ASCO GU 2024: Latest in PARP inhibitors for prostate cancer
Dr Friederike Schlurmann – Centre Hospitalier Universitaire de Brest, Brest, France
Dr Nabil Adra – IU Health University Hospital, Indianapolis, USA
Dr Emmanuel Antonarakis – John Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, USA
Dr Hiroshi Kitamura – University of Toyama, Toyama, Japan
FS: Hi everybody and welcome to the ecancer round table discussion about the newest developments in PARP inhibition in metastatic prostate cancer. I’m Dr Friederike Schlurmann, I’m a GU oncologist in France at the University Hospital of Brest. I’m happy to be joined today with my three colleagues who are going to introduce themselves.
HK: Hello everyone, my name is Hiroshi Kitamura, a urologist at the University of Toyama, Japan.
EA: Hello, my name is Emmanuel Antonarakis and I’m a GU medical oncologist at the University of Minnesota.
NA: Hello, my name is Nabil Adra and I’m a GU medical oncologist at Indiana University.
FS: Great. So Dr Adra, we have had so many data since 2022, since the first data presented from PROpel at the ASCO GU. So we have updates at every congress, so what have we seen this year at ASCO GU 2024? Something new? Just tell us a little bit.
NA: Sure. It’s an exciting time for PARP inhibition in prostate cancer for sure. So at ASCO GU we saw updates from two major trials, the TALAPRO-2 trial and the MAGNITUDE trial as well. Just to recap, the TALAPRO-2 trial is a randomised phase III trial that evaluated patients with metastatic castration-resistant prostate cancer in the first line metastatic CRPC setting. It randomised patients to receive enzalutamide plus talazoparib versus enzalutamide plus placebo with a prospective evaluation of next generation sequencing using tissue and blood analysis for genomic testing. The results of that trial showed that patients who were randomised to the enzalutamide plus talazoparib had an improved radiographic progression free survival compared to enzalutamide plus placebo. This improvement was overall more pronounced in patients who had BRCA1/BRCA2 mutations prospectively tested and also that improvement was more pronounced in the patients who had HRR mutations altogether. There was still improvement in radiographic progression free survival in that subset of patients who did not have any HRR alterations but that benefit in that subgroup was less pronounced. At ASCO GU this year we saw updates from the TALAPRO-2 trial which showed mainly reporting the patient-reported outcomes which highlighted our concern that perhaps treating patients with enzalutamide and talazoparib might increase the adverse events and have a negative impact on quality of life. Actually, the patient-reported outcomes show no substantial deterioration in quality of life in those patients, actually they’re quite similar to patients who are on single agent enzalutamide. So it was no concern in that aspect.
The other update that we had this year was from the MAGNITUDE trial and, again to recap, the MAGNITUDE trial was a randomised phase III trial with two major cohorts – patients with HRR mutations and another cohort with patients who did not have HRR mutations. Specifically, in the first cohort patients were randomised to receive abiraterone plus niraparib and in the second cohort patients received abiraterone plus placebo. In the HRR cohort patients who had received abiraterone plus niraparib had improved radiographic progression free survival compared to abiraterone alone. Again, similarly at GU ASCO 2024 we saw results from patient-reported outcomes looking at the combination of abiraterone plus niraparib and we did not see substantial detriment in quality of life in those patients. So it seems that we’re getting benefit, as far as progression free survival at least, in that cohort and now we’re not seeing a substantial decline in quality of life in this patient population.
FS: Thank you so much Dr Adra for this really important resumé of those studies. It’s really important to say that patient-related outcomes are really good because we talk a lot about efficacy but it’s really important to know that patients still tolerated pretty well those combination therapies. So thank you so much for that. So, Professor Antonarakis, I think we had another study that was presented, BRCAAway, let’s talk about this a little bit.
EA: Yes, so BRCAAway was presented by Maha Hussain this year. One question that comes up is why should we care about a 60-patient study when we already have three randomised trials leading to FDA approvals. But this trial had some unique aspects which are really important for our clinical care of patients. The question was a combination of olaparib plus abiraterone, and we’ve had the PROpel data which shows that these combinations are efficient in the BRCA1/BRCA2 subset and that has led to the FDA approval. The BRCAAway study was a unique design, there were three arms in the trial, not just two arms. These were patients with metastatic castration-resistant prostate cancer who generally had not received androgen receptor targeting therapy or a taxane chemotherapy. They were randomised to receive either olaparib as a monotherapy, that’s the unique aspect, or abiraterone monotherapy or a combination of olaparib plus abiraterone. So the first unique aspect is one of the arms was the PARP inhibitor by itself. The second unique aspect was radiographic progression free survival was the primary endpoint of the trial. If radiographic progression free survival was met patients had the option of crossing over. So the crossover was permitted and built into the design. For example, if a patient was randomised to abiraterone alone they could cross over to receive olaparib. If he was randomised to olaparib first he could crossover to receive abiraterone. This was a trial focussing in on the three genes at the time that we thought were important – BRCA1, BRCA2, ATM snuck in there as well.
There were sixty patients enrolled, about twenty per arm. So a very small number of patients per arm but again with some unique aspects to this trial. Progression free survival in the combination arm was miles ahead of the other two arms. In fact, we’ve never seen an rPFS this high, it was greater than three years, it was about 39 months, which is incredible. Of course, it could have happened by chance but the point is it far exceeded the rPFS in both the olaparib monotherapy and the abiraterone monotherapy. But the part that was most interesting to me was the crossover results. So in arm A and arm B who didn’t get the combination upfront but had the option of crossing over from olaparib to abiraterone or vice versa, when you add the progression free survival interval 1 and the progression free survival interval 2, sometimes known as PFS2, it’s a composite progression free survival, even that composite was about 16 months in both arm A and arm B. So once you get drug A followed by drug B or drug B followed by drug A, that combined PFS was still in the order of 16 months. Again, remember versus about 39 months in the combination. So this is the most compelling, although indirect, evidence that there is biological and clinical synergy because if there wasn’t synergy you would have expected the addition of the two PFS estimates to be roughly the same as the third arm and it was still far less.
FS: Thank you so much. I think that’s really important data because we always have this question do we start with a single agent or do we do a doublet. This is really important for clinicians, I think. Do you want just to say really something really short about the big question that we are asking ourselves sometimes. If a patient is on NHT or Ara-C should we put a PARP inhibition it on it if the patient is resistant? I don’t think that BRCAAway is really responding to that question but do you want to say something about that?
EA: Yes, at the time that all these studies were designed the majority of patients on all of these studies, including BRCAAway and the phase III trials, were men who had become castration resistant, had generally not received the ARPI in the hormone sensitive setting and most of the studies allowed taxane chemotherapy but again only for that hormone sensitive setting. But in the real world many of us, we all agree now, that a doublet systemic therapy consisting of at least ADT plus ARPI is the standard of care for the vast majority of patients for metastatic hormone-sensitive disease. When that patient now becomes castration resistant first line and he has a BRCA2 mutation, for example, we have a dilemma. Because these trials did not replicate what we’re seeing in our current day practices. So there are some inconclusive answers that one can give, in other words hand waving, and in general, because we try to be logical about this, there is an appetite to alternate. So, for example, if we have a patient who has previously received ADT plus abiraterone, they now have progressed, they are found to have a BRCA2 mutation, that person could receive, although it was a little bit outside the scope of the trials, enzalutamide, the alternative antiandrogen, plus in this case talazoparib. The inverse may also be true – if a patient has received ADT enzalutamide up front then they progress, one option would be abiraterone plus olaparib. Of course, in both of those scenarios you could still use the PARP inhibitor as a monotherapy, that would be on label for olaparib or rucaparib which we have not talked much about today. But in those cases it would mainly be olaparib as a monotherapy.
FS: Okay, thank you so much. So we’re talking a lot about different HRR mutations. So we have some updates at ASCO GU ‘24 about single gene analyses. So, Professor Kitamura, do you want to tell us something about that?
HK: Yes. First of all, we have already known that BRCA1/2 mutations are more favourable than other mutations in the PROfound trial, published a couple of months ago. And in this ASCO GU meeting the TALAPRO-2 or PROpel, such trials also showed BRCA1/2 mutations are better than other HRR mutations.
FS: Are there other genes that we might think about sometimes, like ATM, we talked about that. Is there anything that was shown this year that might give some hint that there is some other activity on other genes?
HK: Yes but we don’t know well because the number of patients with each gene mutation are quite small. So we don’t know exactly.
FS: If there is activity on PFS. So we would rather say today that we will stay with BRCA1/BRCA2 probably, like the labels are normally, and maybe we’ll learn other things on other single genes analysed from other studies maybe. But BRCA1/BRCA2 is probably the most promising HRR mutation that we should look at. We’re okay with that.
HK: Yes. We need real world evidence.
FS: Evidence about that.
HK: Much more number of patients.
FS: Okay. So after having said all of that, do you want to add something? Is there something that you would like to say out of everything that we’ve said about the studies?
NA: Similar to what my colleagues mentioned, there are situations where the decision point is more clear, such as patients with BRCA1/BRCA2 mutations who progressed on first line ADT, now they’re in second line therapy. That’s a perfect situation where you would treat with an ARPI and a PARP inhibitor, whatever choice we choose. I think those decisions are easier and in real world a large number of patients still get ADT only as frontline therapy unfortunately. And so this is still relevant today. However, as the practice moves more and more to patients getting doublets and triplets in first-line therapy, we’re going to see more patients who are getting to first line CRPC who have been previously exposed with an ARPI such as what Emmanuel mentioned. This is the situation where it becomes more difficult, potentially with a BRCA2 patient we feel more comfortable going with a combination of an ARPI plus a PARP inhibitor. But what if we are dealt with a patient who has an ATM mutation or CDK12 or CHEK in that first line CRPC but previously exposed on the ARPI? The evidence is not clear over there and that’s going to be a challenge with how we approach those patients.
FS: Thank you. Professor Antonarakis.
EA: Yes, I think I’d like to go back to the real world evidence, not of therapeutic choices but of the germline and somatic genetic testing. It’s amazing to me, and this is not a criticism, that most American and European and probably Japanese guidelines are strongly recommending at minimum germline genetic testing in every patient with metastatic disease. And, in addition, most guidelines are also strongly recommending, or at least to consider, somatic testing of a tumour sample, whether that’s an archival tumour sample from the prostate biopsy or their first metastatic biopsy or even a metastatic biopsy performed at the time of castration resistance. When you talk to key opinion leaders like the four of us here, we all claim that we do it in every patient but the reality is when you look under the microscope. There were three abstracts at ASCO GU 2024 that suggested that the uptake of these recommendations, at least in the United States, based on a few national databases and claims data, is not as high as we might expect. Doing a germline test is a little bit easier than a somatic test because it can be done through a saliva specimen or a blood test but the somatic analysis where you need a tumour sample, I think there is a lower appetite for that, especially perhaps in private practice or community settings. So only 50-60% of patients who are eligible for germline and somatic testing, according to these three abstracts, were receiving it.
And then the second piece is once you do get the test and the result comes back showing a homologous recombination repair HRR mutation, what proportion of those patients are then subsequently being prescribed the PARP inhibitor or PARP inhibitor combination? Again, there’s a drop-off there. So 60-70% of those patients with a documented homologous repair mutation are getting PARP inhibitor. Now, we don’t know what the reasons are for those that aren’t, whether their comorbidities prevent it or their progression is happening too fast or whether alternative therapies are being used, such as chemotherapy. But there are two levels of attrition, one is at the testing level where we’re not testing as many people as we should, and the second is once we do the test and we find the mutation there’s a second level of attrition – many of those patients who are eligible for a PARP inhibitor may not get it. So this is a reminder to all of us, including myself, that when we see a patient with metastatic prostate cancer in our clinic for the first time, in addition to all the other clinical considerations we should be thinking in our heads has this patient been offered germline genetic testing, if not, let’s do it today. And has this patient had a somatic analysis. By the way, you don’t always need a new biopsy to do that, you can do it with an archival biopsy. The circulating tumour DNA tests are now getting better and better and I think we are at the point where in patients that have a reasonable volume of disease, you have to have the higher volume of disease to detect it, these ctDNA analyses can be used.
FS: Yes, you’re so right. There are really two big problems – the testing itself and then the testing is done maybe too late so it’s too late for patients to get the right treatment. So I think we should all think about testing the patients, as you said, as early as possible, for various reasons. It’s also because the testing will be better. If you do it in fresher tissue it will be better, you will have more patients that will have a positive test result and then you can treat them earlier. We have studies now coming where we test patients in the mHSPC study. We have a lot of studies that are already full, we’re just waiting for the results. We have new studies coming, I think we will move earlier and earlier in the course of the prostate cancer history of our patient. So something that you want to add, Professor Kitamura?
HK: Yes, I and you are waiting for the results of the frontline setting PARP inhibitors phase III trial. As Emmanuel said, not only germline but also somatic mutation tests are required. I personally think that the patients with mCSPC are good candidates for germline and somatic testing, both mutation tests. We’ll see.
FS: So you’re saying we should do it at the earliest possible, right away when metastatic disease is found then we should do the testing really early. You’re so right. So thank you so much for all of those updates from today. As you have seen, it’s not that easy, we still have a lot of things to learn. Still a lot of updates coming at the next congresses, at ASCO, ESMO. So thank you so much to listen to us today and I hope we will see each other again in the future.
