Genetic testing and PARP inhibitors in metastatic prostate cancer

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Published: 7 Jun 2019
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Dr Neal Shore and Dr Joaquin Mateo

Dr Neal Shore (Carolina Urologic Research Center, South Carolina, USA) and Dr Joaquin Mateo (Vall d'Hebron Institute of Oncology, Barcelona, Spain) provide an overview on the history and mechanisms of action of PARP inhibitors. They discuss the relevance of defects within the DNA damage repair (DDR) pathway and introduce the concept of PARP inhibitors for treatment of prostate cancer.

The experts go on to summarise the difference between germline and somatic mutations and provide insights into the difficulties and considerations when testing for these mutations.

Dr Shore and Dr Mateo reflect on the importance of genetic testing for families and for the selection of treatment for patients. They address the need for comprehensive genetic profiling to detect future mutations and conclude by offering advice to clinicians on how to obtain samples and what is required from the clinical community who treat patients with prostate cancer.

PARP inhibitors and their mechanism of action in breast and ovarian cancers
Utilising PARP inhibitors for the treatment of prostate cancer
Considerations and challenges for identifying somatic and germline mutations
Clinical paradigms for genetic testing
Future prospects and recommendations for clinicians

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

NS: Hi, I’m Neal Shore, I’m a uro-oncologist in the United States. I’m really pleased to be here with my friend and colleague Joaquin Mateo from Barcelona, Spain and we’re really appreciative of ecancer to give us this opportunity to talk about an area of interest that you’ve had, Joaquin. You’ve been really one of the pioneers in developing leading research, many have assisted you and myself, but you’ve really been really out there in understanding the role for PARP inhibitors. So I’d like to get your thoughts and maybe begin with a little bit about the history of how PARPs began and maybe also ask you to describe how PARPs actually work. Then we’ll talk about the testing that has to be done in order to utilise PARPs effectively and where we stand in particular as it relates to men with advanced prostate cancer.

JM: Yes, well thank you. Thank you for your kind introduction. PARP inhibitors are a class of drugs that target the mechanism of the tumour cell to cope with external damage. So any cell, tumour or non-tumour cell, is continuously exposed to damage from inside our bodies or from outside – radiation etc. The cell has a number of mechanisms to just repair and carry on. The problem is that we know that some tumours are less capable of doing so and tumours use this defect in the capacity to repair to actually become more aggressive by being easy adaptors to the evolution of the disease. So PARP inhibitors are drugs targeting one of the mechanisms of repairing. The observation that was initially in cell-line models in the laboratory and then later in patients is that those tumours that have reduced capacities to repair external damage, if you actually expose them to a PARP inhibitor that further decreases their capacity to repair, you just basically push them to death because they are unable to maintain a minimum level of repair for the cell to survive. So that was the principle and this class of drugs was initially developed. Then the next observation was that a number of women with breast or ovarian cancer had mutations, so gene alterations, gene twists, in their tumour in two genes in particular called BRCA1 and BRCA2 that were in charge of maintaining this capacity of repairing. Different studies among different populations suggested that in breast and ovarian cancer there were a significant number of patients harbouring these mutations so PARP inhibitors were initially developed in this population. The results were pretty good and actually now several PARP inhibitors by different companies are approved for the treatment of subsets of patients with breast and ovarian cancer.

What has happened in the field of prostate cancer recently is three things. First, that we observe that actually men with advanced prostate cancer do sometimes have the same mutations and that makes sense because these mutations are inherited and don’t make a difference based on gender. Let me say that this is happening more often than we thought, probably because prior studies focussed in men with localised prostate cancer whereas when we move to the more aggressive cases it seems more that we find this mutation more often. The second thing that happened is that we learned that actually sometimes the tumour just spontaneously generates these mutations. We didn’t know about this long ago and it’s happening also in breast and ovarian cancer, maybe in a smaller proportion of patients, but suddenly we thought, okay, it’s not only the patients who inherit the mutation but also some patients that develop this mutation spontaneously that maybe could benefit from these drugs.

The third thing that happened is that when we did a first study testing PARP inhibitors in prostate cancer, one in particular that is called olaparib, we observed that, yes, patients that have these inherited or spontaneous mutations in BRCA1 or BRCA2 seem to respond well to olaparib but we saw some responses in other patients too that we didn’t expect. When we looked at their tumours we saw that many times, not always but many times, these other tumours had mutations in genes that do very similar functions to BRCA1 or BRCA2, suggesting that maybe this effect could be extended beyond this population to other tumours that have other types of difficulties to repair damage to DNA.

NS: This is really great, it’s an observation of seeing these particular gene mutations that were notable in women and then recognising that men also have them too and then taking an approved drug and looking at it in men who had these same mutational events. So thanks to the work that you’ve done, and others, now we have a couple of large phase III trials that are going to read out and potentially we’ll have two different PARP inhibitors available in 2020. I know there are two more PARP inhibitors that are being trialled as well. So suddenly we may have a lot of other options for us to consider for our patients with advanced prostate cancer. But let me ask you a little bit more about the testing. You mentioned that the patients who are particularly responsive had BRCA2 or breast cancer gene 2 and BRCA1 and there’s a whole list of less common ones in the panels that we look at that have these particular gene defects. I’d like you to talk a little bit more about that and then maybe the difference between germline and somatic tissue testing, why one alone is not simply the answer and how do our colleagues, particularly GU oncologists who aren’t treating breast or ovarian cancer, how do they start to think about getting this testing?

JM: The main difference between germline and somatic testing is that when you do testing of germline DNA you are only looking at DNA that your cells have inherited from your parents and the genes, or the gene alterations, you may have in every single cell of your body. When you look at somatic testing, that means looking at the tumour cells and extracting DNA from a sample in the tumour, you are looking also at those things that happen once the tumour has been formed and evolves. We know that not all the BRCA defects in prostate cancer occur from germline mutations but some of them are spontaneous. So by looking only at germline DNA we would be missing many other patients who could potentially benefit from these drugs.

A couple of years ago we did report a large study between the US and UK investigators looking at the prevalence of these inherited mutations, the germline ones, in advanced prostate cancer and we saw that they were occurring more often than we thought. That was enough for the NCCN guidelines to recommend germline testing in all patients with metastatic prostate cancer, not because there was a treatment for them, because at that time, even now, there is no treatment approved yet for them, but because it has implications in identifying families whose members may be at risk of prostate, breast, ovarian or pancreatic cancers. It’s true, we should stop thinking in just BRCA as a women’s thing, it also implies risk for men for other tumours.

So that’s okay but somatic testing also will detect the germline mutations. So somatic testing is probably a more comprehensive way to go but it’s also more challenging. It’s more difficult because it means getting a sample from the tumour, processing it in the right way, sometimes the DNA that we extract from the tumour is highly fragmented and is of poor quality for our test, whereas germline testing is taken from the blood or from the saliva, it’s much more easier technically. So we have to ponder the technical challenge but also the number of patients and being there for every patient that could potentially benefit from the drugs.

NS: Some great points. I think that we need to do, clearly, much better family histories.

JM: Correct.

NS: It’s not enough to have somebody come in, a young man or an older man with aggressive prostate cancer who gives a family history that you can obtain and says, ‘Oh yes, my father died of prostate cancer, my brother has prostate cancer and my mother had pre-menopausal breast cancer. I have a sister who has pancreatic cancer.’ It’s like alarms should be going off that there’s a very high risk that they could have a DNA repair mechanism defect and could be a good candidate, ultimately, for a PARP inhibitor or other genetic sequencing testing and therapeutics that we’re studying. So I think that’s a really important point.

Just so that the audience really understand, in your clinic when you have a patient, and you mentioned the NCCN guidelines which have changed and keep changing to become more inclusive and more expansive for testing, so when you have somebody comes into your clinic who has advanced prostate cancer, whether it’s hormone sensitive or castration resistant, what is your paradigm for both germline and somatic tissue testing?

JM: In my case particularly, I work at an academic institution where we are trying to push forward precision medicine strategies. So I’m lucky to have access to these tests so I’m trying to do somatic testing in every patient with metastatic prostate cancer. However, it is true that this is not happening when you look at the wider picture and why is this? First because not every centre will have the capacity of running these tests, these are complex tests. It’s not only the tests but interpretation of the data – it’s complex and requires some expertise and we need to train the next generation of doctors, urologists, oncologists and in other specialities to understand this data and to be able to use it in the clinic. Also because, of course, it has a cost that we need to see how from the different health systems we can cover it. But I think that all the evidence from these trials, but also other trials that will come, will support implementing testing of the genes in the tumour.

NS: I fully agree. As you’ve already pointed out you can get a blood test, you can get a mucosal saliva and the germline testing and the cost has come down rather significantly worldwide. But it’s important to also get the somatic tissue testing, maybe it’s with a fresh biopsy from a soft tissue lesion which are a little easier to get than, say, a bone lesion. Or maybe it’s using archival samples from a prostatectomy specimen or even the biopsy specimen from the original biopsy. Because it increases your yield and the somatic testing from just the germline alone and why is that important? Because in the near term we have potential actionable information of PARP inhibitors that hopefully will be approved very soon.

JM: Totally. And tomorrow maybe PARP inhibitors but maybe in two years it’s another drug to another target so doing more comprehensive profiling on the tumours would also help us understand which are the other targets that we can target in the future that maybe today we don’t even know about.

NS: It’s an incredibly important point. And then PTEN loss, PIK3/AKT, there are so many of these out there and if you have the information then you can really help patients. Then, as you also said, the cascade genetic testing implications for family members, other family members, to know that they may benefit from more intensive screening looking for other risks of cancer. So I think with that, Joaquin, that’s a great summary. Any last thoughts, so if you’re a busy medical oncologist, uro-oncologist out in the community, what are some tips or advice you would give regarding testing and things that are going to happen in the near-term future?

JM: I think that it’s important that we all, physicians at our sites, take a moment to look at what am I missing at my site? What resources would I need and sometimes maybe access to the technology? But that’s normally easy to overcome by collaborating with either academic or private laboratories that can do the test. Is it expertise at the time of interpreting the data? Is it access to these drugs, depending on the health system you’re working in? I think that doing this reflection teaches us what do we need to be ready for when this becomes standard of care for everyone is important now because we are not going to fix it from today to tomorrow. This takes time, this is a complex issue, it can lead to a lot of frustration when you order genetic tests and you just get inconclusive results coming back. So we need to get ready for a different way to manage prostate cancer that we hope can help our patients better by treating them in a more precise way.

NS: I love your point about the burden, and it’s a good burden, is on all of us who treat men with advanced prostate cancer to become more educated and get experience and comfort. It’s always great to say, ‘Oh, I have a certified genetic counsellor that I can work with,’ but not everyone has that. Not getting the testing and not getting the information is not the solution but for us to all become better educated. So thank you for the great work that you’ve presented here at ASCO this year on PARP inhibition and the trials that you’ve been leading. So with that I want to again thank ecancer for putting on this programme, I hope this was informative for you. Things are really changing for our advanced prostate cancer patients and a lot of different opportunities to help them. Thanks very much.