Episode 139: The Uromigos Paper of the Month – Talazoparib in biomarker positive prostate cancer

Dr. Tanya Dorff discusses this paper and the role of PARP inhibitors in prostate cancer.

 

Brian:
[inaudible 00:00:21] to another Uromigos podcast. We’re doing a paper of the month now, and Tanya Dorff is with us for a Talazoparib monotherapy and metastatic castrate resistant prostate cancer, recent Lancet Oncology publication. Tanya, welcome. Thanks for joining us. If you want to give us sort of a brief introduction, relevant conflicts, and then maybe just give us sort of a sentence or two about the basic design of the trial, that’d be great.

Tanya Dorff:
Sure. Hi. This is Tanya Dorff. I’m a medical oncologist and section chief of the genitourinary cancer program at City of Hope near Los Angeles.

Brian:
You’re very welcome, Tanya.

Tanya Dorff:
So the TALAPRO-1 study, which was just published in Lancet Oncology, was a phase two single arm open label study testing what we believe is a very, very effective PARP inhibitor Talazoparib in metastatic castration-resistant prostate cancer, who harbor DNA repair alterations.

Brian:
And so take us behind, maybe just give us sort of a sentence high level summary. This was a single arm phase two trial, and it was in patients who had one of several potential mutations, correct?

Tanya Dorff:
Right. Panel of 11 genes, ultimately that were included in the study and it was dominated by [inaudible 00:01:52] as one might anticipated, but there was a reasonable [crosstalk 00:01:56] PALB2 and also ATM.

Tom:
And I guess one of the questions from our perspective… There was activity and there were responses and PARP inhibition in prostate cancers got a really strong kind of, I don’t know, press at the moment. There was the press release with Olaparib in unselected patients with CRPC. Are we… What’s going on with this biomarker? Is it all around BRCA2? Are there other components which are relevant? Some people slickly say, “Well, if by bringing in other biomarkers, you can broaden the net and treat more patients, but they may or may not benefit.” Have we nailed the biomarker story in prostate cancer?

Tanya Dorff:
Well, I certainly [inaudible 00:02:40] not. So right now it’s really a very small subset of patients who can benefit from PARP inhibitors as currently defined by Olaparib in the profound study and as well with the other PARP inhibitors. 1400 some patients were screened to identify the hundred [inaudible 00:03:02] who were eligible. So we would like to find biomarkers that would expand that group, allow more patients to potentially benefit. So there’s been some work done on BRCAness, right? Trying to find other types of cellular changes that might make a cell [inaudible 00:03:23] , and then there’s very interesting story evolving around PARP regulation of androgen receptor signaling. So Karen Knudsen’s done some [inaudible 00:03:34] showing that downstream targets of AR including things like Tempus Two, that their expression is impacted by PARP inhibition. So I think we very much need to continue to explore biomarkers.

Tom:
Tanya, when you- [crosstalk 00:03:54] You go first.

Brian:
I was going to say, Tom; currently, I’m looking at the table in the paper and it looked like, as you say, most of the responses were confined to BRCA one or two. That response rate was almost 50% whereas responses and everything else was fairly anecdotal; I think maybe just three responses. So I guess just thinking currently about applying this to practice, I mean, would you give this agent, or perhaps similar agents, broadly if patients had any mutation, or would you confine it more to BRCA?

Tanya Dorff:
Well, so I think it’s pretty impressive to see complete responses. Radiograph [inaudible 00:04:30] in one of the ATM patients granted one out of 17, but 25% of the PALB2 had confirmed partial responses. So I wouldn’t write off the other subsets yet. There was a lot of disease stabilization. The [inaudible 00:04:47] pre-survival was quite impressive. Although again, truly dominated by BRCA, but I think what we need to really do is look at maybe using this drug differently. Maybe in combination, maybe in earlier phase of the disease to try to leverage some of its other properties.

Tom:
Tanya, the way the EMA is going to look at this, I suspect, is they’re going to come out and say, “It’s all good and well, you picking the biomarkers you like, but we’re interested in those which clearly are of benefit.” And BRCA2 appears to be dominating. It’s the Jupiter of the solar system of DNA repair biomarkers. And perhaps some of the other ones look much more like Titan or Mars, somewhat insignificant compared to two-

Brian:
Does Jupiter dominate the solar system? I don’t know what that analogy means.

Tom:
I think it does Brian. I think you should be-

Brian:
Okay.

Tom:
… I mean, I imagine you did a little bit of this at school, but you see your [crosstalk 00:05:49] it’s actually if you put all the other planets together, it’s still bigger than the-

Brian:
I see, I see, okay.

Tom:
So yeah, it does. It’s a very fair analogy, Brian.

Brian:
Yeah, please go on please.

Tom:
Unlike the Irish analogy in the last one, which I’m still sorry for. For all of those emails I got from the Irish community, I apologize.

Tanya Dorff:
[crosstalk 00:06:06] … clear. I think at first we’re going to be using this largely in BRCA mutated, metastatic castrate resistant prostate cancer patients. But I hope there will continue to be work to find additional utility for the drug and I’m doing part of that work. So whatever the regulatory agencies decide as the biomarker, we’re all going to play nicely in the sandbox, but it doesn’t mean that’s the end of the story.

Tom:
Tanya, are we barking up completely the wrong tree in going back to tissue banks, fishing out biomarkers that might been taken years in advance? Is that just… Should we be using circulating biomarkers? We can look at these DNA alterations for these, what we described as DDR type panel, which is yet to be defined. And then the second question I’ve got is do we need as a group to get together and agree what a real DDR panel is? Or should we less let different groups explore different biomarkers?

Tanya Dorff:
Well, I do think going back and digging out additional biomarkers seems like a Herculean effort that may not yield huge dividends. I think where we’re more likely to find success in combination strategies or in earlier stage disease. So if PARP inhibition impacts AR signaling, then there’s reason to believe using it upfront prior to castration resistance might have the PARP inhibitor serve a different function.

Tom:
Now, clearly, Tanya, you don’t know the results of the AZED CRPC first line trial, where it’s abiraterone versus abiraterone plus PARP, I think is the trial design. We know from the press release, that’s positive. And we also know that’s it unselected patients. Are we just going to ditch this biomarker altogether? Obviously we need to look at the results of the trial and truly don’t talk about them if you know them I’m assume you don’t; but if you do please don’t. But what we… Someone once did that on one of our, I think on one of our podcasts. It was a very popular podcast. So what’s your take on that issue of that trial is? Because again, you might argue that if it’s working in unselected patients, we’re barking up the wrong tree with a biomarker.

Tanya Dorff:
Yeah, it’s going to get complicated, isn’t it? I think we need to see the data because it could be that there was a component of DNA repair altered patients that drove the benefit. We certainly are going to want to drill down and see what the genomics show in this population. And I think there still may be room for different approaches for different patient populations. I don’t think we will end up using this combination for everyone. I certainly hope not. I think we’re starting to see really interesting biomarker stories emerge, whether it’s the PAM50 Luminal Basal or specific genes that might tell us someone who doesn’t need the PARP inhibitor, because they do really, really well with the AR targeted [inaudible 00:09:26]. We know there’s some toxins, they do that comes from PARP inhibitors. I will, excited to have a broader population that could benefit from the combination, but I don’t think we’re just going to write off biomarkers altogether. I hope [inaudible 00:09:40] that will be increasingly using them to [inaudible 00:09:43] as their treatment plan.

Brian:
Is it possible maybe that earlier on in the course of disease, you might use the biomarker? This is probably in distinction to what Tom just said about those results, but earlier on, you’re going to use the biomarker because those patients have a higher likelihood of benefit via BRCA or anything else; whereas later in the disease, which is where the Lancet Oncology paper was. Even if the responses are rare, those patients have very limited treatment options, so you might just try that more broadly. Is that fair?

Tanya Dorff:
That’s interesting.

Brian:
I mean, yeah, I don’t know. I don’t know if that makes sense or not. I just sort of, as I think about it-

Tom:
I mean, be rude if you like Tanya. It’s not the first bad question he’s asked.

Tanya Dorff:
No, it’s challenging thinking about PARP inhibitors because we are actually studying them- [crosstalk 00:10:31] I’m sorry?

Brian:
Go ahead. Go ahead. I’m sorry.

Tanya Dorff:
We’re actually studying them in medicine [inaudible 00:10:37] patients unselected, because of some very interesting preclinical work that looks like they may prune aggressive clones early on. So to try to get rid of the bad that evolve when castration resistance evolves. So if you’re right, then my trial will be a failure. So I’m hoping you’re wrong.

Brian:
Or maybe it’s the exact opposite, right? That you would try them broadly upfront for the reasons you mentioned. And plus those patients have time, if you will, to try other things. Whereas very late in the course of a disease, if you’re choosing between this and somebody else that patient may just have one shot left, so you may want to target it more.

Tanya Dorff:
Yeah and it may be that there are so many changes that [inaudible 00:11:19] the disease has evolved through castration resistance and through multiple lines of therapy that this isn’t the dominant strategy that the very sensitive to,

Tom:
Tanya, are all PARP inhibitors the same? I’ve just been, I did a little bit of reading too, for a change, and I was reading about Olaparib, which has got a lot of data in [inaudible 00:11:44] data and Talazoparib, there’s an Olaparib there. There are different… Are they all the same or are they like VEGF targeted therapies, which actually have some nuanced differences between each other?

Tanya Dorff:
Well, pharmacologically speaking, you can certainly quantify differences between the PARP inhibitors and [inaudible 00:12:03] as perhaps the strongest inhibitor. It does more trapping than some of the other agents. I think it’s hard to tell from individual experiences, whether there’s a difference in efficacy because these patient populations are probably quite different. I mean, in TelePro One, half the patients had had two different taxing lines of treatment.

Tanya Dorff:
There are very [inaudible 00:12:30] and I think that’s probably not quite who was treated in profound, right? So we can’t really try to look across trials and we’re never supposed to do that anyway, although everyone sort of does in their presentations, right? But whether it’s more effective or less toxic, I think would be worth studying, right? Because wouldn’t it be great if we had a PARP inhibitor that we got the most bang for our buck out of, and the least toxicity. And in my experience during TelePro One, I was really quite impressed, not only with the efficacy, but the relative lack of toxicity. Although I think when you look at the published tables, you see kind of similar rates of anemia, perhaps as with the other drugs.

Brian:
Tanya, is there any reason to believe that if a patient failed one PARP inhibitor, they would respond to another, either in immediate sequence or later on?

Tanya Dorff:
I’m so interested in that question to some of my women’s cancer colleagues to see, because they’re ahead of us in many ways; whether they think there’s any utility for one PARP after another. And they had really a lack of enthusiasm for that.

Tom:
Tanya, the adverse event profile, sometimes we get clues from the efficacy signal associated with adverse events with different drugs. So VEGF being obviously an on target adverse event associated with, sorry, hypertension being an on target adverse event associated with VEGF target therapy, where some others perhaps being off target. Do we get any clues from the efficacy signal around adverse events? What are the [inaudible 00:14:10] adverse events in your experience?

Tanya Dorff:
Well, that’s a genius question and I’m sure someone’s going to-

Brian:
A genius question [crosstalk 00:14:18]. Congratulations.

Tom:
Yeah.

Tanya Dorff:
And look at that, because it gets maybe on target since it’s shared anemia that is, it’s shared across all the PARP inhibitors. So really the only grade three and four toxicities, I mean the most common grade toxicities are hematologic; very few grade four in the TelePro One experience. But 31% of patients with grade [inaudible 00:14:46] about a third of patients requiring a blood transfusion. So I hope it’s not partnered to efficacy because our patients really do feel that anemia and that might limit enthusiasm for [inaudible 00:15:02] very broadly, if we’re going to end up needing to use a lot of transfusions. But otherwise the safety profile really is very, very similar across the class of drugs when you look at the numbers, direct comparisons of course pending.

Brian:
So Tonya, do you want to talk… You presented some CTC work in this paper and it looks like maybe not surprisingly, most of the responders were the converters of more than five to less than five cells or other parameters. Do you want to talk about those results and maybe if they’re helpful in, I don’t know, selecting patients or monitoring patients?

Tanya Dorff:
It’s so sad that circulating tumor cells have so little relevance. I mean, we all know they’re important and they’re dependent prognostic indicator compared to just looking at PSA, since we don’t have measureables, it’s really nice to have. But not really in daily practice. So I don’t know how impactful that will be when this rolls out into patient care, right? But certainly it is a proof of principle. It helps support the story that this is a very effective treatment. Only 21 patients had more than five cells at baseline. And of those 81% converted. And so we know that that’s significant indicator that they’re benefiting, but I don’t know about you guys, but we’re not able to get circulating tumor cells in our patients and try to really use them in our practice.

Tom:
Tanya, since the principle of synthetic lethality is DNA targeted, many chemotherapy agents are also DNA targeted. When one looks at this principle of targeting DNA, and I realize there are differences between the way chemotherapy and PARP inhibitors work. Is there a rationale for combining with chemotherapy, number one. And number two, is, was there potential cross resistance between the two?

Tanya Dorff:
Yeah, so again, not to rely too heavily on Karen Knudsen’s work, but she really did explore how PARP inhibitors with AR and one of the aspects that she looked at was whether it destabilized the cells in a way that made the [inaudible 00:17:28], also to radiation. So I do think that prevents a rationale for combination studies and… Rana McKay has a study looking at PARP inhibitor together with radium 223. I think it’ll be really interesting if this is radio sensitizing to look at other radio pharmaceuticals, obviously Lutetium-177-PSMA. NRG [inaudible 00:17:54] cooperative group probation oncology is studying Niraparib together with definitive radiation and hormone therapy in very high risk, localized prostate cancer patients.

Tanya Dorff:
And I’m sure there are chemotherapy combination studies also that I don’t know of offhand quite as well, but there’s definitely this study this in combination. And that may be where it ends up having its biggest impact.

Tom:
Do you want to talk about your trial?

Tanya Dorff:
Of course. Thank [inaudible 00:18:26]. I mean, if you look at one, just some concerted efforts on the part of the sponsor, there’s very limited diversity, right? There was I think 3% black and 4% Asian patients. And that’s really means that we’re missing out on opportunities to find biology that might drive responsiveness to this treatment outside of the traditional predictors. So we’re doing a study of first line metastatic hormone sensitive prostate cancer patients receiving ADT plus abiraterone. And we’re adding Talazoparib with a goal of enrolling 30% African-American and 30% Asian patients. We’re going to be studying androgen receptor triplicate repeats, which do vary among different groups, different backgrounds, and do have impact on AR function that we think might impact [inaudible 00:19:26]. So we’re hoping to increase from the matsubara analysis of latitude that 55% PSA nadir to less than zero point [inaudible 00:19:39] predictive for overall survival. We’re aiming to increase that, to increase the number of men who get a good deep remission that on track for long cancer control.

Brian:
Tanya, last question from me, just about sort of the future of this drug. Obviously you just mentioned some of it, but I don’t know if you know, or able to say if these data will be submitted to regulatory agencies for approval based on a single arm trial, and there’s some, at least one phase three trial, or maybe two mentioned in the article. If you just want to touch on those in terms of what’s coming.

Tanya Dorff:
Being a relative small potato, I don’t have inside information about whether they’re going straight for approval with the phase two. I should probably make it my business to know that, but the ongoing studies are in combination. So for example, with enzalutamide in persistent first line disease, so there’s going to be a need, presumably if ABBI works well with Olaparib, but some patients can’t get abiraterone for, let’s say their comorbidity reasons. Enzalutamide based combination, also that’s successful to provide options to providers. So that’ll be an interesting study to see how that reports out. And of course we really want to see the Olaparib data too.

Tom:
My last question, Tanya too, is where do you see yourself using these drugs in, let’s say, and I know it depends a bit on the furniture and where it’s placed, but where do you see yourself using these drugs at the moment with the information you have, assuming you could use the drugs and they had regulatory approval? Where is the space? Is the activity enough to convince you to give it to patients as it currently stands? And if that is the case, where would it be?

Tanya Dorff:
Definitely use these drugs. And I sequence my patients with the hope of finding an alteration that predicts for benefit from a PARP inhibitor. And I think there’s a lot of discussion about whether it should be sequenced before or after chemotherapy. Granted in most of the clinical trials that have reported out thus far, patients are primarily chemotherapy pre-treatment, but it’s very appealing in our own practices when someone’s progressed on ABBI or Enza, and is relatively asymptomatic and functional to want to use an oral therapy that might not tether them to our clinics, or might not cause as many [inaudible 00:22:18] as jumping to chemotherapy. So I’m hopeful that we will get some data that helps us decide whether there is an optimal sequence before versus after chemotherapy. And ideally, it would be nice to have some flexibility so that we use the right option for the right patient in the moment.

Brian:
Hey Tanya, this has been great. Thanks a lot. We think you’re a big potato, so thank you for joining us and appreciate you-

Tom:
That’s right. [crosstalk 00:22:46] potato-

Brian:
Better than Tom’s Jupiter analogy. Thanks for talking about the paper. We appreciate it.

Tom:
Tanya, thanks for your time today. Thank you.

Tanya Dorff:
Thanks so much guys.

Tom:
Terrific. Bye bye.

Brian:
Take care.1

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