, but then we included docetaxel as a stratification factor, which is again, protecting from any bias.

So, in other words, given patients really had the same chance, whatever his tumor burden, his prognosis, et cetera, his prognostic factors, to receive abiraterone yes or no. So, there’s no imbalance. And actually, this is reflected by the patient populations. They’re really, really similar.

Brian:
So, Karim, just a final comment from me, not really a question. First of all, congratulations on another great practice impacting dataset. As we were talking, it was just interesting the parallels between prostate and kidney cancer in terms of treatment of the primary one that represents the bulk of the disease, which is something we’ve been wrestling with in RCC for decades.

And then the moving from doublets and triplets, which is sort of right where we are in RCC again, which we’ve talked about on previous podcasts is sort of the way we cure solid tumors is multi-agent therapy. And it seems like that’s right where prostate is, is on the precipice of moving to triplets, if you agree.

Karim Fizazi:
I totally agree. I totally agree.

Tom:
Karim, super exciting, super exciting. Anything you want to say before we call it a day?

Karim Fizazi:
All right. Yeah, no, it’s great to report this data and it’s also great that it comes from an academic trial. I think this is an important message to all of us. I think …

Tom:
Prostate cancer’s been exceptionally good at that. I don’t want to talk about this for too long, but you’ve got STAMPEDE and you’ve got the ENZAMET and ENZARAD. You’ve got your PEACE program. We’re really wrestling. I don’t know, Brian, we should talk about this another time, Karim.

We should get you back on, but you guys have done an exceptional job in prostate cancer with academic trials because it gives you control and it allows you to have a different dialogue also because it’s successful, it builds its own success if you know what I mean.

Karim Fizazi:
You’re right. And actually, you can use your trial to ask several questions, including some of them which are not necessarily key priorities to the industry, such as the radiation question, for example, in PEACE-1. Those are so important to our patients.

Brian:
Yeah. Agreed.

Tom:
Karim, we really miss you. It’s going to be soon though. I might be able to travel to France at some point in the not-too-distant future. And if I do, I’m going to stop by whether I’m invited or not.

Karim Fizazi:
Happy to have [inaudible 00:27:19] on PEACE-1.

Tom:
Oh, Karim, what a fantastic result. Congratulations to the whole team.

Brian:
Thanks, Karim.

Tom:
Everyone involved. Thanks for joining us.