NS: Hello, my name is Neal Shore, I’m a uro-oncologist from South Carolina in the US. It’s a great pleasure and privilege for me to be with two of my very close colleagues and really good friends, Joaquin Mateo from Barcelona, Spain, Karim Fizazi from Paris, France. What an honour to present to you today on behalf of ecancer some of the really most relevant and interesting aspects of ASCO 2019. We’re going to focus today on some of the new data that’s coming out in castration resistant prostate cancer or, for many of us who are not really devotees of the field, patients with advanced prostate cancer when traditional first line treatment such as hormone suppression are no longer working.
Prior to 2004 we didn’t have any therapeutics approved to prolong survival for men who had metastatic castration resistant prostate cancer after they had progressed after androgen deprivation therapy. So in 2004 we see the approval of the first taxane, docetaxel, a microtubulin inhibitor. Then six years later in the US we received the approval of sipuleucel-T, it works on T-cell activation. And then very quickly after that in 2011 we saw the approval of cabazitaxel, a second taxane that had prolongation of survival in men who had progressed after docetaxel exposure. Then very rapidly, almost at the same time, we had the approval of a first oral agent, abiraterone acetate with prednisone, in the post chemotherapy setting followed by enzalutamide in the post-chemotherapy setting. Both of these oral novel hormonal agents prolong survival. Very soon after that we had pre-chemotherapy studies for both abiraterone acetate and enzalutamide also demonstrating survival prolongation. So suddenly we had two novel hormonal oral agents, an immunotherapeutic, as well as two taxanes. Then shortly after that we saw the approval of the first radiopharmaceutical, Radium-223, which also had prolongation of survival, in 2013. Most recently, a year ago, we had the development or the approval of another novel hormonal agent which delayed what’s known as metastasis free survival known as apalutamide. So it has really been a tremendous amount of advancement in the last nine years. Moving forward we’re going to discuss today the role of another novel oral therapy known as PARP inhibition and we’ll talk about some of the other therapies that are in additional trial development.
So, gentlemen, thank you so much for being here. ASCO 2019, always great, always a lot of interesting information. Let me start with you, Joaquin, you gave a wonderful presentation on work that you had done previously on molecules known as PARPs. So what I’d like you to address is a little bit about how do PARPs work but, most importantly, about TOPARP-A and really what you presented this year, as in TOPARP-B, some follow-up, really profound, interesting data.
JM: Thank you. This is work that we started a few years back with the idea that maybe there are some prostate cancers that deserve a different way of treatment rather than the drugs we’re using in the majority because of having a specific biological characteristic that other prostate cancers don’t have. So the challenge we are facing is, one, to find these drugs, to prove that they work, but also at the same time to understand what is the best strategy to find those patients who are going to benefit from these drugs. This is why we ran this trial that has several steps. In the first part that is called TOPARP-A, we reported this a few years back, what we did is we gave this drug olaparib that is a PARP inhibitor to a group of patients with advanced prostate cancer without looking a priori to the different characteristics in terms of the biology of the tumours, we just treat them all and then correlated whether they did well or not with the treatment with the biology of the tumour. What we found is that those tumours that are incapable to repair the damage, the damage is the insult that the tumour cells are having all the time, were more likely to develop a response to olaparib. That made sense based on other studies in ovarian or breast cancer and other tumour types that suggested that those patients, primarily women because it was primarily in breast and ovarian cancer, that had mutations in a gene called BRCA, there are two actually, BRCA1 and BRCA2, that renders the tumour incapable of repairing this damage were highly likely to respond to this drug.
So in prostate cancer we saw the same. The difference that we observed were actually that it was not only when you inherit this mutation from your father or your mother but actually in some cases it’s the tumours that develop this mutation spontaneously. It was very interesting to see that some patients that did not have this mutation but had a mutation in other genes that do a similar function also were responding to the drug. So this is why we did the second study that is called TOPARP-B that I presented here at ASCO ’19, on a larger population where all the patients were selected based on sequencing of the tumour first to look at these particular mutations. We treated a group of around 90 patients that had mutations in all these genes.
What we saw is that, again, those who had these mutations in the BRCA genes, regardless of whether it was inherited or developed in the tumour, had very nice responses, like four out of five responded to the drug in a group of 30 people and most of them for a long period of time. And again we saw some responses in patients that had mutations in other genes but we are basically facing two big challenges. One, some of these genes are really infrequent so it’s very difficult to validate the rate in a big population and the other is that some of the genes that are more frequent, and there is one called ATM, sometimes we see some responses but many times we don’t. As of now we are still incapable of differentiating which of the patients with mutations in this ATM gene will be in the group that may benefit a bit or the ones that are not benefitting at all. That’s probably the homework that we are taking home from this meeting.
NS: That’s a great summary, a lot of really important data. Oral medication that has a compendium diagnostic to it by looking at the genetic profile, that really speaks towards more precision therapeutic, right? So the three of us are all part of a larger phase III trial now known as the PROfound. So, Karim, your thoughts on the role for PARPs and what are you looking forward to in terms of that trial, perhaps also the trial of another PARP inhibitor known as the TRITON trial as well?
KF: As you rightly said, probably the first time we will really enter the precision medicine history for prostate cancer with the PARP inhibitors. It really seems, again this is still debatable and controversial, but it really seems that we are quite able to identify who are the patients that might benefit. Of course they don’t benefit 100% of them but obviously patients with BRCA1 or BRCA2 mutations are very good candidates for benefit. Some other genes that are rarer, as was just said by Joaquin. Now ATM I’m still struggling with the idea and we probably need more data, but obviously across the programmes olaparib, rucaparib, niraparib, we don’t see much benefit for ATM patients.
Now, I’m saying that it’s controversial because there are also some data suggesting that if you combine olaparib with abiraterone you have superiority, or you may have superiority, over abiraterone alone in a randomised phase II trial. But you and me are old enough to have seen so many positive, apparently positive, randomised phase II trials that did not convert into or translate into phase III positive trials. So I do think that the PARP inhibitors will be much more for patients with mutations. Now, the open questions, or among the open questions, are does the efficacy that we see long enough to be meaningful for patients? That is a very important question because even patients with BRCA1 and BRCA2 who respond may not benefit long enough so this is really something we need to figure out. As you said, PROfound will tell us and tell us whether not only they respond but also whether progression free survival is being postponed. Of course I really hope it is and we should not wait very long to know which is also very nice. Super-big, worldwide effort to conduct PROfound, thousands of men screened, many centres open. It is doable to do that at a global level and we will soon have the answer which is, by itself, very, very important.
NS: I think you’re absolutely right. In some of the TOPARP-B you had some patients there who had really tremendous durability of response.
JM: For some of them they did and these were patients in the third line or later stage or patients that, unfortunately, had very advanced disease. So in those patients it is true that we achieve very long-lasting responses but in some of them only. Again we need to get better in understanding who is the subset that derives the most benefit.
KF: And perhaps also on top of that why patients do not benefit or why don’t they benefit anymore. Perhaps we can circumvent that.
NS: Yes, like in so many other studies, both TRITON-3 and PROfound are in very heavily pre-treated patients, some of the sickest, but yet with reasonable performance status. So I think that data will be forthcoming relatively soon. It’s certainly possible that some time in 2020 both of these drugs could be approved and available for further consideration. So the field continues to blossom. I would be remiss if I didn’t have an opportunity here to cover some additional CRPC things that have happened in the last few months. Karim, you were the principle investigator for the ARAMIS trial, maybe just a sentence or two about what’s interesting about that study?
KF: That’s also a nice story because darolutamide is a drug which was invented in Finland that we tested in phase I and virtually all the patients in the phase I programme benefitted, it was really impressive – first patient, second patient etc. etc. And it was quite non-toxic – during the phase I actually we decided to stop the phase I dose escalation due to PK data, not due to dose limiting toxicities. Then ARAMIS was the very first phase III trial, pivotal trial, testing the drug in the non-metastatic castration resistant space and, as you know, we were able to establish that the primary endpoint of metastasis free survival was significantly and, I believe, very clinically meaningfully improved with about a 60% reduction in risk. Overall survival is still immature at this point, still we see a three year rate of 73% versus 83% for darolutamide. On top of that, the quality of life data that we just reported are very reassuring. Basically we are maintaining quality of life in these men, mostly asymptomatic, we are reducing the risk of pain deterioration, we are reducing the risk of local symptoms because some of these men actually have local progression and not necessarily metastatic deposits that we were not able to see on the imaging. So all green lights on top of a safety profile which is just neat. Even the slight difference in fatigue, 16% rate versus 11% with placebo totally disappeared when adjusted by duration of exposure. All the rest is basically nothing – no cognitive impairment, no hypertension etc. So a very nice profile and hopefully we will have soon this drug for the patients.
NS: Yes, so it’s another great advance, right? So now we’ll have a third drug potentially approved. It’s not approved yet but it’s up in front of various regulatory authorities. It will be another great possibility for physicians to treat patients with mCRPC with what appears to be a much cleaner profile. But let’s talk about some of the earlier phase but really interesting therapeutics. Actually, one is in the phase III and that’s the PSMA antibody-drug conjugate with lutetium also known as the VISION trial. I’d like to also talk about this concept of BiTE technology, B-i-T-E, maybe Joaquin you want to tackle one of those?
JM: I think that overall targeting PSMA is showing to be a very promising strategy in prostate cancer. Probably we still have to get a bit better at it because we still don’t understand exactly how the expression of this biomarker works throughout the evolution of the disease. But clearly the data is very compelling in terms of patients benefitting from the drug and hopefully these trials that you mentioned will help us to position it in the landscape of treatment for patients.
NS: So you and I are both doing the VISION trial, there are 60 sites worldwide, 30 in North America, 30 mostly in Europe. So these are patients who are heavily pre-treated, they’ve been exposed to usually at least one or two NHAs, clearly have had taxane progression. Then we get this PSMA antibody conjugate with lutetium. How has your experience been so far? Certainly we’ve seen a lot of lutetium-based institutional trials going on in Germany but this is really, to my understanding, the most unique phase III trial prospectively performed to really get an answer to the validity of using this therapy.
KF: That’s correct in this setting and with this design. There is actually a second phase III trial against cabazitaxel but you’re very right, this is really the first time we will know truly what we are doing with PSMA lutetium to older patients. The population is a population of quite advanced men with prostate cancer, they have exhausted most of the existing treatments, they might or might not have received cabazitaxel and radium might be also an option. But honestly there’s not much remaining.
In my experience, but again we will need phase III data, PSMA lutetium is usually quite well tolerated. Of course patients might complain from dry mouth and this is because the salivary gland expresses PSMA, but it’s not something very bad, let’s call it like this, in my experience from my patients telling me it’s okay mostly. Some of them might also experience some GI tract symptoms because also PSMA is slightly expressed in the GI tract. So nausea can be a symptom, you need to use drugs that are preventing nausea. But, again, generally speaking it’s quite well tolerated, infusions are being given once every six weeks or so. The data from Germany and also those from Australia that were reported a year ago are quite compelling. That’s also, to be honest, my experience in the few patients that either I treated in the trial or who I sent to Germany in the last years. Many patients seem to be benefitting and generally it’s a quite tolerable treatment.
NS: That’s a really great summary. We’re enrolling patients in that study now, I think it’s enrolling very fast. It strikes me that here we are right now, 2019, we have six therapeutics that have been approved that are life prolonging and then with the potential for PARP phase III roll-outs that will similarly lead to a potential survival prolongation and then PSMA lutetium, we could in the very near term have seven, eight, additional classes of therapeutics that prolong survival to patients who heretofore has been a really big unmet need. We have significant prostate cancer caused specific mortality globally. So we’re able to keep patients longer alive and also keeping them with fairly good quality of life. As you said, in the data that you presented here at ASCO on darolutamide, that was particularly impressive.
But let’s talk a little bit, and we have a few minutes left, about another really cutting edge. We mentioned a second ago this concept of BiTE technology which I think is absolutely fascinating, at least to me. It’s essentially taking an immunotherapeutic and combining the tumour cell and the T-cell without necessarily a payload but working to basically combine the target so you end up getting an apoptotic effect. Your thoughts, gentlemen, on the BiTE technology?
KF: As you said, it’s really promising, it’s smart which we all like. Based on what we know from the immunotherapy treatments, even in other cancers in the last years, it obviously has a potential in different cancers including prostate cancer. It’s even better when you do have a strong target that you can target, for example PSMA is one. It’s quite broadly expressed in many CRPCs, most men with CRPC actually have PSMA positive cancers which doesn’t mean, by the way, that all their cells are positive which is still an issue. But still we’re not talking about a minority of men with a biomarker that you need to identify etc. So I think the BiTE technology is very nice, of course there are side effects so we need to learn how to deal with them and be cautious. But it’s definitely worth pursuing and there are several PSMA BiTEs that are currently under development, including some with no need for continuous infusion, by the way.
NS: So arguably another pathway that could be quite disruptive, especially for patients who have potentially failed other lines of therapy and have been heavily pre-treated with large tumour burdens. So, Joaquin, maybe some final thoughts? Because thanks to all the work that you’ve done really pioneering…
JM: And many others.
NS: And many others but they’re not here right now. But, yes, you’re absolutely right. But with PARPs, for our colleagues who are listening, oral medication but if we combine them or if we use them as stand-alone therapy, what are some advice or some experience you’ve had in terms of adverse event profile?
JM: The adverse event profile of PARP inhibitors is quite well described because, as I was mentioning earlier, these drugs have been used and actually are approved as several PARP inhibitors for women with breast and ovarian cancer or with subtypes of these diseases. The main side effects that we are observing are haematological toxicity, so a decrease in the haemoglobin or the blood cell count or the platelet count, and that just requires some monitoring from the physicians checking blood tests and stopping the drug every now and then when it’s necessary. It is true that in the ovarian cancer studies that were the original studies there were some issues with nausea and vomiting which actually in prostate cancer we have not seen much, you would agree? Probably because of the different distribution of the disease for patients with advanced prostate cancer compared to women with ovarian cancer that have much more disease in the abdomen and maybe that also affects how they tolerate these drugs.
NS: And we’ll have an opportunity to talk more about this but in order to really carefully and appropriately utilise these drugs, at least on trial for men with prostate cancer, for women who have metastatic breast or ovarian cancer, there has to be either a germline or somatic tissue testing to delineate that they have BRCA1, BRCA2 or some of the rare HDR defects.
JM: Yes, and until now this testing in other diseases was done basically based on germline DNA, so looking for inherited mutations. In prostate cancer but also in other tumour types, today there was another presentation in breast cancer, very interesting, is seeing that these responses also can occur when these mutations arise spontaneously in the tumour and were not inherited. So that means that the field should progressively be more forward towards testing the tumour rather than the germline DNA which is important but testing the tumour will also tell you about the germline defects. Of course testing the germline DNA has implications for the identification of families at risk of developing other cancers so we still have to pay attention to it. But in order to implement these drugs in clinical practice we have to get better at tumour testing.
NS: Great points. So on behalf of ecancer, Karim and Joaquin thank you so much. Thanks for everything that you do, thanks for all the research and the papers that you’re writing and the education. We really thank you and hope that this was beneficial and inspiring for additional trial enrolment and also look forward to the therapeutics that hopefully we’ll see to expand our ability to take care of our patients with advanced prostate cancer. Thanks very much.