Episode 1: Clinical implementation of PARPi monotherapy for prostate cancer patients – a US and EU perspective

Transcript

Welcome and thank you for listening to this podcast from COR2ED independent medical education.  In this episode, you will hear from internationally renowned experts Dr Elena Castro and Dr Neal Shore how they implement PARP inhibitor monotherapy in clinical practice for their prostate cancer patients. They discuss whether all PARP inhibitors are the same or different, when to initiate a PARP inhibitor as well as the relevance of genetic testing and various gene alterations on treatment decisions.

This podcast is an initiative of COR2ED and developed by GU CONNECT, which is a group of international experts working in the field of GU Oncology.  The podcast is supported by an independent educational grant from AstraZeneca. The views expressed are the personal opinions of the experts and they do not necessarily represent the views of the experts' organisations, or the rest of the GU CONNECT group. For experts disclosures on any conflict of interest please visit the COR2ED website. Now with that being said let’s get started.

Neal Shore

Hi everyone and welcome to our first broadcast in our series covering PARP inhibitors for prostate cancer. Today we're going to discuss the clinical implementation of PARP inhibitors as monotherapy for prostate cancer patients.

I'm Neal Shore. I'm the Chief Medical Officer for urology and surgical oncology with GenesisCare in the U.S. and the Director of Carolina Urologic Research Center. I’m really happy and delighted to be joined today by my good friend and colleague Dr Elena Castro and I’ll let Elena introduce herself. Thank you.

Elena Castro

Hi, Neal. It's a pleasure to be here with you today. I'm Elena Castro. I'm a medical oncologist at Hospital Universitario 12 de Octubre in Madrid, Spain. I treat mostly patients with advanced prostate cancer and my research is focused in prostate cancer and cancer genetics.

Neal Shore

Fantastic. Well, why are we talking about PARP inhibitors? Well, clearly, with patients with prostate cancer, we've had great progress over the last decade and a half. It wasn't until 2004 that we had our first mechanism of action in taxanes. And now if you fast forward from 2004 to 2023, we now actually have seven distinct novel mechanisms of action to offer patients with prostate cancer. And what we're going to talk about today is PARP inhibitors and PARP inhibitor in terms of a monotherapy for our patients with resistant disease, have now been available for nearly three years. We have two approved treatments that really were approved almost within 48 hours of each other by FDA. And that is olaparib, which was based on data from the global phase three trial known as PROFOUND as well as rucaparib from a very significant phase two study known as the TRITON-2, and that received an accelerated approval in the US.

The PROFOUND trial led to both FDA and EMA, a level one evidence approval, for patients with resistant disease. There are some nuance differences regarding the product information indications in Europe and in the US, so for example olaparib in US is approved for patients with mCRPC and homologous recombinant repair mutations who have progressed on either enzalutamide or abiraterone acetate. Classically, what we refer to as androgen receptor targeted agents or antigen receptor blockers or novel hormonal agents. In the EU, olaparib is indicated for monotherapy for patients who are only have the BRCA mutation, so B2/B1 who've also progressed on a novel hormonal agent or an ARTA as we sometimes call it.

In the US there are 14 gene alterations within the family of HRR that have FDA approval. So, there's a distinctive difference.

Now rucaparib is a US only approved based upon the TRITON-2. We're going to talk about the TRITON-3 today in a second and have Elena address that. It has an accelerated approval based upon the TRITON-2 phase two study and it's approved for BRCA mutated patients only. So B2/B1 who've progressed on an AR directed therapy and a taxane. So that makes it also, its inclusion for approval a little bit more involved than the olaparib indication.

So, we have now seen a lot of excitement, the TRITON-3 data that was presented at the Prostate Cancer Foundation this fall, 2022, this is the confirmatory phase three trial for rucaparib. And so I think that's was really exciting. I think we're going to hear some additional data coming forward at GU ASCO as well. So maybe... let me stop here, Elena, and ask you to comment on TRITON-3 and how that may further inform our colleagues, but also anything you want to comment as well on the PROFOUND trial and the olaparib approval.

Elena Castro

As you said, there is a difference in the approval of olaparib by FDA and by the EMA, basically based on perhaps lack of enough evidence to treat patients with alterations other than BRCA1 and BRCA2 because these alterations are less frequent. So, the number of patients that were included in PROFOUND was smaller than for BRCA, and it isn't clear at this time whether these patients may also

benefit from treatment with PARP inhibitors. This is why I think it's so relevant, TRITON-3 and other trials that will help us understand the real predictive value of other alterations, not only BRCA1 and BRCA2.

And the TRITON-3 is a phase three randomised trial that included only patients with alterations in BRCA1, BRCA2 and ATM. These were mCRPC patients who had already progressed to treatment with an hormonal agent, abiraterone or enzalutamide. And these patients were randomised to receive either rucaparib or the physician's choice that could include docetaxel or the hormonal agent that they have not received previously, so either abiraterone or enzalutamide.

So, this is the first time that a PARP inhibitor has been compared with docetaxel and I think it is very relevant because what we see is 50% reduction in radiographic progression-free survival for patients with BRCA alterations with rucaparib compared to the physician's choice and for patients with ATM alterations, the benefit is only 5%.

So, I think this is very important because in PROFOUND, to be eligible patients had to have progressed only to a hormonal agent, most of them, about 65% of them, had also received a taxane before entering the trial. So, the TRITON-3 trial tells us that perhaps for patients with BRCA alterations, it will be better to treat with rucaparib rather than waiting until they progress to treatment with a taxane. So early treatment for these patients may really improve their outcomes. Of course, we still don't have overall survival data, but the difference in rPFS is really significant for these patients.

What I don't know is whether this benefit that we observe with rucaparib could also be extrapolated to other PARP inhibitors. I don't know. Neal, what do you think?

Neal Shore

Yeah, that's a great question and gets asked so often. And one of the challenges is the low prevalence of some of the 14 HRR mutations that we see listed by the product information in the US for the approval of olaparib. I think that of those 14, originally 15 in the PROFOUND trial but 14 were accepted, we have had, at least I have had anecdotally, and I think many of our colleagues, some very good responses with PALB2, the RAD51 subsets, certainly ATM, as was noted in the TRITON-3 here and even to some degree also in PROFOUND, the CDK12, CHEK2.

Some of the alterations, they're not high in prevalence, but we don't always see great responses. You know, that said, and I'm a big proponent of using taxanes, docetaxel and cabazitaxel, but overall there's always something more appealing I think for many clinicians and certainly for patients when they can have an oral option as opposed to going to a parenteral option. And again, I think taxanes by and large have become better managed. I think that even though we do see grade 3/4 toxicities, they can be very well managed and clearly effective therapies.

So that is a little bit of a conundrum right now, I think, in terms of the product information acceptability in Europe versus the US. I'm curious what you think about that, Elena, for the patients who are, for example, the RAD51’s, the PALB2’s. But then also there's clinical trials that we're working on for ATM selectivity, there's some IO or pembrolizumab data supporting the use of it in CDK12. I wonder how you think about that?

Elena Castro

Well, with regards to the predictive value of some of the HRR alterations, I think for ATM we have now enough evidence suggesting that a PARP inhibitor in monotherapy perhaps is not the best option for these patients, as a group it is true, as you mentioned, that some individuals seem to benefit from this and we need to understand better which is the type of ATM alteration that is associated with a benefit from a PARP inhibitor but it doesn't seem to be an ATM mutation as could be the case for BRCA2 for instance. For PALB2, these are infrequent alterations, rare alterations and we are slowly getting data from different series and trials and it seems that these patients may benefit significantly from PARP inhibitors. For other, less frequent alterations, still we have to wait. But as you say, there are some of these alterations that seem really to predict a benefit from PARP inhibitors.

Neal Shore

Yeah, I totally agree, and the ATM of all those 14 gene alterations after BRCA2 and CDK12, it actually has a high prevalence and I think it's a big unmet need. One of the things I'm curious about Elena and maybe you can weigh in on this, is patient comes to you and their BRCA alteration, whether it's 1 or 2, maybe there's a difference in your mind thought, accessibility is not an issue, they're mCRPC. And now they either didn't tolerate or they progressed after abi (abiraterone) or enza (enzalutamide), and assuming you have rucaparib at your disposal, it's approved and you have olaparib and you could use docetaxel. How do you frame that for patients? How do you have that discussion with them in the clinic?

Elena Castro

Well, for patients with BRCA alterations, particularly for BRCA2, I will say that we have the possibility of using a therapy that seems to work particularly well in patients with this type of alteration. Well, of course, we still need to wait until we have the approval for patients who have received chemotherapy, for rucaparib. But I will say that it seems that with the data of TRITON-3 study, patients with these type of alterations may get better outcomes when treated with a PARP inhibitor as soon as possible.

It is an oral medication, of course, but we still need to monitor the blood counts carefully because it is still has some toxicities that we may be able to prevent or to manage. And we are aware that eventually the tumour may become resistant to this treatment and we still may have to use chemotherapy in a later stage. For a BRCA patient I would like to try a PARP inhibitor as soon as possible.

Neal Shore

Yeah, I fully agree with that. I think what we're going to see fairly soon based upon the TRITON3 data, prior TRITON2, but of course the excellent data from PROFOUND, if you have the luxury or what's sometimes called an embarrassment of riches, you have the opportunity to choose amongst two approved, who knows maybe with time we'll have even three and four different PARP inhibitors approved based upon some additional studies. Many of our colleagues are probably wondering, are all PARP inhibitors the same? And particularly, do you think we'll start to delineate differences in subtle differences or even more significant differences in toxicity? Clearly the myelosuppression, you have to check a CBC monthly for patients on a PARP inhibitor.

Will there be differences in terms of that myelosuppression? Variances between RBC, WBC, platelet counts and then maybe Elena, you can also comment on that first part question and then also on any GI side effects?

Elena Castro

Yes, the most frequent side effects are anaemia and with some of them thrombocytopenia has been more frequently observed with talazoparib than with other agents. And gastrointestinal toxicity, mostly nausea up to about 15-20% of patients can refer grade 2, up to grade 1/grade 2 nausea. There is not a big difference between PARP inhibitors in terms of toxicities. In all the trials these have been quite consistent with the different agents. We don't have any trial with a direct comparison of the different agents, so we don't know whether there is a different efficacy when we use these agents in monotherapy. What we know from pre-clinical trials and early trials is that it is true that the potency of the agents is different and it may be important, whether due to toxicities or other issues, we may have to reduce the dose to improve tolerability with a PARP inhibitor. So yes, there may be some differences between agents.

Neal Shore

Yeah, I agree with all of that. And maybe just in closing, and I know it's a big topic to cover and you've done an amazing amount of work on this. It's just the whole notion still around testing. When should our uro-oncology colleagues, our medical oncology colleagues be testing our patients with prostate cancer? Maybe just some top-line views regarding the use of germline and somatic testing. And somatic, of course, has the nuances of tissue versus, you know, liquid-based testing.

Elena Castro

Yes, the alterations in BRCA1 and BRCA2 seems to be early events that are already present in the primary tumour. So, we could detect it from diagnosis. But from a practical point of view, just to test in those patients that will be eligible for a PARP inhibitor. Also taking into consideration that the test may take some time, that we may have to repeat the test or acquire a new tumour sample.

I will say that a good idea will be to start considering testing when the patient is progressing to the previous hormonal agent. For instance, when the PSA starts to go up. That will allow us to liaise with all the struggles of testing. For the purpose of a PARP inhibitor, I will test the tumour or I will proceed with circulating DNA analysis, a plasma analysis. And because in prostate cancer, HRR alterations are more prevalent in the tumour than they are in the germline.

If we do identify an HRR alteration in the tumour, then we should proceed with germline testing to exclude that that alteration is indeed germline. With this procedure, we may only miss about 7% of the germline alterations. There are some germline alterations that we may not be able to detect in the tumour. So, my advice is that if you have a patient that for whatever reason you suspect that could be a germline carrier, because of their family history, because of the presentation of the disease, and you do not identify anything in the tumour. It doesn't matter, refer the patients for germline testing.

The reason why we do germline testing is to identify families who may be at risk of not only prostate cancer, but also other types, other cancer types. So, yes, it is important to take into consideration both aspects. The possibility of a targeted therapy and also the possibility of early detection of cancer or even prevention.

Neal Shore

Well, that was great. That was really well said and super, super important for all of our colleagues who treat patients with advanced prostate cancer to understand that the absolute key indication to get both germline testing when it's appropriate, almost virtually universal now for patients with advanced prostate cancer, even localised prostate cancer with significant family histories. And then the somatic based or the tumour-based testing, as you say, there's tissue, there's liquid-based ways to optimise. And why it's so important, because now we have novel mechanism of action in the form of a PARP inhibitor to complement taxanes, to complement our androgen receptor targeted agents, to complement radiopharmaceuticals and other immunotherapies. So very, very important. I think you summarised that as expertly as you always do.

So with that, Elena, thank you so much. It's been a great pleasure to work with you on this podcast.

Elena Castro

Thank you, Neal. See you in our next podcast.

We hope you found this podcast informative and enjoyable.  If you liked this episode, you should look on the COR2ED channel for more! In particular, look out for another podcast with experts Dr Castro and Dr Shore, where they discuss how combination therapy of PARP inhibitors and novel hormonal agents could be implemented into their clinical practice for prostate cancer patients. Make sure to listen to that one too.

Also, don’t forget to rate this episode on the COR2ED website and share our podcast on social media or with your colleagues. Thank you for again listening and see you next time!

Episode 2: Clinical implementation of PARPi and NHA combination therapy for patients with mCRPC – a US and EU perspective

Transcript

Welcome and thank you for listening to this podcast from COR2ED Independent Medical Education. In this episode, you will hear from internationally renowned experts, Dr. Elena Castro and Dr. Neal Shore, when they discuss how combination therapy of PARP inhibitors and novel hormonal agents could be implemented into their clinical practice for prostate cancer patients. They discuss which patients to consider for the combination treatment, how to manage hormonal sequencing and other practical considerations.

This podcast is an initiative of COR2ED and developed by GU CONNECT, which is a group of international experts working in the field of GU Oncology. The podcast is supported by an independent educational grant from AstraZeneca. The views expressed are the personal opinions of the experts and they do not necessarily represent the views of the experts' organisations or the rest of the GU CONNECT Group. For experts disclosures on any conflict of interest please visit the COR2ED website. Now, with that being said, let's get started.

Neal Shore
Hello everyone and welcome to our second podcast in our series covering PARP inhibitors for prostate cancer. Today we're going to discuss the clinical implementation of PARP inhibitors in combination with novel hormonal agents for prostate cancer patients. It's a pleasure to be here. I'm Neal Shore. I'm a uro-oncologist. I'm the Chief Medical Officer of urology and surgical oncology at GenesisCare in the U.S. and the medical director of Carolina Urologic Research Center. It's a great pleasure and privilege for me to be joined today again with my dear friend and colleague, Dr. Elena Castro. Elena, would you please introduce yourself?

Elena Castro
Hi, Neal. It is my pleasure to be here with you. I'm a medical oncologist at Hospital Universitario 12 de Octubre in Madrid, Spain, and I treat mostly patients with advanced prostate cancer. And my research is focused in this field and in cancer genetics and I'm delighted to be here discussing with you PARP inhibitors in combination as this is a very hot topic.

Neal Shore
Yeah. Thank you so much, Elena. You know, in our first podcast, we just talked about the use of monotherapy PARP inhibitors, olaparib and rucaparib for our mCRPC population.

You know, it's great to have this opportunity to talk about combinations. But really now exciting data has been presented and published at major congresses. The PROPEL Data, which looked at an all-comers population for mCRPC first line therapy, abiraterone and olaparib versus a control of abiraterone demonstrated a benefit of combining olaparib and abiraterone in an all-comers population. It's really great to see that the EMA and CHMP have had a positive recommendation for the data that was presented in PROPEL. So, the data for PROPEL is in front of FDA now as well.

And then we also have the MAGNITUDE trial, which is a little bit more of a complicated trial, but nonetheless looked at combining niraparib PARP inhibitor with abiraterone versus abiraterone and also saw positive efficacy in the biomarker positive population. A particularly more significant hazard ratio for the patients who were BRCA alteration positive, both BRCA1 and BRCA2. So, there were some nuanced differences in the trial design as well as some of the inclusion criteria, which I think we'll want to talk about.

And most recently, we now have a correlative trial, the TALAPRO-2 which looked at talazoparib and enzalutamide as opposed to abiraterone in an all-comers population and the public statement press release at the end of 2022 has clearly stated that it's a successful trial and we eagerly await the results which will be presented in plenary presentation at ASCO GU 2023. So, I think that's really super exciting to see that data set.

And so now we have two trials where we have combination of an androgen receptor targeted agent, abi (abiraterone), enza (enzalutamide), with olaparib and talazoparib respectively, showing benefit certainly from an rPFS standpoint in an all-comers population. So, this is super exciting.

It leads to a lot of questions. Are these combinations equally well-tolerated? Are the efficacy end points comparable? Are they similar in terms of monitoring? What about some of the overall tolerability and safety issues? Some of these are really interesting areas of debate. And then ultimately, how do we most importantly think about using combination of two therapies with different novel mechanisms of action? Why would they necessarily lead to a benefit in allcomers population within the construct of lessening resistance to the androgen receptor for patients who would normally develop resistance by adding a PARP inhibitor and then likewise, how to create further PARP sensitivity to patients who would not necessarily have at baseline an HRR alteration.

So, a lot right there to unpack. I think it's fantastic to have you weigh in and give your thoughts on this Elena, you've spent so much time reviewing these trials.

Elena Castro
Yes, there is a lot of data and that generates a lot of questions actually. The first is, as you just mentioned, whether it would be the same to have androgen receptor targeting agent that inhibits the production of androgens. Whether these would be comparable in these combinations to an agent that inhibits directly the androgen receptor, whether this synergy that is created with a PARP inhibitor could be different if we are discussing different, not mechanisms of action but somehow these are different molecules with different mechanisms of action and perhaps the effect is different.

The second thing is that the PARP inhibitors are not the same and the PARP inhibitors were used, some of them, at the regular dose whilst others were used at a reduced dose because otherwise they will be not well tolerated. And perhaps this reduction in the PARP inhibitor also causes a decrease in the effect in this synergy. And this could be behind the differences that are being observed between MAGNITUDE for instance and PROPEL and TALAPRO-2 with regards to patients without HRR alterations, that in MAGNITUDE no benefit was noted and then that cohort of patients was not allowed to continue with the combination. And in PROPEL and TALAPRO-2, the benefit seems to be observed in all patients with and without alteration.

That said, the analysis of the PROPEL data presented at ESMO this year reported a clear difference in the benefit in rPFS, because this is the only data that has been presented so far, a clear difference between patients with BRCA alterations in which there it was a very clear benefit in rPFS with a hazard ratio around 0.2 with the benefit noted in patients with other HRR alterations, including also the BRCA but the HRR group that was around 0.5 hazard ratio and in patients without any alterations in which their hazard ratio was almost 0.8.

So, it's a very different benefit I would like to see how that translates in an overall survival benefit because if we are affecting the biology of the tumour somehow, will that result in a later alteration of the biology? Will that affect the response to further treatments, and will that have an impact in the survival of these patients? We don't know yet.

With regards to side effects, there's not overlapping toxicity between the hormonal agents and the PARP inhibitors, but the PARP inhibitors per se are associated with anaemia and nausea, and I think it will be acceptable for patients in which we expect a great benefit. But perhaps for patients who may benefit less, this is a discussion that we will clearly have to have with our patients, whether they will accept the toxicity from the combination.

So, I think there is still a lot that we need to learn from these trials, but it poses very interesting questions.

Neal Shore
Yeah, I fully agree. It seems to be remarkable data at least we saw early on in PROPEL that's been presented. Eagerly await the breakdown of the BRCA patients versus the other HRR alterations versus the non-HRR. As you point out, the hazard ratios are positive, but there are differentials. We certainly look forward to seeing the long-term or the more advanced analysis of survival data.

I completely agree with you that there is some additional toxicity whenever you combine, but I think it'll be very, very manageable. There may be some differences in terms of the frequency of taking pills. For example, I believe tala (talazoparib) is QD as opposed to BID, and of course enza (enzalutamide) is QD as opposed to abiraterone, which requires prednisone BID and there are some differences.

And obviously so the safety and tolerability well known to either abi (abiraterone) versus enza (enzalutamide) and additionally, there may be some nuanced differences amongst the PARP inhibitors regarding impact of their myelosuppression, perhaps on platelet count versus anaemia. Some of our colleagues may see some differences in even some of the GI toxicities, but a big advance in terms of having an opportunity to offer a patient who wants to have a very proactive approach towards treating their biology, as you say, with a complementary mechanism of action approach by adding a PARP to an AR and so there's this ongoing debate as to, you know, the combination and why it should have benefit in patients who don't have HRR mutation, whether it by tissue or by blood based testing.

You know, Elena, I'm curious. You know, one of the things that gets brought up is, okay, well, if it's beneficial in all-comers and EMA just gave a positive recommendation for a combination of olaparib and abiraterone, its pending FDA approval, what do you tell a clinician who says, well, if I'm going to use it in first-line mCRPC combination, do I still need to test? Do I still need to get genetic sequencing?

Elena Castro
I personally think that we will need that data because that will help us to inform the patient better and to inform the patient about the chances of responding to this combination. As we just mentioned, the probability or the efficacy of the combination depends on whether the patient has a BRCA alteration or other HRR alterations or no HRR alterations so I think it would be useful.

I also agree that testing is sometimes a struggle so if we have this combination approved, in many cases it would be difficult to test and we will still have the opportunity of using the combination without testing. But if you have the opportunity, I think we should continue to test.

Neal Shore
What about this one? Here's a tricky one. I think you and I both agree on this, but I think our audience wants to hear this. So, I present with low or high volume mHSPC, and, you know, maybe I was initiated on couplet therapy with an ADT and an ARTA or even maybe I had triplet therapy, ADT, doce (docetaxel) and an ARTA and now I need treatment for my first line mCRPC. And I'm on ADT and abi (abiraterone) or ADT and enza (enzalutamide) and let's assume there's in a theoretical world we have approval of combination tala (talazoparib) and enza (enzalutamide) or abi (abiraterone) and olaparib.

What are your thoughts now on just maintaining the abi (abiraterone) or the enza (enzalutamide) for this mHSPC patient who now requires first-line mCRPC therapy? Would you just add olaparib or talazoparib respectively, for the patient who was on abi (abiraterone) or enza (enzalutamide)? Or do we need more trial data to look at that?

Elena Castro
Oh, definitely we need more data. We need more information because we know that once patients have become resistant to one hormonal agent, the probability of responding to a second one are very small. What we don't know at present is whether the addition of the PARP inhibitor may help to further silence the androgen receptor pathway, and that could really improve the chances of responding to the switch in the hormonal agents or even we don't really know whether we would need to change from one ARTA to a second one or whether we could continue with the same one and just add the PARP inhibitor on top of them.

With respect to that, I think it will be different if the patient is progressing just by PSA than if the patient is also progressing with radiographic and new lesions. So perhaps in that situation, the addition of the PARP inhibitor, if the patient doesn't have any HRR alteration, will not result in a benefit. But as you said, we need more data.

Neal Shore
I completely agree. Maybe just another opportunity for you to give your thoughts. It's more of a theoretical, a biologic construct regarding why the combination of an ARTA and a PARP inhibitor would be of value in an all-comer population, particularly in the patients who don't have germline or somatic HRR mutation. Do you think it's an enhancement or a lessening of AR resistance or more so, an enhancement of PARPness or BRCAness, as some have called it?

Elena Castro
I don't know of course. The truth is that there is a crosstalk, there is a very clear correlation between the androgen receptor pathway and the DNA repair pathway. And PARP also promotes the expression of AR dependent genes and at the same time androgen deprivation causes overexpression of PARP. So, I don't really know whether one of the two mechanisms will be more predominant than the other one. What do you think?

Neal Shore
Yeah, I think it's an area that's hotly debated. Maybe there are some other mutational alterations that we're not even fully aware of. So, I think it's super exciting. I think we've addressed previously the importance, it's still important to test, but then now we have an opportunity, especially in our patients who are BRCA positive. I mean the hazard ratio in combination is just remarkable. The rPFS is remarkable and I'm sure the OS will eventually be correlative to that.

As you said earlier too, there are some clear differences in tolerability and side effects and some of the monitoring nuances.

Neal Shore
So, thank you and really great pleasure to speak with you on this topic. And it's really great for our colleagues across the globe, and I mean for patients, having an opportunity to delay progression of disease, ideally to have survival benefit. And even though we're combining therapies and there's always a risk of a little bit more toxicity, the toxicity I think is going to be manageable. And for our patients who are fit and accessibility is not an issue, cost will hopefully not be too much of an issue, we can do better for our patients in the clinic. The ultimate goal.

So, thanks again Elena for being with me today. It was a great pleasure.

Elena Castro
Thank you, Neal. It was great.

We hope you found this podcast informative and enjoyable. If you like this episode, you should look on the COR2ED channel for more. In particular, look out for another podcast with these experts, Dr Castro and Dr Shore, where they discuss how they implement PARP inhibitor monotherapy in clinical practice for their prostate cancer patients. Make sure to listen to that one too.

Also, don't forget to rate this episode on the COR2ED website and share our podcasts on social media or maybe with your colleagues. Thanks for listening and see you next time.

Episode 3: Overview of efficacy and safety data of combination therapy with PARPi and NHAs, incorporating the latest data presented and the impact for the treatment of patients with mCRPC

Transcript

Welcome and thank you for listening to this podcast from COR2ED, independent medical education. In this episode, you will hear from internationally renowned experts Dr Tanya Dorff and Dr Neeraj Agarwal, when they discuss the latest data on PARP inhibitors in combination with novel hormonal agents and the impact of these for the treatment of patients with metastatic castration-resistant prostate cancer.

They discuss recent data from the PROpel, MAGNITUDE and TALAPRO-2 studies and debate whether PARP inhibitor plus an AR-targeted therapy should be used upfront for all patients with CRPC regardless of HRR status or if the combination should be used in a more select patient population.

This podcast is an initiative of COR2ED and developed by GU CONNECT, which is a group of international experts working in the field of GU oncology. The podcast is supported by an independent educational grant from AstraZeneca. The views expressed are the personal opinions of the experts, and they do not necessarily represent the views of the expert’s organisations, or the rest of the GU CONNECT group. For experts disclosures on any conflict of interest, please visit the COR2ED website. Now, with that being said, let's get started.

Tanya

Hello and welcome to the third podcast in our series covering PARP inhibitors for prostate cancer. Today, we're going to discuss the latest data on PARP inhibitors in combination with novel hormonal agents and the impact of this for the treatment of patients with mCRPC. I'm Dr Tanya Dorff, section chief for Genitourinary Cancers at the City of Hope. And I'm joined today by my colleague, Dr Neeraj Agarwal. Neeraj, would you mind introducing yourself?

Neeraj

Of course. Very happy to be here. My name is Neeraj Agarwal. I'm a Professor of Medicine and Director of Genitourinary Oncology Program at the Huntsman Cancer Institute, University of Utah in Salt Lake City.

Tanya

Well, I'm so pleased to be able to chat with you about this very important topic. Last year, we saw data from two large, randomised trials, PROpel and MAGNITUDE, which both investigated the combination of PARP inhibitors with novel hormonal agents. So why don't we start by reviewing those before we move into the really exciting new data that you presented this year at ASCO GU?

So, the PROpel study was for patients with first-line mCRPC and randomised all-comers without knowing their genomic status to abiraterone plus olaparib or abiraterone plus placebo. So, there was an overall benefit in the radiographic progression free survival endpoint regardless of genomic status. Of course, there was a greater benefit seen when they did look at the genomic alterations. And this was strongly positive with a very, very strong signal in those with BRCA mutations who we know tend to have poorer outcomes with standard of care. The trend for improved radiographic progression free survival held up even in those patients who did not have mutations in homologous recombination repair. So that was what was new about this, besides it being a combination study was the potential for patients to experience benefit based on synergy of this these classes of drugs rather than synthetic lethality with the PARP inhibitor in the setting of homologous recombination repair deficiency, which is how we've traditionally thought about these agents.

Now the MAGNITUDE study, which was presented at the same time presented a bit of a conundrum. So, in this study, the metastatic castrate resistant prostate cancer patients in the first line setting were first evaluated for genomic alterations, and then separated into two cohorts, those with a homologous recombination repair mutation and those without. Now, within each of those cohorts, they were randomised to abiraterone with or without niraparib. And as you know, that cohort without genomic alteration had to be closed early due to futility for a lack of benefit. While we did see a consistent signal in the BRCA altered population for a benefit in terms of the combination.

We saw no new safety signals when adding these two agents in combination. Although the dose of niraparib in MAGNITUDE did have to be reduced so that it could be combined safely. But in general, you know, the biggest added side effect that we see with a PARP inhibitor on top of a drug like abiraterone is anaemia, which is sort of a class effect in the PARP inhibitors. There's a little bit of GI toxicity as well but again, what we did not see was some new toxicity or some new degree or severity or frequency of toxicities. It was very consistent with what you would see with the agents alone. So that was reassuring.

And now we were, of course, waiting for overall survival data rather than just rPFS. So, we saw at ASCO GU 2023 the updated survival analysis from PROpel which did show an (numerical) improvement in overall survival by greater than seven months.

So, I'm curious what you thought about this. And then of course, we'd love to hear you summarise the data, which were the data from TALAPRO-2 that you presented at ASCO GU.

Neeraj

Of course, when we saw these results in the GU ASCO 22, actually it was quite intriguing to see two very similar trials having different results, which is, although this showed benefit in the HRR positive subsets, HRR negative patients did not seem to benefit with abiraterone and a niraparib combination, but they seemed to benefit with abiraterone plus olaparib combination.

And obviously I was intrigued by those data. But then we also know that the PARP inhibitors are different.

We also know that the dose of niraparib had to be decreased by 33% because of the toxicities experienced in combination with MAGNITUDE. But then there are different patient population, the way they were selected, different composition of HRR positive patients, there were differences in the number of patients with BRCA2, BRCA1 and so many different other HRR gene alterations.

So, of course, intriguing data and we were really hoping to have some hint or indication from TALAPRO-2 trial whether the combination of a PARP inhibitor and a novel hormonal therapy may be effective in HRR negative patients given preclinical rationale, which also exist there. So that provides a nice segway to the discussion of the TALAPRO-2 trial, which I had the honour of presenting in the GU ASCO 23.

So TALAPRO-2 trial, as we know, was a phase 3 trial in first line mCRPC setting. These patients could not have received any life prolonging therapy for the castration resistant state and patients were randomised to talazoparib plus enzalutamide versus enzalutamide plus placebo. Radiographic progression free survival per independent radiology assessment was the primary endpoint and we saw benefit in both homologous recombination repair altered patients, the patients who did not have those alterations who had unknown status by prospective tumour tissue testing, they seemed to benefit. We did a separate analysis looking for specifically in those patients who are HRR negative by prospective tumour tissue testing and there was a significant benefit as far as delaying of radiographic progression free survival.

So combined together, the results from the TALAPRO-2 trial are in sync with what we saw with PROpel trial, that patients seemed to benefit with the combination of enzalutamide plus talazoparib versus enzalutamide plus placebo, regardless of whether they had homologous recombination repair mutations are not. With the caveat that of course the magnitude of benefit is much higher in the HRR positive patients versus HRR negative patients.

Tanya

And that speaks to the importance of continuing to do genomic testing of our patients so that we kind of know what to counsel them about the relative benefits and risks. So speaking of risks, the dose of talazoparib had to be reduced for use in combination with enzalutamide. Can you speak to that? And to what sort of toxicity profile was seen in the TALAPRO-2 trial?

Neeraj

Again, as we saw, this is a class effect, anaemia dominated the toxicity. In fact, 46% patients developed grade 3/4 anaemia. And I'd like to bring this to our listeners attention, that 49% of patients actually came into the trial with grade one or two anaemia and the haemoglobin requirement, the lowest haemoglobin they could have to get into the trial was nine gram per deciliter. And really, we need one point decline in the haemoglobin to achieve a grade 3/4 toxicity. So we didn't really want to decrease the dose of talazoparib for grade one or two anaemia, because that would have basically required half of the patients to have dose reduction even before starting treatment. And I think that strategy worked very well. The onset of anaemia was 3.3 months. That was a median duration of onset of anaemia.

So overall, I think the message here is these patients are expected to develop anaemia and they need to be monitored closely in the first three, four months.

The other side effects that seem to affect quality of life, such as anorexia, fatigue, nausea and vomiting. If we look at those side effects, the grade three or four side effects range between 1 to 4% patients. So overall, I think this is an acceptable toxicity profile. We didn't see any new safety signal with the combination, and I look forward to regulatory approval of this combination.

Tanya

Yes. So, it seems like the toxicity profile when we're using the PARP inhibitor in combination with either abiraterone or enzalutamide looks really similar to when we use it on its own. And I guess that's part of the discussion we have as we think about expanding usage of these agents to a broader population, those without a BRCA 1 or 2 mutation, for instance.

What do you think about using these combinations in all comers?

Neeraj

As we saw the level of benefit, that is in BRCA1 versus BRCA2 versus HRR positive cohort versus HRR negative and when we all are making decisions in the clinic, we look at the magnitude of benefit and the side effects and we make a decision together with the patients.

So, of course we have to wait for the regulatory approval of these data and once these are approved, I look at discussing these benefit versus toxicities with my patients and depending upon what other options are available. I would like to be offering these options.

Definitely I will put them on the table and it will be informed decision making by my patients.

Tanya

So, in the PROpel trial, up to a quarter of patients had docetaxel in the upfront metastatic hormone sensitive setting. But of course, this was intended to be first line mCRPC so patients had not been exposed to prior abiraterone or enzalutamide^a. What do you think about patients who present to your clinic who have already been exposed to abiraterone or enzalutamide for metastatic hormone sensitive disease? Can we offer these combinations of the novel hormonal agent with the PARP inhibitor to those patients?

Neeraj

This is great question. So, the most important line of decision making for me is, is the disease progressing on a novel hormonal therapy such as enzalutamide, apalutamide, darolutamide or abiraterone or resistant to novel hormone therapy?

So, in those patients the data are not there, I think we will have to generate the data. But only 5 to 10% of patients develop de novo metastatic hormone sensitive prostate cancer as a presentation of prostate cancer. 90% of patients ultimately develop mCRPC from a localised prostate cancer and then there is a whole continuum of disease. They go from localised prostate cancer to receiving radiation therapy and receiving androgen deprivation therapy for, say, six months to 18 months. And we know many of these patients never recover their testosterone before developing mCRPC.

Then we saw the data from STAMPEDE trial. Many of my patients are now receiving two years of abiraterone based on the STAMPEDE trial, and they stop abiraterone after that and their disease slowly progressed. If they if they were to have disease progression down the line and they are not really resistant to a novel hormonal therapy. Then many of my patients with radiation therapy or surgery develop hormone sensitive biochemical recurrence and they receive intermittent androgen deprivation therapy, and then they develop mCRPC.

And of course, we cannot forget about those hormone sensitive patients who experience exceptional response and these are 70% patients on a novel combination of ADT plus novel hormonal therapy with the PSA at 0.2 ng/mL. And we just showed in our Annals of Oncology paper last week that these patients are 65% less likely to die of the prostate cancer than those who do not receive a PSA or experience a PSA of 0.2 or less. And many of these patients over the years discontinue novel hormone therapy because they want to take a break from the chronic side effects. And they develop mCRPC, while not being on novel hormonal therapy.

And the last but most important point, until two years ago, less than 40% patients receive novel hormonal therapy for metastatic hormone sensitive prostate cancer. And all these patients are going to develop mCRPC over the next 2 to 5 years. So, I expect a substantial number of patients in next 2 to 7 years who are going to be developing mCRPC, without progressing on a novel hormonal therapy and will remain candidate for a novel hormonal therapy, plus a PARP inhibitor in first line mCRPC setting.

Tanya

Yeah, thanks for raising that distinction. I think it's really important to understand whether patients have progressed on a novel hormonal agent versus just having been exposed since prior exposure was actually not an exclusion in TALAPRO-2. And of course, the patients who have homologous recombination repair alterations, who develop mCRPC after exposure while on the abiraterone or enzalutamide to your point there, they can still access PARP inhibitors as monotherapy but patients without a genomic alteration if they are in the first line mCRPC setting providing them with combination therapy as per PROPEL or TALAPRO-2 really gives them an extra treatment option that they wouldn't otherwise have. And I know you and I have often discussed these studies that show that there's a significant drop off in the numbers of patients who receive subsequent lines of therapy and just how important it is to use our most effective therapies first. And that kind of fits with the whole paradigm of the importance of upfront intensification and how that provides not only progression free survival benefits, but overall survival benefit.

So one question that I think many listeners may have is, you know, they may be choosing abiraterone versus enzalutamide based on a patient's comorbidities. And are we really bound to use olaparib with abiraterone and talazoparib with enzalutamide, or do you think the PARP and the novel hormonal agent could be mixed?

Neeraj

Great point. I would like to again re-emphasise on the very important point you raised, Tanya, that is a substantial number of patients do not get to see next line of therapy. For our elderly patients with metastatic prostate cancer, that is around 50% based on so many different real-world data or patient level data.

And talking about the combination, can we combine talazoparib with abiraterone or olaparib with enzalutamide? I think we have to wait for the data to be generated.

So, I think it will be very interesting to see the data which will be generated by our peers, our colleagues, by us, about how these PARP inhibitors can be combined with other novel hormonal therapies so that we can use them in a more personalised fashion for our patients.

Tanya

Yes, I agree with all the potential for drug-drug interaction and the need to use different doses potentially of a PARP inhibitor when combining it with a novel hormonal agent, it is best to stick with the data and we will have a study and we have a clinical trial ongoing right now with talazoparib and abiraterone that hopefully will shed some light on that. But I agree for now, I think it makes sense from a safety perspective, from a cost perspective to get reimbursement for these very expensive medications to stay on label. And of course, that supposes that FDA will approve these drugs in combination and the labels will be updated.

We definitely think about abi and enza as having different side effect profiles and we might choose an agent based on the expected side effects or the patient's comorbidities. Do you find substantial differences between the PARP inhibitors from that perspective?

Neeraj

I think so and based on our experiences ever since olaparib got approved and is available in the clinic and then we have used niraparib and talazoparib and rucaparib in our clinics, beyond cytopenia’s it seemed to be different as far as obviously not surprising, but I see more GI side effects with olaparib, more hypertension with niraparib, more elevation of liver enzymes with rucaparib, more thrombocytopenia with talazoparib. The good news is most of these side effects are so easily manageable compared to when I look at those chemotherapy cocktails in my clinic, when we used them, these side effects are so much more manageable with dose reduction, with the temporary hold of these agents and our patients, most vast majority of my patients are able to tolerate PARP inhibitors without having to discontinue them, unlike many other chemotherapies we use on clinic.

So, I think overall, I feel very optimistic that we will be able to get a combination of novel hormonal therapy and a PARP inhibitor for a given patient who has constraints as far as drug interaction is concerned. I'm optimistic that we will be able to find a good combination for all our patients, and that's the beauty of having so many different combinations being available in the clinic.

Tanya

Yes, I agree. Thank you so much, Neeraj, for what was a very interesting discussion. And I think just to summarise, I think we all agree genomic testing and genetic testing are still very, very important because it informs not only what treatments are options, but what the amount of benefit a patient might expect to experience from these agents. But there's a consistency across all these trials that we've talked about that patients with mCRPC who have genomic alterations in homologous recombination repair have a greater benefit. But what's exciting is to see that there's benefit from PROPEL and now from TALAPRO-2 even in patients who are genomically unselected. So this could potentially add a therapeutic option that previously wasn't available for them.

Of course, have to balance risk against benefit and talk about the added risk, particularly of anaemia and to a lesser extent some GI toxicities. But overall, as we've discussed, a favourable safety profile and manageable sometimes with dose holds and dose reductions.

So, thank you again and thank you to our listeners. We hope that you have found our discussion helpful.

Neeraj

Thank you very much.

We hope you found this podcast informative and enjoyable. If you like this episode, you should look on the COR2ED channel for more. In particular, look out for two other podcasts in this series with experts De Elena Castro and Dr Neal Shore, where they discuss how they implement PARP inhibitors as monotherapy and in combination with novel hormonal agents in their clinical practice for their prostate cancer patients. Make sure to listen to those two. Also, don't forget to rate this episode on the COR2ED website and share our podcast on social media or with your colleagues. Thank you for listening and see you next time.

This podcast was brought to you by COR2ED Independent Medical Education. Please visit cor2ed.com for more information

 ^aPer PROpel protocol, before metastatic castration-resistant prostate cancer, treatment with next-generation hormonal agents (except abiraterone) was allowed, provided patients had not had PSA or clinical or imaging-based progression during the treatment and the treatment was stopped at least 12 months before random assignment. However, only 1 patient enrolled to PROpel had received prior treatment with NHA