EMUC 2024: Optimising strategies in mHSPC and mCRPC
Prof Gert Attard – UCL Cancer Institute, London, UK
Dr Lynda Corrigan – Tallaght University Hospital, Dublin, Ireland
Dr Jochen Walz – Institut Paoli-Calmettes Cancer Centre, Marseille, France
Prof Wolfgang Fendler – Universitätsklinikum Essen, Essen, Germany
GA: Hello, thank you for dialling into this ecancer webcast. My name is Gert Attard, I’m a medical oncologist in University College London, UK. We have an excellent panel today to discuss precision oncology and I’ll let each of them introduce themselves. Wolfgang?
WF: My name is Wolfgang Fendler, I’m a nuclear medicine physician and attending at the Essen University Hospital.
LC: My name is Lynda Corrigan, I’m a medical oncologist in Tallaght University Hospital in Dublin.
JW: My name is Jochen Walz, I’m a urologist at the Institut Paoli-Calmettes Cancer Centre in Marseille, southern France.
GA: Excellent, thank you. So we’ve been given a very broad remit – precision oncology in metastatic hormone sensitive prostate cancer and metastatic castration resistant prostate cancer, so really across the domain. I think we’ll focus on imaging and mHSPC and then in molecular testing in mCRPC, that’s probably where we’ve had most discussions recently. Starting on imaging, who better then to talk through this than Wolfgang. So there’s clearly some tension between conventional imaging and PSMA-PET and I think the next few years this will all sort itself out. How do you think PSMA-PET should be used today in practice and what’s the direction of travel? How is that going to change?
WF: I think we are very specific users of PSMA-PET currently, mostly as an imaging modality that has higher accuracy and more sensitivity in the space of early recurrence, biochemical recurrence for example, detection of disease whenever localised treatment would be possible. The second application that is very specific and it’s absolutely needed is the selection of patients before a PSMA-directed treatment such as Lutetium-PSMA. How would we use PSMA-PET in the future? I think the use will probably expand into other fields as well. So we have three major fields of using imaging in precision oncology and one is localising disease, so just your management works better. In localising disease it will really excel, because of its higher accuracy, in the future in many trials. Risk stratifying patients is very important for precision oncology – conventional imaging is doing a very good job on this but maybe PSMA-PET might add on to this or also deliver some extra prognostic accuracy in the future. And the third area is response assessment, and this is really an ongoing debate how PSMA-PET might contribute to response assessment in the future.
GA: Agreed, I think you’ve nailed the three key areas. So focussing on patients presenting with de novo disease, high PSA, let’s say 29, currently non-metastatic on conventional imaging which, as we all appreciate, is a measure of probably poor sensitivity, but a couple of mets on PSMA-PET. How would you handle that patient? How would you manage him?
WF: That’s really a challenging situation currently for the tumour board and for treatment decision, I totally agree. Particularly we have an imaging test that just has a much higher sensitivity but these are still the same patients, these have been high-risk profile patients but now we see metastases on PSMA-PET. I would not entirely change the treatment choices. I think it should still be guided by what we have learned from conventional imaging evidence. The PSMA-PET can add on extra precision for treatment decisions, to maybe escalate treatment whenever it’s feasible and it’s reasonable in a patient setting. So those metastases might guide a metastasis-directed treatment or might guide a choice from a monotherapy to maybe a triple therapy if it’s available in those patients. So imaging currently guides decisions within the corridor of what we have in terms of treatment options based on conventional imaging. The way we should use it in the future is really to understand what those extra metastases that we detect mean and how we can target them so patients really have an oncologic benefit from this imaging test.
GA: Yes, I agree. I guess if a patient is very high risk localised, they’re going to get ADT and an RP probably, abiraterone primarily nowadays, and radiotherapy and then using PSMA-PET to tailor that somehow. Now, Jochen, are you using radiotherapy to the primary in metastatic patients and, if you are, are you using PSMA-PET or bone scans to make that decision? Or neither?
JW: The other scenario that you were mentioning is the other way round – you have a high-risk patient that goes directly to a PSMA-PET, ends up being positive on the PSMA-PET and then you’re deciding whether that would be also a patient being metastatic on conventional imaging. Because we have our algorithms right now calibrated on conventional imaging it’s another difficult task then to understand if that patient would qualify for low volume according to CHAARTED and conventional imaging or if that would be rather high volume. So the question is would we need to redo, then, conventional imaging in order to have our algorithm applicable and know exactly what situation we find in a patient? I think the important information is, in this scenario you were mentioning, you have M0 on conventional imaging, being metastatic on PSMA-PET, these are per definition low-volume patients so you should not skip the local treatment. So I think that is a message to keep – if you have this scenario where you find metastases do not forget the local treatment, that is a clear benefit for the patient. Then what we need, or should add to it, that’s another question and we can have a lot of ideas of what we could add but do not skip the local treatment. I think that’s very important.
GA: Agreed, a key message. So now moving on to molecular testing, for now in the mHSPC indication we don’t have a clinical indication for molecular testing but clearly we should be performing BRCA testing in mCRPC. But there’s a multitude of challenges to implementing that into clinical practice and I know you’ve worked hard to establish that locally, Lynda. Can you talk us through some of the efforts or practices you’ve put in place to get around the challenges we’re facing every day?
LC: Anybody familiar with doing testing for BRCA or HRR alterations will encounter these, I think it depends a little bit on your local availability of testing. The sort of things that we’re considering are what sort of testing are you doing, whether it’s germline or somatic. We know we want to be doing somatic testing, hopefully you can do both because we may miss some germline mutations if we test only somatic. We have managed to implement that in Ireland. When it comes to trying to identify somatic mutations we have the option of tissue or circulating tumour DNA where we are reusing tissue testing. The challenges to that are that… really one of the significant challenges is the failure rate of tissue testing. We know from some data that has been published, for instance from the PROfound trial, that the older the tissue is, the more likely you are to have a failed result and that fresh tissue is more likely to be successful, particularly fresh tissue from soft tissue like nose. So there are some processes you can put in place within your own local set-up to try and help improve successive testing. One of those is trying to test early, if that’s within your approvals to do that testing up front in metastatic castrate sensitive disease if it’s tissue testing that you’re doing. There are caveats to doing that with circulating tumour DNA. Then having a discussion with your local labs about selecting out those slides with high tumour content so that you’re more likely to get a successful result. Then also ensuring that your processes within your essential molecular labs, working with molecular pathologists, to ensure that those process are as refined as possible.
GA: You mentioned that in your talk – testing at mHSPC – which, to me, seems like a no-brainer. Eliminate the failure rate, it’s going to be cost effective doing it that way but many of us are being restricted to testing in mCRPC on tissue which is ten years old and you’re struggling to find it, it’s been stored somewhere offsite in a mine or something somewhere. What are you doing, Jochen? Are you testing up front or do you wait for mCRPC?
JW: As you said, we have a bottleneck with the amount of tests you might do or the tissue quality where we might ask for a test, it will not be informative. So I think we need to identify the sweet spot which, for sure, is CRPC because that is actionable. What we do in addition is when we have a patient with a family history of prostate cancer where that testing might be relevant for the patient but also for the family behind, so probably the benefit you might derive from this testing might be a little bit broader than just for an individual patient because you might have also the family that takes the benefit out of it. That’s the sweet spot for us if we have limited access to the germline testing or somatic testing.
GA: So no reflex testing of metastatic patients?
JW: Not at the metastatic hormone sensitive stage, that’s not feasible at the timepoint for us in a systematic fashion for all patients. We would like to but it’s not yet feasible.
GA: Not feasible because you’d flood the test, you’d flood the lab. And you, Wolfgang, is it reflex testing up front or are physicians waiting for mCRPC?
WF: We are really mostly called in the mCRPC space because of the nuclear medicine treatments available there. The testing procedure that we approach is that we try to rebiopsy. We need to get fresh tissue for metastasis if it’s feasible for the patients. That has been done as part of a prospective clinical trial protocol where we before and under treatment approach biopsies, mostly bone metastases but also lymph node metastases, and by this approach I’m amazed to see that even in patients with large metastases and we target a rebiopsy we have failure rates of tissue sampling – in ten patients maybe one or two patients. Even though there is a large metastasis we don’t obtain enough material or any material of the tumour to do testing. So it’s really a challenging situation even if you approach a new sampling. And, of course, in those patients we still have the old samples available.
GA: You’re clearly in a unique ivory tower, being able to rebiopsy metastases. Globally that is really challenging, especially bone biopsies. What proportion of mCRPC patients are eligible for biopsy you manage to include in this protocol?
WF: For the ones that are… This is being done in patients with Lutetium-PSMA therapy and I would say that maybe 50% of patients would approve to doing rebiopsy as part of this protocol. So at baseline before we decide for type of treatment, the rebiopsy informs us about BRCA and other mutations in addition to imaging that is being done. Again, I would say around 50% of patients consent to doing the extra biopsy for those testings.
GA: That’s excellent. The infrastructure you need for that to rebiopsy CRPC patients I think is going to limit it. And, as you said, even when you see a large met, because that is our experience, when you see mets on imaging about 20% have no cancer in them which therefore doesn’t entirely resolve the situation. Now, ctDNA is one option, we discussed this earlier today. ctDNA can work in end-stage disease, earlier stage you mentioned the challenges with tumour content Lynda?
LC: So the ctDNA fraction is important when it comes to testing for these alterations with circulating tumour DNA. There are two parts to that, one is if you’re testing circulating tumour DNA early in metastatic castrate sensitive disease after somebody has been initiated on treatment their ctDNA may have fallen to a point where you’re getting these false negative results and you need to remember that actually this patient may have an alteration that may become apparent when their ctDNA fraction increases in castrate resistance. The other part is that there are certain alterations that may not be picked up if your ctDNA fraction is low, like deletions. So we know patients with homozygous deletions with BRCA, they are some of the patients who respond the best to PARP inhibition, we don’t want to miss those but you need a decent ctDNA fraction to show that.
GA: I really worry about that because there’s pretty good evidence now that the homozygous deletions get the best response from PARP inhibition and we’re excluding them due to the technical limitations of our assays. The key message you’ve given is when a ctDNA test is negative do not label that patient as BRCA or HRR negative because that could be an artefact of low tumour content. We’ve focussed on BRCA, there are, of course, a number of other genes involved in homologous recombination repair that are much less commonly altered. Are you testing for anything outside BRCA? Jochen?
JW: So we have a panel, I would not be able to tell you exactly what kind of mutations are in there but we screen for several. So not only for BRCA, we screen for several mutations but there was the recent FDA commissioned analysis on looking at what kinds of mutations would be the best candidates for PARP treatment. There are actually not that many mutations that stick out, there’s BRCA obviously, the best effect in BRCA2, but then you have PALB2 and CDK12 and the others which used to be the usual suspects, actually, inside of this field actually not such a strong response to this treatment. There seems to be a sweet spot in some of the mutations but there are not as many as there might be, maybe, for other cancers. I think ovarian cancer does have really a broad field of mutations that might be applicable for the PARP inhibitor treatment but for prostate cancer it seems a bit more restricted.
GA: CDK12 is clearly the big splash in that. It’s looking for a home. We initially were proposing CDK12 as a biomarker for immune checkpoint inhibition and that’s not really panned out. The benefit rate from CDK12 mutants appears really low, maybe it’s found a home at PARP inhibition. We probably need a bit more data but, as you say, that meta-analysis from the FDA was very intriguing. How about you, Lynda, do you have access to CDK12 testing?
LC: We don’t unfortunately. So we’re restricted to BRCA mutation only but I agree with everything you’ve said. I think there’s more to it than this PARP inhibition is beneficial in HRR mutant, it’s a lot more complex than that. I think the BRCA story is clear, I think it’s less clear for other mutations.
GA: Agreed. And on that note I think we’ll wrap up. It’s been a great discussion. It’s clearly exciting. 20 years ago we couldn’t spend more than five minutes talking about metastatic prostate cancer, we now could spend a whole weekend and not cover everything. Thank you for your time and I hope all the audience has found that interesting.
