PARP inhibitors in prostate cancer: Guidelines, who to test and the patient pathway

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Published: 5 Jun 2020
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Dr Neal Shore and Dr Elena Castro

Dr Neal Shore (Carolina Urologic Research Center, Myrtle Beach, USA) and Dr Elena Castro (Spanish National Cancer Research Center, Madrid, Spain) discuss the emerging and crucial field of genetic testing in prostate cancer.

Dr Castro begins the discussion by outlining the main recommendations for urologists and medical oncologists regarding testing for prostate cancer patients - with reference to the PROfound trial. She states that every patient with advanced disease should be tested for DDR alterations.

Dr Shore elaborates on this, by giving a brief overview of the results achieved in the PROfound trial and states that two PARP inhibitors, olaparib and rucaparib have recently been approved by the FDA to treat patients with HRR-gene mutated metastatic castration-resistant prostate cancer.

Dr Castro explains the differences between somatic and germline testing and the importance of both methods. Dr Shore reflects on his own experiences in his clinic, where routine germline and somatic testing is carried out in metastatic patients following the evolving NCCN recommendations.

However, Dr Castro also adds that most clinical guidelines currently do not include germline or somatic testing for DDR alterations, and believes these must be incorporated in light of the current evidence.

Dr Shore concludes by emphasising both testing methods should be actively implemented into routine clinical practice, to guide the use of PARP inhibitors which can delay progression and improve survival for these patients.

This programme has been supported by an unrestricted educational grant from AstraZeneca.

NS: Hello, I’m Neal Shore, I’m the Medical Director of Carolina Urologic Research Center in South Carolina. It’s a great pleasure for me to be joined today with Professor Elena Castro. Elena is an internationally renowned medical oncologist who has really been doing pioneering basic science and clinical research in genetic testing PARP inhibitors, as well as all of GU oncology. She’s at the National Cancer Centre of Spain and also located now in Malaga. So, Elena, it’s fabulous to have you join me today, thank you.

EC: Thank you, it’s my pleasure.

NS: So one of the things that really we’re going to focus on today is this burgeoning field and super-important area which we call genetic testing and the implications for personalised medical decision making and as it relates specifically to a class of medications, oral targeted medications, known as PARP inhibitors. So maybe we’ll begin, Elena, by me asking you simply what are your recommendations for uro-oncologists and medical oncologists regarding testing? What type of testing do you recommend, why is it important and what is the prevalence of positive findings for patients who might have what we describe as DNA repair mechanism defects in both localised, metastatic and mCRPC patients?

EC: The PROfound study that has just been released has provided the data on the largest series of metastatic patients tested for DDR defects. The prevalence of such alterations in this population was 28%. With the data that we have at the moment we are not able to identify which are those patients most likely to have a variant of these alterations. There are some histologies that have been suggested to be associated with these alterations but there are other studies that do not confirm these associations. So at the moment we cannot exclude one of these DDR alterations in any patient.

So, to your first question, I think we should test DDR alterations on any patients with advanced disease. For localised disease we don’t have a conclusive figure but there are many studies going on that will provide us with those data quite soon.

NS: No, those are great points. So the PROfound, which was presented at ESMO 2019, Maha Hussain and Johann de Bono the PIs on that, demonstrated a really marked improvement in patients who had progressed on novel hormonal agents such as abiraterone or enzalutamide both before and after receiving taxane-based therapy, specifically, patients who had homologous recombinant repair mutational alterations. It was largely powered by BRCA2. Recently they’ve had a press release that overall survival data has also been achieved and I think that we may see further announcements and presentations of that at ESMO in 2020 hopefully. But let me ask you, now that we clearly have data supporting the role for testing and, most recently, in the US, I think it has also happened with EMA but the FDA now has, just last week, approved two PARP inhibitor medications for mCRPC patients who specifically have HRR mutations – olaparib and rucaparib. So what are your recommendations now for germline and somatic testing? And maybe just explain simply the difference for our audience.

EC: Yes, the germline mutations are alterations that are present in all the cells in our body because these are in DNA in the eggs or in the sperm of our parents. So it’s present in every single cell in our body. The, what we call, somatic alterations are alterations that are only present in the tumour because these have been acquired by the tumour because it provides some advantages to the tumour cells for growth or aggressiveness. So in prostate cancer, unlike in other tumour types, more or less half of the alterations we identify when we test dead tumour are also present in the germline. So we may analyse only the tumour tissue but if we find an alteration we should make sure that that mutation is not also present in the germline. The reason for that is because as most likely the patient has already inherited this alteration from his parents, he may also have transmitted it to his descendants and also other siblings or other relatives in the family could have inherited that alteration. As you mentioned, the most commonly altered gene is BRCA2 which is also associated with an increased risk of breast and ovarian cancers and also less common such as pancreatic cancer or melanoma. So by identifying those germline mutations we may also benefit and help those families because the identification of one of these germline mutations should trigger cascade testing in the relatives. If we do it the other way around, if we only test the germline we may be missing approximately half of the patients who could have an alteration only acquired by the tumour. Then we may dismiss a treatment opportunity for half of the patients who could benefit from PARP inhibitors. So ideally we should do both testing, somatic and germline.

NS: Yeah, that’s a great point and it’s interesting, right? There’s a lot of different data sets. You’ve been incredibly instrumental in publishing on this but you’re absolutely right. If you just do the germline, what we inherit in all of our cells from our parents, we may see homologous recombinant repair mutations, the fifteen or so that we study and investigate in maybe 5% of localised prostate cancer, approximately 10% of metastatic but upwards of 20-25% of mCRPC patients. Then if we only do germline we might miss half of those mutations that occur in somatic. In the somatic we test those patients with tissue and now also with what some have described as the liquid or a blood test. Metastasis directed biopsies or archival prostate biopsies or prostatectomy specimen is the tissue basis for somatic testing which largely was the factor in the PROfound trial. But, interestingly, just last week the FDA approved two different blood-based assays, one with Foundation Medicine, one by Myriad, to look for these somatic-based alterations. I think this is really important because I don’t think the vast majority of our uro-oncology and medical oncology colleagues are doing that testing. Prior to just last week it was a clinical trial concept, but now that there are two approved oral PARP inhibitors that have demonstrated an rPFS, the PROfound trial as you described which was published in The New England Journal and recently the rucaparib data from their TRITON2 study also received approval by the FDA. I think this is really advancing the level of personalised medicine for everyone. So, yes, for me in my clinic we’ve been routinely getting germline testing and somatic testing and we’re following the evolving NCCN recommendations which are strongly recommending for getting this testing for patients with metastatic disease, metastatic prostate cancer – patients with these hereditary breast, ovarian, colorectal syndromes that you describe so nicely. So, yes, are you doing that pretty routinely now?

EC: Yes. We have just started also testing all our metastatic patients, metastatic castration resistant prostate cancer patients. But I would like also to remark that unfortunately most clinical guidelines do not include germline or somatic testing for DDR alterations in their recommendations. So I think we need to update all those guidelines based on the current evidence and the significant benefits that this testing could provide to these patients. We just recently conducted a systematic review and we were very surprised to find that only three guidelines across the world recommend strongly germline testing.

NS: Yes, that’s rather amazing, isn’t it? I know the NCCN has been evolving fairly rapidly in doing that recommendation and consideration for somatic testing now in all mCRPC patients. I think that we’re moving at really a breakneck speed, as they say, and literally we now have two oral PARP inhibitor agents that are available. There are multiple other PARP inhibitor agents – niraparib, talazoparib – which I’m sure will probably also eventually meet approval alongside rucaparib and olaparib. I think this is vastly important and, as you also state, not only do we have this to help our patients with mCRPC who have the appropriate DDR alterations, we now have both a basis for getting blood testing germline, you can do a saliva test as well. The costs have decreased rather significantly and tissue and liquid somatic testing is now available as well. So I think these are really important evolutions and you’re absolutely right, the guidelines across the world need to support this so that there’s a reimbursement methodology. It’s not of any value if you have testing and you have drugs if you can’t get accessibility to them.

So thank you very much. I think just you’ve made so many fantastic points. I thank you for all that you’ve been doing in the field. I guess if I were just to summarise for our audience, you can’t really just be thinking about it, you need to be doing actively, developing your clinic for both germline and somatic testing for DNA repair mechanism defects or homologous recombinant repair mutations. Sometimes we get a little bit twisted up in the acronyms but the reason for saying this is if you’re not testing and you’re not finding these patients you are potentially missing an opportunity to treat these patients with newly approved oral PARP inhibitors which can delay their progression and ostensibly improve their survival. And you made the point also that the issue around cascade family genetic testing is so incredibly important. So I think these are all some of the really key take home messages. I think our colleagues need to look at the guidelines, they should follow EMA and NCCN guidelines, they’re regularly evolving and I think this will really allow us to continue to do what we’re all striving for, which is the optimisation of advanced prostate cancer care. So, gracias Elena, thank you very much.

EC: Un placer.