The Uromigos Episode 115: Triplet Therapy for First-Line Metastatic Prostate Cancer

Dr. Eric Small is quizzed about triplet therapy for first-line metastatic prostate cancer, and Tom gets confused about York and Leeds.

Episode Transcript

Brian:
Welcome everyone to another Uromigos Podcast. Tom and I are joined by my good friend and colleague, Eric Small from UCSF, and we’re going to talk today about some of the recent triplet therapy in prostate cancer. We did a podcast with Karim Fizazi around ASCO and the peace one study, and as you know, that study looked at triplet therapy, had a great RPFs hazard ratio of 0.54 pending overall survival.

There’re some ends in that data, which doesn’t seem to show a survival benefit to triplet therapy, and so we wanted to have Eric on to give us the big picture perspective on that. So, Eric, welcome to the podcast. You can just introduce yourself and then maybe give us your take on the landscape and where we are, and then we’ll interrupt with lots of questions.

Eric Small:
Sounds good. Hi, Brian and Tom, it is my pleasure to be here. This is Eric Small. I’m a professor of medicine at the University of California, San Francisco, where I’ve led the prostate program for many years. And I’m excited to be here with you guys.

Tom:
[crosstalk 00:01:28] I will jump in.

Brian:
Yeah, jump in. I mean, tell it, maybe we can start with piece one since that was the most recent data. Tell us how you interpret, interpret that data and how it impacts practice now.

Eric Small:
Sure. So, as I think of piece one, the first question that I’ve asked is what have we learned directly from it? So, what did the data show before we interpreted it, and we’ve alluded to it? I think one of the most important things to remember about this study is that it really, to Karim and the investigator’s credit demonstrated incredible agility to adapt design based on a rapidly changing field, which we’re all facing in your logic oncology which is great.

It’s a wonderful problem to have, but it really makes interpretation of the data challenging for people who I know. You’ve heard Karim speak to this, but for the longest time androgen deprivation therapy was our standard of care, and then docetaxel was the very first agent that was really shown to benefit, and piece one had begun to accrue prior to docetaxel being standard of care.

So, it had to adapt to that. Then shortly thereafter abiraterone was shown to be significant in this setting. In fact, Karim presented the latitude study at ASCO, I believe is in 2017, and I was a discussant at the plenary session. The key point from that was that it looked like abiraterone was identical in its impact compared to docetaxel.

That was what we thought back then, and then somewhere along the line, the addition of radiotherapy was added. So, piece one really tried to adapt to this, and I think they’ve done a good job in trying to say, well, we’re going to add to the standard of care and see if that helps. So, the standard of care changed, and the patient population changed. Initially it was patients just getting ADT and then it was patients getting ADP plus Taxotere.

So, what the data show is that in patients with metastatic hormone sensitive prostate cancer, the addition of abiraterone to standard of care, six patients, 60% of whom had received docetaxel was beneficial, and it was as substantial as you alluded to increase in RPFS, from 2.2 years to 4.5 years at Delta is 2 to 2.3 years, it’s very impressive.

The hazard ratio is very impressive. The issue is that we already knew that adding abiraterone 82 was beneficial, right? That’s not new. And so, the question is, “Does adding abiraterone to docetaxel of benefit,” and the answer is yes, but docetaxel is no longer the standard of care as frontline therapy. So, it’s a largely, in my estimation, less relevant question.

Brian:
Sorry to interrupt, but it is a standard of care.

Eric Small:
It is, and so let me first, there’s two things to address, I think. One is issues with the study design and then the second is, is docetaxel the standard of care? Well, what we can say, I’ll address the second first, what we can say is that we can improve on docetaxel by adding abiraterone.

I think that’s probably a fair statement, but in no way, does this validate docetaxel abiraterone as the standard of care as, as Karim implied. It simply says that doce-abi is likely better than doce alone, but a far better study testing triple therapy should have been abiraterone versus abiraterone plus docetaxel.

Brian:
Do you think that study will ever happen?

Eric Small:
No, I think it’s un-American

Tom:
Can I ask a question? Why do you think that’s the better control or do you think the PFS would be longer for that arm? I mean, because you’re still in the guidelines, you don’t have to give LHRH plus.

Eric Small:
Right.

Tom:
You can give LHRH plus chemotherapy. So why are these two control arms not interchangeable?

Eric Small:
Yeah. So, I don’t think they are, again, they haven’t been directly compared, but as you well know, an analysis of concurrent arms from the stampede study suggested a slight advantage to abiraterone over docetaxel. A meta-analysis has suggested that abiraterone generally translates into better outcomes.

A network meta-analysis demonstrated a quality of bandage to abiraterone, and even back in 2017, the latitude hazard ratio was 0.47. We really shouldn’t compare these side to side, but charted was 0.53, latitude had an 18-month survival advantage, charted had a 14, abiraterone charted chemotherapy. So even back then the hazard ratios overlap, but they are, these are not going to last.

Tom:
I’m going to ask my question in a different way. So, what’s happened is that it looks like the benefit associated with piece one has knocked it out the park with, as you said, this sort of two-year PFS advantage and the numbers you’ve said here, comparing indirectly that latitude and charted the benefits a month here a month there. Is the quantity of the benefits so much greater with in piece one with a triplet that you can actually say that it could have been 20% worse, but actually it’s still 80%. It’s still out of the park.

Eric Small:
Yeah, I think the answer is no, and here’s why this now gets at the design of the study. So, couple of comments, first this study was not placebo controlled and RPFS appears to have been done locally, not centrally. So, it introduces a bias, I think in this ascertaining the RPFS. We also have no idea of the proportion of patients that ultimately will go on to receive secondary therapy, right? What this study tested was docetaxel, abiraterone versus docetaxel. It did not test docetaxel abiraterone with doce followed by abi.

Brian:
Every doublet or triplet study will always have that criticism right as well, but we still give plenty of doublet and triplet therapy and our doublets kidney cancer, not everybody’s going to get salvage therapy, and sometimes that’s an argument that you should give it up front, right? If patients can never make it to that effective salvage therapy, then you should give it up front.

Eric Small:
Perhaps, but again the study that was presented is listen, doce-abi is the standard of care because we’re comparing it to doce, but for many reasons that’s not reality. The real world, we’ll get back to the question that Tom asked.

The real world is that in point of fact, absent costs or availability or other issues, chemotherapy doesn’t need to be used hers, it’s not the standard of care. Most people who have a choice are using abiraterone. It’s probably a slightly better agent and you haven’t really tested the utility of sequential therapy. I think that’s a fair criticism, Brian, that you can never really, really do.

Brian:
Right.

Eric Small:
But the study, I think it’s a little bit disingenuous to say that ADT plus abiraterone is better than any standard of care and therefore it should be used. In fact, if you look at, for example, with latitude, when you add abiraterone alone, the ADT, the total RPFS in that study was 2.7, five years, and the Delta, the improvement over background was 1.5 years, 1.54 to be exact. So, 1.54 versus 2.3 in piece, I don’t, that’s not an out of the park, that’s not hitting it out of the park to me.

I think that the abiraterone is a good agent and adding it to the ADT is absolutely appropriate. But for the patients who are going to start therapy on, for whom chemotherapy is not necessarily being contemplated, it, I don’t think it follows that you should be using docetaxel plus abi.

Brian:
I have a comment and a question, the comment is we may have to have you back on to debate Chris Sweeney about using doce versus abi upfront, because I’ve heard him give some good arguments about doce the upfront. We don’t have to dwell on that, but my comment is, what if the overall survival is positive? Right. I don’t know when that’s going to come, but I’ve heard that it might be soon, and so what if the overall survival is 0.68 or whatever it is, and it’s significant, would you change your mind?

Eric Small:
Yeah. So, a couple of comments, first of all, we know, there’s precedent with enzymat, RPFS is positive, and survival was not. I would have to in order to look at the survival data and Karim did not report this, I would need to know what proportion of patients who received docetaxel alone, went on to receive abiraterone in the sequential arm.

Because if the proportion of controlled patients that get crossover therapy is low, well then sure, survival’s better because you’re not getting active therapy to the placebo patient or to the controlled patient.

Tom:
I got a question for you.

Eric Small:
Wait, let me just answer Brian’s question. So that said, if the proportion of patients that received crossover abiraterone at progression is substantial, and for me substantial is 70% or higher.

Brian:
Okay.

Eric Small:
Then if I saw a survival advantage, I would believe it, and I would say, it looks like the triplet is better than the sequential therapy. I don’t think that’s going to be the case. I think that. But we’ll see. But it would change the perspective.

The other comment that Karim made that I want to comment on is that he talks about how we should spare men, we should go to triplet therapy to spare men the anguish of RPFS. But honestly, a lot of RPFS is not symptomatic. It’s maybe psychologically anguishing, and we’ve all bought into the concept that it’s a really good thing, but if survival is not enhanced, then RPFS may not be the do all and end all.

Brian:
In and of itself. It’s not a reason to give it in your opinion.

Eric Small:
That’s correct.

Brian:
Yeah. Go ahead, Tom.

Eric Small:
I’m sorry, Tom [crosstalk 00:13:37]

Tom:
Eric, I love the way you don’t let me interrupt. That’s very [inaudible 00:13:40]

Eric Small:
I’m sorry. [crosstalk 00:13:43] I’m so sorry. That’s because you’re my friend.

Tom:
And you only get away with it. Eric, one of the things that confuses me a little bit is the enzymatic trial. So many people come to me and say, the enzymatic trial actually influences their interpretation of piece one, but ends them out, asked a very different question. What are those people are alluding to?

Eric Small:
Well, I think that the thought is that, in enzymeth there was a RPFS advantage that did not translate into survival advantage. I think that’s the perspective that people are taking.

Tom:
It’s a subset, in enzymet, where subgroup of the patients did get chemotherapy too. So, some patients who had enzymet were treated with the triplet, and the benefit to that, is that the subset analysis that you’re referring to?

Eric Small:
That’s correct. And it is a very different question, right. This was really, it’s not entirely clear in enzymet who got chemotherapy and why, whereas a lot of that may have been investigator discretion just was never very clear. And in piece one, it was more carefully outlined, and it was chronological.

Tom:
Because in the endometrial, some patients were allowed to go into the trial, having had chemotherapy. And so, it wasn’t controlled.

Eric Small:
Nor was it necessarily concurrent therapy.

Tom:
And that didn’t show the survival advantage that you feel is so important.

Eric Small:
I think the survival advantage is very important [crosstalk 00:15:35].

Speaker 4:
But in enzymet, it didn’t show the survival that you feel is [crosstalk 00:15:39]

Eric Small:
That is correct.

Tom:
Eric, my next question comes to the tolerability profile and toxicity profile. Other people have come to me and said, actually, it doesn’t look any more difficult to tolerate the triplet. And so, assuming all else being equal, it has a clear, I mean the disease-free survival benefit is better. The OS we don’t know yet, but it doesn’t appear to be worse. What have we got to lose?

Eric Small:
So, a couple of comments, I mean, what we have to lose is that there are the occasional patients that have substantial docetaxel toxicity, including pulmonary toxicity, and if you have that one patient who develops pulmonary toxicity that may or may not have been picked up in this study, you’ll be kicking yourself, right?

I think we make these decisions every day, we use toxic therapy when we have to, but if you don’t have to, and if you can gain from sequential therapy that may be appropriate. The other comment that I want to make about the toxicity that was reported.

I think Karim was appropriate in pointing out that the prednisone is a wonderful drug and that really may have helped with a lot of the potential toxicities observed in the, it was interesting that in the docetaxel population, in the first six months of therapy, the febrile neutropenia was identical, which, I actually, you don’t see a lot of febrile neutropenia anyway with docetaxel, so there’s no reason to believe that hematologic toxicity would necessarily be worse by the addition of abiraterone.

You know, he did, they did not report specifically on pulmonary toxicity. And I’d be very curious to see that and make sure that we’re used to seeing a little bit of pulmonary toxicity when docetaxel was used, and so it’d be useful to see that.

It is encouraging that the overall deaths that we’re seeing where there was one more death in the abiraterone group, so it was very comparable. I think the toxicity doesn’t scare me away that much, but there are issues with it, of course. And the other issue is, you have to, in order to have gotten on this study, you needed to be able to get Taxotere.

That excludes a lot of patients that we in practice would say, ooh, 85 years old, I have a choice of taxotere or abiraterone, I’m going with abiraterone. I think that there is a, although this is a randomized phase three study, there is patient selection here as to who actually can get docetaxel. Yes, it’s a [incomplete word 00:19:09] as you point out Brian. Yes, it’s a standard of care, but it’s not a standard of care for everyone.

Brian:
Right. Eric, my last question, I was to give Tom as any is right now with just the data at hand, no survival data yet. Are there any patients who would walk into your clinic, who you would say, I’m going to give you a triplet therapy or any circumstance that you would do it?

Eric Small:
No, there really isn’t. There is no subset of patients that I would, other than patients who I really worry about, small cell neuroendocrine cancer or something like that, that I would want to give docetaxel and carboplatin or cabana or something like that.

But other than those obvious patients, no, there are people who’ve made an argument that patients with visceral disease should get docetaxel upfront, and there’s no evidence to support that contention abiraterone works just as well. There’re very few patients that I would choose to do that.

Number one, I do think the rare patient who, not the rare, the patient who, where there’s financial toxicity and they can’t afford the abiraterone or abiraterone is not available or has rip-roaring brittle diabetes that you just don’t want it to be throwing these agents. Then docetaxel might be the appropriate agent for those patients. But for the average patient, there is not a patient that I would do triplet therapy, given the data today.

Tom:
Eric, I’ve got one last question. Do you feel your opinion is aligned with the rest of the community? Are you at one stream extreme, and how unified is the community going to be on this issue?

Eric Small:
Oh, I think the very fact that we’re having this discussion suggests that it’s going to continue to be fairly contentious. I don’t think these data support triplet therapy.

Speaker 4:
There are people who do.

Eric Small:
I think there are people. I think in the community most people will not at least, in the people who I see, referred to me, and that in America, at least the preeminent frontline therapy is in fact abiraterone. It’s not docetaxel.

This study didn’t ask the question of adding docetaxel to those patients, and so I don’t think that this will impact practice dramatically. I’m a little less sure about what the case is in Europe. I mean, you might address that.

Tom:
I’d struggle a bit, to be honest Eric, as with many things in my life, listen, this has been gold dust Eric. We haven’t heard the end of this discussion. We probably [crosstalk 00:22:03] a number of different boxes, so we’re going to get back to you on that. Eric, thank you so much for your time today. I hope we can see each other sooner. Remember, our walk around the walls of Leads together popping into one or two pubs on the way. And I hope that’s not too far around the corner.

Eric Small:
Tom. I remember that really. I was actually just thinking about it. It was not Leads; it was York. Too many pubs, but I do remember it. It was quite some time ago, but I remember it very fondly.

Brian:
Tom. You’ve never taken me on such a walk. I’m kind of jealous.

Tom:
I can’t believe I got the city wrong, it’s so embarrassing. Okay.

Eric Small:
Yeah. It’s your country you’ve forgotten.

Brian:
Thanks, Eric.

Eric Small:
Appreciate it, gentlemen. Thank you so much.