PC: Thank you very much for joining us for this discussion on updates on PARP inhibitors and prostate cancer. I’m Phil Cornford, I’m a urologist from Liverpool.
EC: Hi, my name is Elena Castro, I’m a medical oncologist at Instituto de Investigación Biomédica in Malaga, Spain.
PC: So we’re going to talk a little bit about the data that was presented at ASCO 2022 and the EAU where we currently are. Perhaps you’d just outline the two studies we’re going to discuss – olaparib and MAGNITUDE?
EC: Yes, at ASCO GU this year these two trials were presented in the same session and I think everybody has been talking about them since. Very briefly, in the PROpel study unscreened men were treated in first line of mCRPC with the combination of olaparib and abiraterone versus another arm with abiraterone in monotherapy. The data that has been presented so far and updated recently shows that there is a benefit in rPFS for all patients, particularly, of course, for those with HR alterations. We are all awaiting more data on that – the definitive overall survival data has not yet been presented. But the data that has been presented already suggests that there may be a benefit for these patients. In the MAGNITUDE trial patients were divided into two cohorts depending on whether they had or not HR alterations. In this study patients were randomised to abiraterone in monotherapy or in combination with niraparib. So the study was stopped for patients without HR alterations because there was no sign of efficacy but there was a benefit in rPFS also for patients with HR alterations, particularly for those with BRCA1 and BRCA2 alterations.
PC: There are also some slight differences in the dose of the PARP inhibitors used, isn’t there? So the olaparib study has used full dose olaparib and that’s not true for MAGNITUDE.
EC: Yes, that is right. In MAGNITUDE the dose was reduced to 200mg instead of 300mg that is the full dose. While with this dose it was well tolerated, no safety concerns have been observed or reported, but it is not clear whether this could affect or not the efficacy of the drug and the synergy that could be there for patients without HR alterations.
PC: And olaparib was also well tolerated in combination in the PROpel data. We saw some data on quality of life and tolerability this morning, what was your view on that?
EC: The combination seems to be very well tolerated by the patients in the trial. No safety concerns have been reported with this more prolonged follow-up. There are still about 15% of patients that present grade 3 anaemia and may require a blood transfusion and about 7% of patients with the combination that present thromobotic events. This could also be a concern when selecting in which patients to use the combination.
PC: We understand quite well why people get anaemia with PARP inhibitors and we understand that this is a manageable side effect. But the thromboembolic events, how is that altering practice? Or doesn’t it?
EC: Actually the patients when they present thromboembolic events, the patients will require anticoagulation and prolonged anticoagulation. So this is something that we may have to consider when selecting patients. We don’t really understand what causes that but it’s true the patients with advanced prostate cancer have also several factors that promote thromboembolic events.
PC: But it’s interesting because lots of these patients didn’t present with symptoms, lots of them were just picked up on scans, weren’t they?
EC: Yes, but still some events could be a bit concerning.
PC: But it might mean you’d need to have a look for that if a patient is on this sort of treatment.
EC: Yes, that’s right.
PC: We’ve seen an interesting thing in the PROpel group because they are a group of patients without obvious gene alterations who also appear to have had some form of response but a much bigger response for those people with BRCA mutations and other similar DNA repair gene mutations. How does that affect what we will do going forward?
EC: It’s true that the data that has presented indicates a clear benefit for patients with HR alterations and also a benefit, less clear, for patients without these alterations detected. But we are still waiting to learn the granularity of these molecular data. So until we have more data and the combination is approved we need to continue screening our patients for HR alterations because in Europe we have the opportunity of treating those with alterations in BRCA1 and BRCA2 with olaparib that is already approved. We shouldn’t miss the opportunity to identify those patients.
PC: But I think it’s more than that, isn’t it? I think that people need to know whether it will be effective as well. So everybody who presents with metastatic prostate cancer should get tumour testing in order to identify whether those tumours are carrying mutations.
EC: Yes, and we can’t forget that also about half of those alterations will have a germline origin. Some germline alterations are poor prognostic factors so we need to be careful with those patients and vigilant, monitor them more carefully. But perhaps it is more important that these will give us the opportunity to test also other relatives who could be at risk of prostate cancer but also other tumour types.
PC: And when we look forward, other mutations may be important for the group? What’s your feeling about the unscreened, the general patients? How is that going to work? Why do we think that has an effect?
EC: I don’t really understand well how it is that some response is being seen in those patients. So there is a lot to learn still about this potential synergy between PARP inhibitors and androgen receptor signalling inhibitors. There are other trials being run and completed at this time that will read out during the year probably and these will also give us a lot of information about this potential synergy and the response of patients without HR alterations.
PC: This morning we saw some data on quality of life. These drugs are reasonably well tolerated in terms of quality of life; these patients are able to maintain quality of life. Some of them were asymptomatic before they joined the study but they’ve actually done really well in terms of tolerability for this combination of treatment.
EC: Yes, in the MAGNITUDE study patients were mostly asymptomatic and what we saw was that this good performance was maintained during the treatment. Of course the treatment was quite well tolerated so I don’t think we have concerns about this.
PC: So which patients do you think this will be a useful combination for?
EC: With the data we have, for patients with BRCA alterations definitely the earlier we use the PARP inhibitor the better. We still have to learn whether in combination or it’s better as a sequential treatment but, yes, we need to identify those patients and treat them as soon as possible. For other patients with HR alterations that don’t seem to benefit as much from PARP inhibitors in monotherapy it could be that the synergy with the hormonal agents really leads to an efficacy that we haven’t seen with the monotherapy.
PC: And the fact that the tolerability is enough to allow a good dose of olaparib may be the difference between the two trials. Do you think there’s anything to support that or is that just wishful thinking?
EC: It could be. It could be because in PROpel the drug was given at full dose whilst in the MAGNITUDE the drug was reduced from 300mg to 200mg. Yes, it could also be affecting this synergy.
PC: And we’ve seen from study 8, which also showed an unselected population, that there was a benefit there, again only in progression free survival and again no survival benefit but a signal that this isn’t just a one-off, is it?
EC: Yes. Study 8 was an early sign that we couldn’t understand well until we called the PROpel later. We probably didn’t pay much attention to it but it’s true, it was there already.
PC: And I’m not sure that many experts would have run PROpel. I’ve certainly heard people talking, saying that if they had been asked whether this was a good idea to do they would have said no.
EC: Probably.
PC: And now we see really interesting data and it will give us new insights into how you might use combination treatment. There are other combinations that might also be important going forward – the idea that you might combine with lutetium and other things that damage DNA is also a really intriguing thing that we might see in the future although not yet ready for prime time.
EC: Yes, but it makes a lot of sense to combine something that damages the DNA with something that prevents it from being repaired, right? Yes, I think it will be very interesting to learn the results of those studies.
PC: And those studies are beginning already to be rolled out so it will be really interesting to see what happens to that data as we come forward.
EC: Yes.
PC: Thank you very much for talking us through the new data that was presented at the EAU and thank you very much for joining us.
