Metastatic CRPC: Expert Insights and Strategies for Combining Therapeutic Approaches 

 

So why target DNA repair in prostate cancer?

 

[00:35:20]

 

DNA Repair Pathways

 

These are the DNA repair pathways. Without getting into too much detail, these are the most commonly recognized pathways through which DNA repairs itself. We are all aware of mismatch repair, single strand breaks and double strand breaks. Just for the sake of recollection, when cells undergo single strand breaks, they are quickly repaired by the enzyme PARP 1 and 2. So PARP, poly (ADP-ribose) polymerase, repairs the single strand break using the base excision repair mechanism.

 

Now somehow if for any reason PARP does not work, that single strand break becomes a double strand break at the time of next DNA replication. And now double strand break, as we can see is not compatible with an intact DNA. And here is where homologous recombination repair process comes into action and repairs the double strand DNA break with the help of all these players. We know them: BRCA2 and many others here. And if they do not do a good job, if somehow homologous recombination repair is deficient, the DNA is repaired through an error prone mechanism known as non-homologous recombination repair. And if this goes on for too long, that becomes incompatible with the survival of the cell.

 

So really, we need cells to do 2 things; make their PARP continue with this action of repairing the single strand break by base excision repair, and when double strand breaks happen, we need homologous recombination repair mechanism to be intact.

 

[00:37:19]

 

From BER to HRR: PARP Inhibition in Cell With HRR Function

 

And this is another way to explain this. So we can see here in this picture, the single strand DNA damage happens, the PARP somehow does not do a good job. And then homologous recombination repair has to come into action. So we can see here that PARP inhibition can affect both the single strand DNA repair and the double strand DNA repair mechanisms. We also know that some of the PARP inhibitors, they can trap PARP at the replication fork. And if that happens, the whole replication stalls. And these are the different ways PARP inhibitors can work. They can stop the PARP from repairing the single strand break and they can trap the PARP at the replication fork.

 

[00:38:19]

 

HRR Mutations Occur in 25% of Patients With mCRPC

 

So why should we be doing this? We know that homologous recombination repair mutations occur in 25% of patients with MCRPC. And these are the seminal studies which showed the presence of these mutations. These are some of the studies, not all the studies, but PROfound trial, for example, showed that about 30% or 28% of these patients had DNA repair defects or homologous recombination repair mutations. We also know from the other paper that these germlines, we call them germline pathogenic variants, which are essentially inherited and shared with siblings and with the children, and this can be present in about 11% of patients with metastatic prostate cancer. And I have a suspicion with the evolving ctDNA technology and tissue sequencing technology, we will find these mutations in more patients.

 

[00:39:31]

 

HRR Pathways Can Be Deficient in Germline DNA, Tumor DNA, or Both

 

And this is a snapshot of which I just mentioned. And that HRR pathways can be deficient in germline DNA and the tumor or tumor DNA or both. And that is why it is extremely important to test for both somatic and germline DNA.

 

[00:39:53]

 

HRR Mutation Testing

 

Sample Sources for Biomarker Testing: Tumor vs Liquid Biopsy

 

And these are the different aspects of tumor biopsy and liquid biopsy. What should we do? I think we should do tumor biopsy first. If that is not helpful, we can do liquid biopsies or ctDNA testing. Fortunately, both technologies are much more advanced that we are likely going to get good results if these tissues are fresh enough.

 

[00:40:13]

 

When to Test: Prostate Cancer Disease States

 

And metastatic prostate cancer setting is the setting where pretty much all guidelines endorse testing for tissue testing and germline testing.

 

[00:40:23]

 

Who to Test: Updated ASCO 2025 Guidelines for Genomic Testing in Metastatic Prostate Cancer

 

These are the ASCO guidelines, and this is the last slide in this section. I know I am over time. That ASCO guidelines clearly recommend every single patient with metastatic prostate cancer should be tested with both somatic and germline testing, and also recommend retesting at the time of disease progression in those patients who did not have positive testing to begin with. So guidelines are very clear. Unfortunately, most patients in the real world are not getting tested and we have to change that.

 

[00:41:01]

 

Current Guideline Recommendations for Somatic (Tumor) Testing

 

And these are the genes which are being covered by these testing recommendations. But if you order a comprehensive genomic profiling, then these genes are automatically covered.

 

[00:41:18]

 

Posttest 1

 

With that, now let us go back to our question. This is the posttest based on the current ASCO guidelines, which are the following best describes the recommended approach to testing for HRR alterations in patients with metastatic prostate cancer?

 

[00:41:52]

 

Alright, so most of the colleagues have responded that somatic testing should be done and germline testing should be done in all patients. So that was the right answer.

 

[00:42:09]

 

Panel Discussion and Audience Q&A

 

With that, we will start the panel discussion and question answer. So please pick up your iPads and ask questions, and I will be seeing the questions here both from online participants and the in-person participants. So any questions regarding genetic counseling? Any hurdles you are encountering in the clinic? We used to have a lot of hurdles until we streamlined our process.

 

Karim Fizazi (Gustave Roussy, France): Neeraj, maybe I can start asking you a question. So here in the us what is the main limitation for actually having patients benefiting from a test? Is that more knowledge simply from patients and doctors, or is that more of a cost of the insurance saying no? What do you think is the main limitation?

 

Neeraj Agarwal: I think the combination of all of this.

 

Karim Fizazi: Okay. Rana?

 

Rana McKay (University of California San Diego): Yes, absolutely. I think it is a combination. I think it is, you know, 1, doctor's offering, patients actually understanding the implications of the test. For germline testing, you know, there can be considerations to be had around even though there's protection for insurance coverage and any sort of like pre-existing conditions, there are considerations to be had for testing children and family members. I think other things, a lot of these tests are not in-house tests. They are external tests through external vendors. So a physician would need to know how to get that set up and send the specimen outside the institution. I think there is a lot of you know, complexity, but quite honestly, I think it is becoming increasingly easier and easier and easier to test. And additional guidelines reinforcing testing has helped with access. So I think we are beginning to overcome some of those. But yes.

 

Neeraj Agarwal: One of the other hurdles which I have seen in patients in the US, the most common way to diagnose prostate cancer is localized prostate cancer. And they get surgery or radiation. So 90% of patients in the US are diagnosed to have prostate cancer in the localized form or locally advanced form. And sometimes by the time they are developing metastatic prostate cancer, tissue is so old and is not able to provide sufficient quantity or quality of testing. So I have had patients who had metachronous or non-de novo metastatic prostate cancer and I send their tissue for testing and if they are more than 5 years old, most of the Clear certified labs will not do the test. They will fail the tissue. And all of us know how difficult it is to do test or a new biopsy in our older patients who have only bone metastasis and often decalcification can lead to unviable tissue. So that is something else which came to my mind.

 

Rana McKay: I think there is a lot of variability in where people get their care. There are some people that are seeing a urologist, there are some people that are seeing a medical oncologist, maybe it is a radiation oncologist who is following them. And I think there may be different pressures within those clinical settings to trigger getting a test.

 

Neeraj Agarwal: So let me ask you this question. Do you have any preference for any particular lab for testing? So in the US there are major players, which one do you prefer? Do you have any preference or you just think most of them are going to provide sufficient information to utilize PARP inhibitors in this context?

 

Rana McKay: I am more than happy to chime in. So, you know, a lot of patients will come in and say, well, ‘I have had my 23andMe, and I know that I am of this ancestry and that ancestry.’ 23andMe or a test like that is not a sufficient germline test. The negative predictive value is not where it needs to be up in like the high 90s. So, but there's a lot of other vendors, you know, whether it be Invitae or Ambry or you know, Color Genomics, and I think those tests that have a high positive and a high negative predictive value are what is needed for a germline test.

 

Neeraj Agarwal: Yes.

 

Rana McKay: And there's some institutions that actually will have an in-house assay as well.

 

Neeraj Agarwal: Yes. How does in France?

 

Karim Fizazi: We have a different system. For germline testing, this would be definitely in-house. And we have a system to validate different labs, academic labs and cross validation. But that is not commercial labs at all. For somatic it is a bit different. It is a mix of in-house and commercial. It is really a mix of the 2.

 

I think that the big thing, maybe we will speak about it, which I think is a big progress, is really ctDNA for prostate cancer because as you said sometimes the tissue is old when it is a prostatectomy specimen or biopsy samples. And as you said, metastatic prostate cancer is a bone disease. So biopsying the bone is not easy, and then you have decalcification issues. So ctDNA is I think really a big plus for the prostate cancer patients with advanced disease. And usually when ctDNA is sufficient in quantity, picking up the mutation is quite easy with most tests. Deletions is sometimes another story, that is more difficult. You really need to have a sufficient and quite high amount of DNA from the blood. But mutations are actually very easy to collect and usually you can rely on the ctDNA findings.

 

Neeraj Agarwal: And ctDNA technology has evolved so much in last 7, 8 years that they have become quite sensitive in picking up all these mutations. You know, when you are ordering ctDNA testing, so we are getting some questions, when you are ordering ctDNA testing in a newly diagnosed metastatic prostate cancer, do you order them after you have started treatment? Before starting the treatment? How soon after starting the treatment? Any idea, what should we do in our clinics?

 

Rana McKay: I mean, ideally you want to order the tests when the tumor burden is sufficient and they are not on a therapy that is going to be highly effective, where you can actually detect the circulating tumor DNA in the bloodstream. And so I like to try to order the test before they have started their hormonal therapy. Sometimes that may not be feasible. Sometimes they have already started ADT and maybe they are seeing you in medical oncology for therapy escalation. I still think it is of value to order the test, understanding that the yield could be impacted depending on somebody's systemic response and how far into the treatment you are actually doing the actual test. And there are things, I think, in prostate cancer that we need to be mindful of about ctDNA testing. You know, burden of disease is going to impact whether you get a positive test. There can also be germline alterations and most tests may not necessarily be equipped to report out on germline alterations, but they will report out on variants of uncertain significance and then you have to sort of look at the allele fraction to see, ‘Oh gosh, the allele fraction is close to, you know, between 40 and 60%.’ That you may think that that is a germline alteration.

 

And I think the other thing that is unique to our patient population, given we are treating older individuals who have prostate cancer, is we can see CHIP, which is clonal hematopoiesis of indeterminate significance. Sometimes that can happen in genes like ATM, which may not necessarily be in the tumor, but may just rather be in somebody's normal cells just as a product of aging. So I think there are some considerations around ctDNA that you have to be cognizant of. But I think as Dr Fizazi was saying, the point mutations are highly reliable from ctDNA. If you detect a point mutation, that is real.

 

Neeraj Agarwal: Yes, and all those are great points. I also recently learned, I was surprised that ctDNA fraction goes down within 2 or 3 days of starting ADT. I used to have a cutoff of 7 or 10 days. Now I am not starting anyone on these hormonal therapies until I have sent out the ctDNA testing. So if a patient reports during the weekend with really high volume metastatic prostate cancer, I may start them on bicalutamide, but I do not start them on injections until we send out the ctDNA testing during the weekdays.

 

One of the questions is how do, how would you help encourage or support genetic testing given slow rate of adoption? And this especially concerns, I will not say the specialty name here, but say you are not a medical oncologist and you are seeing the patient and you are not sending, what should we do about this? Because testing is less often being done by certain specialties.

 

Rana McKay: I mean, I think that it is all about education and all about making the path really simple for people in the clinic who have a busy clinic, they are seeing a lot of patients, making it really easy to get the test. And also patient education also I think is helpful. And I think a lot of times, you know, I do not know if you feel this way for our patients with prostate cancer is talking to the children or getting the message out to like the family members that, and to the patient that, hey, this could affect your daughters for breast cancer, it could affect your sons for… you know, sometimes the patient does not really care about themselves, they, but if you tell them it is going to affect their family member or their child, you know, that really changes the context. So I think it is education and making it easy, you know, educating the doctors, educating the APPs. A lot of practices have nursing support, mid-level AP advanced practice providers, and sometimes they probably do a better job than others in ordering the test.

 

Neeraj Agarwal: Yes. Any other comment before we conclude this section? Karim?

 

Karim Fizazi: About testing? Well, I think your message was clear. We need to test. That is very important for the patient himself and for the rest of the family. Germline testing will allow you potentially to save a woman's life from dying from ovarian cancer, simply. So that is very important.

 

Neeraj Agarwal: Okay. Thank you very much. This this concludes this section and we will move on to Dr Fizazi.

 

[00:53:19]

 

PARP Inhibitors as Single Agents in mCRPC

 

Dr Karim Fizazi: Thank you very much, Neeraj. So, my task now is, is to try to briefly summarize the role of PARP inhibitors when used as single agents. And we now do have level 1 evidence and quite strong data about this.

 

[00:53:35]

 

Poll 3

 

So I have a question for you first. Let us say this is a 65-year-old typical patient with metastatic castration resistant disease. He already exhausted an androgen receptor pathway inhibitor, the one you like, abiraterone, enzalutamide, darolutamide or apalutamide, and obviously the cancer is now progressing. So would you currently recommend testing for somatic alterations of DNA damage repair genes? Yes or no? Or you just do not know?

 

[00:54:23]

 

Okay, I think we can move to the next one. Yes, that is very obvious. I guess you will have a direct, I mean, you may expect direct consequences to this gentleman’s management given he has already exhausted an ARPI. So I think this is really key. So thank you.

 

[00:54:45]

 

Poll 4

 

Let us move to the next slide. So in this scenario, if a bracket 2 gene alteration is found on somatic testing invest in this patient with MCRPC and no family history of cancer, would you recommend systematic germline testing or not? Okay, vote.

 

[00:55:19]

 

So BRCA2 and somatic, no family history is 65-year-old. Yes, I agree with you. You cannot predict a germline alteration just based on the family history. And this also applies to age by the way. I saw patients with family history who were 80 years old. So it is not only young folks with a terrible family of cancers, so we have to test, that is really important. Next, please.

 

[00:55:43]

 

Pretest 2

 

So still the very same patient. Progression on an ARPI, he has the somatic bracket 2 deletion. Which of the following would you recommend? And let us say that everything is available, do not think about money or anything, it is just about medicine. Docetaxel, Lutetium PSM, a PARP inhibitor, second ARPI, PARP inhibitor plus a second ARPI; what would be your preferred choice in this scenario? Please vote.

 

[00:56:25]

 

Right. Okay, I guess I will comment on that one afterwards. Next, please.

 

[00:56:33]

 

Defects in DNA Damage Repair Pathway

 

Alright, I will be really brief on that because Neeraj already explained you about the main enzyme that we know that can fix DNA damage, and indeed most importantly, we have enzyme fortunately to salvage all the DNA from single strand breaks and some other enzyme that can fix double strand break.

 

[00:56:58]

 

BRCA-Related Synthetic Lethality With PARP Inhibition

 

What is actually important in the story for cancer is that it is a 2 hit story. Basically, if a PARP works, DNA will be repaired in case of a single strain break. If you use a PARP inhibitor but the homologous recommendation system works, also this will fix a double strand break. But if you have the 2 events, both a PARP inhibitor and a homologous recommendation that is missing or not working properly, then you may end up with hopefully cancer cell death.

 

[00:57:40]

 

DNA Repair and Prostate Cancer

 

Why DNA repair is important? Overall, approximately 20-25% of all patients have at least 1 DNA repair defects in their genes or proteins. And obviously the definition depends on which gene you are looking at, which alterations, and you will see that they are not made equal. And I will come back to that in a second.

 

[00:58:08]

 

Phase III PROfound: Olaparib vs Physician’s Choice in Progressing mCRPC With HRR Gene Alterations

 

But this clearly, with the ground for developing PARP inhibitors, for the sake of time, we won't show you much of the phase I and phase II experience, but clearly there is signal for efficacy. And then the PROfound phase III trial was really the first one to deliver and to show benefit. In this particular phase III trial there were 2 cohorts. One was made with the genes most likely to benefit from a PARP inhibitor, at least based on the knowledge of this time: BRCA2, BRCA1 and ATM. ATM was mostly added because it is also quite frequent.

 

And cohort B was made by other alterations, which we did not know well at this time whether they might actually benefit from PARP inhibition. And it was a quite long list of rare genes or rare alterations.

 

Anyway, all patients had MCRPC, they had exhausted 1 AR pathway inhibitor, sometimes more treatments. And actually many of these men had exhausted docetaxel as well. So they had quite advanced disease. They were randomized to receive either Olaparib single agent or a physician choice of treatment, which was really mostly a second AR pathway inhibitor. And there was a crossover when the data were out.

 

[00:59:45]

 

PROfound: rPFS and OS in Cohort A With BRCA1, BRCA2, or ATM Mutations

 

So this slide shows you basically the first success in phase III trials with the PARP inhibitors. rPFS was dramatically improved with approximately 70% reduction in the risk, or 65%, let us say, median 7.4 vs 3.6. But most importantly, overall survival was also improved in this first cohort of men. Again, those with BRCA2 alterations, BRCA1 and ATM. So that was really good news.

 

[01:00:25]

 

PROfound: OS in Cohort B With Alterations Other Than BRCA1, BRCA2, or ATM Mutations

 

On the other hand, the second cohort did not really benefit, as you see, and this was true for both rPFS and for overall survival. And even adjusting for crossover, it was a bit better, but still not really significant. And again, it is a mixed bag of very different alterations.

 

[01:00:45]

 

PROfound: Safety (Cohorts A + B)

 

Obviously, that did not come without some toxicities. And this is true across the board when we speak about PARP inhibitors, you will see hematological toxicity, mostly anemia with olaparib, but also GI tract toxicity. The GI toxicity is usually not that hard to circumvent; diarrhea, nausea, but we have drug to deal with that. Anemia is much more difficult to deal with. And basically you need most often either to dose reduce, transfuse your patients, give them a break, all those things. And by the way, there, there was also an excess in pulmonary embolism in this trial. So this really was the first trial.

 

[01:01:30]

 

TRITON3: Rucaparib vs Physician’s Choice in Progressing mCRPC With BRCA1/2 or ATM Alterations

 

The second trial actually addressed almost the same question, should we use or not a PARP inhibitor as a single agent? But this time in an earlier setting, in patients with MCRPC who had exhausted only an ARPI but not docetaxel chemotherapy. This time Rucaparib was tested and patients had alterations in BRCA2, BRCA1 or ATM.

 

The beauty in this trial, and obviously I am biased here, but the control arm was actually a physician choice of either a second ARPI, which we started at this time to know that it was not very efficacious, or docetaxel, mostly reflecting how we were actually treating patients who had exhausted an ARPI. In some patients, we would go for docetaxel, in some others we would give it a chance to the second ARPI if they were frailer or not willing to go for chemo. So really reflecting the practice.

 

[01:02:39]

 

TRITON3: rPFS (BRCA Subgroup) by Physician’s Choice Treatment

 

The trial was positive as a whole with this primary and by its primary endpoint of [inaudible] progression-free survival. But actually, very importantly I think, and I guess this was the first time, both control arms were actually beaten. The second generation, second ARPI, but this was expected, I guess because we all know it does not really work well. But probably for the first time in 20 years, docetaxel lost a battle against a new drug, which was better, and I guess clearly better. So this, this was really good.

 

[01:03:22]

 

TRITON3: Do Patients With ATM Mutations Benefit From PARPi?

 

Also, what we learned from the second phase III trial was that the most frequent genes, again, are not made equals in terms of predicting for benefit. BRCA1 or BRCA2, clear benefit for the PARP inhibitor. While for ATM, there was really no benefit from the PARP inhibitor. And remember in the first trial, these patients were pulled together, if you will. So that was very, I guess, informative for decision making.

 

[01:03:57]

 

TRITON3: Survival Benefits by Mutated Gene (FDA Pooled Analysis)

 

There were some other trials and the FDA, which has the possibility to collect all data from everybody, can actually do what we cannot do or what the pharma industry cannot do, which is basically pulling together data and ending up with sufficient numbers for patients with rare alterations. And what they were able to show, and I think this is important, was that patients with BRCA1, BRCA2, CDK12 or PALB2, appear to benefit in terms of efficacy from a PARP inhibitor. While those with CHEK2 and probably most patients with ATM alterations, just do not benefit. So again, this is, I think, super helpful when it comes to making decisions when you are seeing a patient and your reading his test results.

 

[01:04:57]

 

Conclusion: PARP Inhibitors in Prostate Cancer

 

So in conclusion, these 2 phase III trials demonstrated that there is a clear role for PARP inhibitors in metastatic castration resistant disease with selected DNA damage repair alterations. This is crystal clear, true for BRCA2. Overall survival is dramatically improved on top of, of course, many other clinical benefits, quality of life, pain, et cetera. And clinically it is super obvious. You will see patients coming back to you after a week and saying, thank you, doctor, I am released. I am not suffering anymore. And it is really true. It is also probably very true also for BRCA1 PALB2 and CDK12. I am saying likely because those alterations are rarer, so it is always more difficult to make sure, but I think we have now a quite a clear demonstration.

 

On the other hand, there is really moderate efficacy and debatable benefit risk balance for men with MCRPC without dose alterations. So again, coming back to Neeraj's first talk, testing is key because otherwise you will not know whether your patient has X or Y alterations. And early use currently being evaluated, we will see more data at the ASCA congress. So looking forward to that. And Dr McKay is also going to speak about early use in MCRPC.

 

[01:06:30]

 

Now, let’s go back to our question

 

Let us go back to our questions about my patients with BRCA2 alterations and CRPC.

 

[01:06:37]

 

Posttest 2

 

So may I ask you to vote again? Somatic BRCA2 alterations, which of the following would you recommend? Docetaxel, Lutetium-PSMA, a PARP inhibitor, a second ARPI, or PARP inhibitor combined with a second ARPI. Please vote.

 

[01:07:14]

 

Nice. Actually, I agree with both groups. I think we have most evidence for the one which is in the green box, which is a PARP inhibitor as a single agent. I showed you the 2 phase III trials we have that directly address this question. The last one you may argue, and we will come back to that maybe after Dr McKay's presentation, because in the trials combining PARP inhibitor and a second ARPI, there were only a few patients who had exhausted 1 ARPI. So the evidence is actually lower, if you will. But you know, I may understand someone going for enzalutamide and a PARP inhibitor in someone who had exhausted abiraterone, for example. That would make some sense, obviously. Next, please.

 

[01:08:11]

 

Posttest 2

 

Okay, so this is the rationale for those of you who need more text. We added it here on this slide. Really, this reflects the 2 phase III trials showing that for BRCA1, BRCA2 alterations, a single agent PARP inhibitor clearly improves rPFS and in 1 trial, actually overall survival as well.

 

[01:08:37]

 

Panel Discussion and Audience Q&A

 

Okay. any questions from you? Please feel free to send us questions. And this is true for you guys that I can see, but also for those who are not with us today in the room. Let us see. I need my glasses to read.

 

Yes, those are questions for the testing, but please send us questions. Maybe let me start with a question to, to the panel. In your experience, if you've been using a PARP inhibitor single agent and actually in combo with an ARPI, and the patients say benefit, but then it progresses and it is time now to go for say, docetaxel. Did you find using docetaxel easy or was there an issue due to the previous PARP inhibitor in your experience? What, what would you say?

 

Rana McKay: I think it is variable. I mean, I think I have, you know, you have to be cognizant around the cytopenias that patients may experience and see where their hemoglobin levels are at or where their platelet levels are at. But you know, sometimes for some individuals you kind of, midway through, may need to titrate the dose or you run into some anemia and you need to make some adjustments. But you know, I think the use of a PARP does not perturb the decision around docetaxel. And so just because they have been exposed, I do not think that there is a fear. They need close monitoring. You do need to monitor their marrow. You know, sometimes you may need to adjust the starting dose, in certain situations you may need to use GCSF. Not in all situations, but yes.

 

Karim Fizazi: Neeraj, the same for you?

 

Neeraj Agarwal: Yes, I will just add, this is a great question, and I used to worry a lot more about using docetaxel or my ability to use docetaxel in those patients who have received PARP inhibitors. But based on my experience in the last 5, 6 years, I have realized that if anemia was well controlled with the previous PARP inhibitor therapy, so anemia happens with PARP inhibitor as a class. If I reduce the dose, after 3, 4 months, patients are on cruise control, they are getting PARP inhibitor, hemoglobin is stable, and if I treat them up with docetaxel after that, I do not have any problems.

 

Karim Fizazi: I agree. This has been also my experience. I think if you start docetaxel with a normal hemoglobin level, things do normally well, let us say. But yes, there is no specific issue.

 

Yes, this is about testing. Yes, all this is about testing. Oh, what is your approach between patients with BRCA2 and ATM?

 

Well, I have totally different approaches for those men. At the beginning, I really did not know. And I still think that some, a few ATM patients may benefit but we still need to do all our homework. And ATM is a long gene with multiple alterations, and I think we need really to dig into the details and better understand which ones actually may predict for benefit. But in most patients, it is frustrating. Honestly, it really does not work.

 

For BRCA2 patients, most BRCA2 patients will derive efficacy. Actually, this is even more true if there is a deletion of a gene, not a mutation. So if ever you find a patient with a BRCA2 deletion, make sure you treat this gentleman with a PARP inhibitor, he may benefit tremendously and very long. So, this is really, really important. So, ATM and BRCA2 are clearly different.

 

Alright, I think we should move on and the next talk will be done by Dr McKay. Please, Rana.

 

[01:12:43]

 

Optimal Use of PARP Combinations in Prostate Cancer

 

Dr Rana McKay (University of California San Diego): Thank you. All right, everyone. Well, I know this is like the moment you've been waiting for, to have all of your questions unraveled around PARP combination therapy. So I know it has been a long day and you all are here listening in on prostate cancer, so that means you are probably staying through Tuesday for oral abstract session. This is the end of day 1. We've got a long way to go with ASCO. It is going to be a great meeting.

 

[01:13:10]

 

Poll 5

 

All right, we are going to dive right in. We are going to start with a poll. A 68-year-old man with MCRPC progresses on abiraterone. His tumor shows a BRCA2 mutation on genomic testing. His PSA is 45, he has bone metastases, ECOG PS of 1. And what treatment approach would you recommend for this individual?

 

1. Docetaxel;
2. Lutetium PSMA 617;
3. PARP inhibitor;
4. Second ARPI;
5. PARP inhibitor plus second ARPI.

 

[01:13:55]

 

Okay, so we kind of have a smattering, some people selecting PARP inhibitors, some people selecting the combination of a PARP inhibitor with a second ARPI, little bit of Lutetium 617.

 

[01:14:15]

 

Pretest 3

 

Okay, go to the next question. All right, here we go. A 72-year-old man presents with de novo metastatic prostate cancer. After initial ADT and docetaxel, he develops castration resistance. He has tissue testing performed and is found to have a PALB2 mutation. Based on current FDA approvals, what treatment would you consider next?

 

1. Olaparib, abiraterone and prednisone
2. Niraparib, abiraterone and prednisone
3. Talazoparib plus enzalutamide
4. Olaparib monotherapy
5. Talazoparib monotherapy
6. Abiraterone monotherapy

 

[01:15:14]

 

Oh wow. So look at that split. Okay, we are going to get, there's clearly a need for clarity around this, so hopefully we are going to make some improvements with the data. So just keep in mind this was an individual that had ADT docetaxel, was ARPI naive, with a PALB2. Okay. So you know, I know that we are escalating in the MHSPC setting and that has become kind of more routine practice.

 

[01:15:40]

 

Overview

 

Alright, so here's an overview of what we are going to talk about today. Going through the combination approaches and delving into the data.

 

[01:15:48]

 

Outcomes of Patients With mCRPC by HRR Gene Status

 

And first I just kind of want to level-set around the outcomes of patients with MCRPC with HRR gene alterations. And this was a very elegant analysis that was done by David Alamos looking at frontline MCRPC for all patients, BRCA mutated, HRR non BRCA, and non-BRCA. And what is in blue is the rPFS for the first line therapy. What is in orange is the rPFS for the second line treatment. And what is in gray is the overall survival. And I think these data maybe kind of highlight what we initially may have presumed, but kind of show it in raw numbers that the BRCA patients have a worse prognosis. Kind of intermediate prognosis with the non-BRCA HRR and the non-BRCA mutated patients seem to do the best.

 

[01:16:48]

 

Rationale for PARPi + ARSI Combinations

 

And then, you know, as we think about PARP inhibitor combinations in combination with ARPI, there is preclinical rationale for why it would make sense to combine the 2 agents together. PARP inhibitors may attenuate ARPI resistance, they may upregulate PARP and may induce PARP inhibitor sensitivity. Again, this is in preclinical models. They may down-regulate AR target genes and may down-regulate HRR genes inducing BRCAness. So it is suspected that these 4 mechanisms may be working together, providing rationale for why it may make sense to combine these 2 agents, or 2 classes I should say.

 

[01:17:38]

 

Pharmacology of Existing PARP Inhibitors

 

And just a little bit of background regarding the pharmacology of the existing PARP inhibitors. So Olaparib and rucaparib are approved in monotherapies and niraparib talazoparib in addition to Olaparib approved with combination. And you can see that not all PARP inhibitors are created the same. They are different with regards to their half-life. They are different with regards to their PARP1 potency. PARP1 we think is really the 1 that is doing the activity with regards to homologous recombination. We think of PARP2 as probably more mitigating the toxicity. And so when we look at the IC50 and we look at sort of the drug levels that it takes to kill a tumor, if you will, you know talazoparib and rucaparib are pretty potent agents followed by Olaparib, which I think is kind of in the next tier and then niraparib in the third tier. And then as Dr Agrawal was talking, there's also the capacity for PARP trapping, which is most pronounced in TA with talazoparib.

 

[01:18:33]

 

Approvals of Existing PARP Inhibitors in Prostate Cancer

 

And then I just wanted to put this up here because I know there is some confusion around where are the approvals, where are the approvals within the US and within the EMA for monotherapy and for combination. And so we are going to go through the data that justifies why this is what it is. But just to kind of level set that Olaparib is approved in the US in an HRR selected population, so kind of 14 panel gene that includes BRCA1 and 2. Rucaparib just approved for BRCA1 and 2 in the US. In the EMA olaparib is approved just for BRCA1 and 2.

 

When we look at the combination data, the FDA approval for olaparib with abiraterone is just in the BRCA1, 2 population but in the EMA unselected. For Niraparib, it is also just in the BRCA1, 2 with abiraterone. And then in the EMA selected for BRCA1, 2. And then for talazoparib, it is for a panel of HRR genes in combination with enzalutamide and unselected by the EMA. So this is kind of a snapshot of what the approvals are, and I know it can get complicated and it can differ from the monotherapy approval with regards to the combination approval. We are going to focus mainly on the combination approval here and going through the 3 key landmark studies.

 

[01:19:56]

 

Key Phase III Trials of 1L PARPi Combinations in mCRPC

 

Okay, so the 3 key landmark trials are PROpel, MAGNITUDE and TALAPRO-2. And each was slightly different in its design and its allowance of prior therapies. For example PROpel did not allow prior NHT use, MAGNITUDE allowed prior NHT, there was an allowance for patients to start abiraterone within a 4-month period of getting on the study to allow for the genomic testing to happen in a prospective fashion, and very small number of patients that had received a prior ARPI for MHS PC. Talazoparib did have about a 6 to 7% population that had received a prior NHT.

 

And then with regard to the type of HRR testing that was done, for PROpel, there was no prospective testing that was done. It was all done retrospective. For MAGNITUDE it was prospective and utilized as an integral biomarker to designate patients into 1 of 2 cohorts. And for TALAPRO-2, it was required prospectively for all patients on tissue. And then you can see the genes that are impacted there.

 

And then you can also see the primary endpoints across these trials. For PROpel, it was imaging investigator assessed rPFS, and for MAGNITUDE and TALAPRO-2, rPFS by independent review.

 

[01:21:28]

 

PARPi Combination Studies: Baseline Characteristics

 

And this is kind of the breakdown of the baseline characteristics. Obviously, I just told you about the variabilities in the design of these trials. This is not meant to be a head-to-head comparison, but I think it really kind of helps us sort of contextualize some of the data regarding the risk of the patients that were involved, the prior therapies that they may have received, the degree of lung and liver meds. And then also trying to tease out the HRR status across these 3 studies because there were differences in the tests that were utilized, the source of the specimen, whether blood or tissue, the timing of when the test was actually conducted, that I think adds a layer of complexity as we interpret this data.

 

[01:22:03]

 

PROpel: First-line Olaparib vs Placebo in Combination With AAP in mCRPC

 

So first we are going to talk about the PROpel study. This was an international double-blind randomized phase III trial enrolling patients with first line MCRPC, having received no prior abiraterone, did allow prior docetaxel in the MHSPC setting, and no screening for HRR mutations was required. Patients were randomized 1-to-1 to Olaparib, abiraterone, with Olaparib dosed at 300 twice a day vs placebo abiraterone. And the primary endpoint was rPFS. And I told you the breakdown of the prior dose of Taxol utilization and very low rates of prior NHT or NHA utilization. Key secondary endpoint was overall survival.

 

[01:22:41]

 

PROpel: Baseline Characteristics

 

Here are the baseline characteristics for the trial. Pretty well matched between the treatment arm and the placebo abiraterone arm. If we look across the board with regards to performance status, whether patients were symptomatic, sites of metastases, you know, fairly equivalent across the board. And while there was no prospective HRR testing that was actually completed, when they analyzed the data, it did seem that there was equal distribution in the assay that was utilized between the 2 arms.

 

[01:23:14]

 

PROpel: Prevalence of DNA Repair Genes

 

And this gives us a breakdown of the prevalence of the DNA repair gene alterations that were seen. Looking at non-HRR mutated basically comprising the bulk of the population at 69%. Most patients had single gene mutations that were found in BRCA2, ATM, and CDK12. There was a very small population, 4% that had co-occurring HRR mutations.

 

[01:23:35]

 

PROpel: Prevalence of DNA Repair Genes

 

And this actually breaks it down even further and looks at it by treatment arm for the single gene mutations to demonstrate that there was a well balance of the mutations between the treatment arms.

 

[01:23:47]

 

PROpel: rPFS at Data Cut-Off 1 (7/30/2021)

 

I really like this depiction of the rPFS after the first data cutoff because what is really nice about it is that you can see the point estimate hazard ratios across each of these uniquely defined groups. So the all-comer population, the HRR mutant, the non-HRR mutated, the BRCA mutated, you know, and so forth.

 

And you can see that at, at least for rPFS, the hazard ratio point estimate is favoring olaparib abiraterone. Across most groups that are seen, you see the most dramatic effect for BRCA2 and also the BRCA mutated. But the point estimates here are kind of all favoring the combination. Again, this is rPFS data.

 

[01:24:32]

 

PROpel: OS at Data Cut-off 3 (10/12/2022)

 

And then now here is the overall survival data. So again, looking at those same groups, we continue to see that the most dramatic effect is in the BRCA mutated and in the BRCA2 mutated. We do not see the BRCA1s signaled out here because they are just such a very small population. But I think there gets to be some nuances here over the degree of effect. You know, the all-comer population was not statistically significant. The non-BRCA mutated population, again, hazard ratio here, 0.91, not statistically significant. The non-HRR mutated 0.89. So I think it is this data that I think colors the labeling and approvals within the US.

 

[01:25:14]

 

PROpel: PSA Response

 

And then when we look at the response data, most dramatic responses that are seen with BRCA2 mutated individuals, 93%, with ATM 76%. Again, not all that different from control. With CDK12, a little bit higher, 83% compared to 62%.

 

[01:25:32]

 

PROpel: Frequency and Severity of AEs

 

And then here is the toxicity data that we can see. So the rates of grade 3 or higher toxicity, that is in the light blue, is at 47% with the combination. Rates of anemia, which is the big thing that we are mindful of, is at 15% with the combination. And then I think other things, just to be mindful of is the thrombotic events that can happen. Rates are pretty low, quite honestly, with within both groups, but still something to be mindful of. And then of course, the toxicities that are related to abiraterone, the hypertension, the hypokalemia, the volume overload.

 

[01:26:13]

 

PROpel: Thromboembolic Events

 

And then delving a little bit deeper into the thromboembolic events, I think we can group those into the cardiac failure arterial events, which seem to be similar between the 2 groups, but when we look at the venous thromboembolic events, they do seem to be slightly higher with the abiraterone olaparib group compared to the abiraterone placebo group.

 

[01:26:35]

 

PROpel: Safety

 

And then this is sort of a safety profile. I know this is a lot of text to look at. When I look at the safety profile, I always want to look at, well, what are the, what is the toxicity that is actually resulting in patients needing to stop therapy? And that is AEs leading to treatment discontinuation, that is at 4%. There were no fatal AEs that were observed in the context of this study. I think the big thing that we look at with regards to anemia is transfusion rate, so 16% with the combination. And then similarly for the pulmonary embolism related AEs, most of these were actually incidental or asymptomatic in both arms.

 

[01:27:13]

 

TALAPRO-2: Study Design

 

All right, so now we are going to shift gears. We are going to focus on TALAPRO-2. So just to reground us with the design: randomized, double-blinded, placebo-controlled trial, patients randomized to talazoparib 0.5 mg and enzalutamide 160 mg vs placebo. The primary endpoint was rPFS by independent review and sampling for HRR gene alterations was done prospectively by tissue for all patients.

 

And then other key secondary endpoints you can see here time to chemotherapy, rPFS2 and other parameters. A key secondary was also overall survival.

 

[01:27:50]

 

TALAPRO-2: Tumor DNA Source and Baseline HRR Alterations

 

And this gene set, I should go back, was a little bit different than the Olaparib gene set. So the gene sets are not 100% overlapping. So if we look at just the source of DNA data, TALAPRO the bulk of the data, everybody had tissue testing and there was an amendment midway through the protocol that allowed for ctDNA testing. So that is what that 14% is. And then you can see the breakdown of the different kinds of genes that were identified. About 20% of the population had a HRR gene alteration.

 

[01:28:26]

 

TALAPRO-2: Survival Outcomes

 

And then here is the data at the first analysis cutoff. The median rPFS showing statistically significant difference with the combination of talazoparib plus enzalutamide vs placebo plus enzalutamide. And then you can see the breakdown by HRR status. Again, this is the rPFS data. And then the median OS is here. This is at the first analysis.

 

[01:28:51]

 

TALAPRO-2: rPFS by BICR (Primary Endpoint)

 

And then this is the rPFS again by the initial primary analysis in 2022 and then the updated analysis, which is consistent.

 

[01:29:01]

 

TALAPRO-2: Overall Survival (Final Analysis)

 

And then this is the updated overall survival. This is for the intent to treat population, this is everybody on the trial, where we see a benefit.

 

[01:29:11]

 

TALAPRO-2: Subgroup Analysis of Overall Survival

 

And the various subgroup analyses. We are going to delve into the subgroup by HRR status, so I am not going to focus on that too much. This is the overall survival subset analysis. So trend across the board, but we are going to delve into the HRR status.

 

[01:29:23]

 

TALAPRO-2: Overall Survival in Subgroups Without Alterations Detected in Either ctDNA or Tumor Tissue

 

So something that was done in the context of you TALAPRO was they had the tissue testing, they implemented the ctDNA testing midway through, and they looked at the overall survival within the subgroup of those that were negative by both ctDNA and tumor tissue. What is here on the left is for BRCA1, 2 negative patients, and what is here on the right is for HRR negative patients. So this is the HRR negative group demonstrating a benefit here.

 

[01:30:02]

 

TALAPRO-2: rPFS in HRR-Deficient Population

 

And then when we delve into the HR deficient, this is where we see the greatest effect. This is the rPFS data, that is statistically significant. The primary analysis is here, updated analysis on the left.

 

[01:30:20]

 

TALAPRO-2: OS in HRR-Deficient Population

 

And then this is the updated analysis for the overall survival. Really, the group that is deriving the greatest benefit is the BRCA1, 2, though when we look at any HRR, we do see a signal there, the hazard ratio of 0.622.

 

[[01:30:30]

 

TALAPRO-2: Safety

 

So I know this is a lot of data.

 

[01:30:31]

 

TALAPRO-2: Most Common All-Cause TEAEs (≥20% of Patients)

 

I know I am coming close to ends. I want to be quick with some of the outcomes data, some of the AE data that I know Dr Agarwal is going to touch on the toxicity.

 

[01:30:44]

 

TALAPRO-2: Treatment-Emergent AEs

 

And here's the breakdown for the treatment-emergent adverse events across the board. You can see that there is more higher grade anemia, higher grade neutropenia that is seen with the combination. Some thrombocytopenia, leukopenia that we see.

 

[01:30:56]

 

MAGNITUDE: First-line Niraparib vs Placebo in Combination With AAP in mCRPC

 

And lastly, MAGNITUDE. A differently designed study where there was a prospective allocation into a HRR positive, HRR negative cohort. The HRR negative cohort actually did not meet the metric to proceed after the futility analysis. So really the bulk of the data is in the HR positive group looking at niraparib at 200 mg with abiraterone vs placebo. The primary endpoint here is rPFS.

 

[01:31:21]

 

MAGNITUDE: Final OS Analysis in BRCA+ Subgroup

 

This is the MAGNITUDE final OS for the BRCA positive group. We see a numerical difference, but this is not statistically significant.

 

[01:31:32]

 

MAGNITUDE: rPFS in BRCA+ Subgroup at IA2

 

And here is the rPFS for the positive BRCA2 after the second interim analysis, a clear benefit in this group.

 

[01:31:39]

 

MAGNITUDE: Safety in HRR BM+ Cohort (Final Analysis)

 

And then here is the safety data. I do not think there are any new safety signals that were seen in the context of the MAGNITUDE study.

 

[01:31:46]

 

MAGNITUDE: AEs of Special Interest in HRR BM+ Cohort (Final Analysis)

 

And this is AEs of special interest. I do think we need to be mindful with these PARP inhibitors of the DNA damaging effect that can happen. People can be at risk of MDS or AML. There was you know, zero cases that were actually seen in the niraparib arm here, though this has been reported with PARP inhibitor exposure for a prolonged period of time.

 

[01:32:11]

 

PARP Inhibitor Combinations: Study Outcomes

 

And so this is sort of the summary slide. We are not going to go through this again because we kind of touched on it. The data broken down by rPFS for all comer, combined, BRCA mutated. The data broken down for OS for all comer, combined, BRCA mutated. And what the approvals are. You can tuck this in your back pocket if you get confused because I think this kind of likes to summarize everything, try to do it on 1 slide.

 

[01:32:32]

 

Areas of Continued Discussion

 

So there are still a lot of areas of continued discussion around what is the appropriate combination. In the current modern era we are escalating in the MHSPC setting and the hope is that most patients are seeing an ARPI in the MHSPC setting. So the question is, is this data applicable and relevant in the modern era when people get escalated for MHSPC? What do we do in the biomarker-negative population, I think continues to be evolving, particularly the non-BRCA1, 2 mutated. I think the FDA has been very intentional about the recommendations and the need for very rigorous biomarker testing in not just the positive group but the negative group, to really show that you are actually improving outcomes for patients. And then what is the optimal sequence, you know, mono or combination.

 

[01:33:22]

 

TALENT: Talazoparib ± Enzalutamide + ADT in mCRPC With HRR Mutation after Progression

 

The TALENT study is an investigator initiated trial being led by Alicia Morgans, which is looking at answering the question in the modern era when people get escalated with an ARPI in MHSPC, does layering in an ARPI with a PARP inhibitor compared to just going to monotherapy, you know, what is the right strategy? So I think this will answer some important questions.

 

[01:33:44]

 

Future Phase III Trials of Combination Therapy

 

And there are some key studies in the MHSPC setting that are currently ongoing looking at PARP inhibitors for metastatic hormone sensitive disease that may further shift the landscape. I think we are going to hear the data from AMPLITUDE on Tuesday, so we are all eagerly awaiting that.

 

[01:33:59]

 

Patient-Centered Care

 

Tips to Achieve Shared Decision-making

 

And I think really at the end of this is just that the patient is the focus of everything that we do in the clinic, and ensuring that there is shared decision making around the treatments that we make is really critically important to optimize outcomes.

 

[01:34:11]

 

Conclusions

 

So with that, I know I am a little bit over the conclusions, and we will go back to our question.

 

[01:34:16]

 

Now, let’s go back to our question

 

Posttest 3

 

All right. I hope I did not confuse you. Hope I tried to simplify the data as best as I could. All right. Here's posttest 3. A 72-year-old man presents with de novo metastatic prostate cancer. And after initial ADT and docetaxel, he develops castration resistance. He has tissue testing performed and is found to have a PALB2 mutation. Based on the current FDA approvals, what treatment would you consider for this individual? So again,

 

1. Olaparib, Abiraterone, Prednisone
2. Niraparib, Abiraterone, Prednisone
3. Talazoparib, Enzalutamide
4. Olaparib mono
5. Talazoparib mono
6. Abiraterone mono.

 

[01:35:09]

 

It is a perfect song for this question. Walking on sunshine. I do not know I would say I walking on sunshine; walking on eggshells.

 

All right, very good. Look at that. Look at it. So, everybody went 20% down the road. Before, I think the right answer, at least based off FDA approvals, is this individual would be eligible for talazoparib enzalutamide. Alright. And that is based off of the TALAPRO-2 study.

 

[01:35:34]

 

Panel Discussion and Audience Q&A

 

Alright, so questions. We will open it up to the audience, we will open it up to our online audience as well. So please share your questions, raise your hands, clear as mud. All right. Maybe I will start us off. And maybe this 1 for Dr Fizazi. You know, given the more expanded label in the EMA for broad use of the combination options, you know, what is sort of your perspective on that and use in the clinic?

 

Karim Fizazi: Well, actually, it has been mostly with Olaparib, let us say historically. Actually I was surprised by the decision of the EMA when it came out to allow a quite broad use. Usually it goes the other way, the FDA is more generous as compared to the EMA, but you know. It actually shows us that with the same data you can really have different opinions and there is not necessarily a good and a bad one. Obviously, patients with BRCA2 derive most of the benefit. So to me, the, the main lessons for all the PARP inhibitor history in the last 5 years is that, again, we should test. And second, if this is a BRCA2, you should really get a PARP inhibitor for sure.

 

For the other alterations, of course, we keep learning. What you just showed us this year was not necessarily known just 1, 2 years ago. And hopefully, we will keep learning more.

 

 I am quite keen to indeed use a combo when a patient has BRCA1. Now I am much more convinced than I was 5 years ago, let us say. There's clear efficacy. PALB2 is rare, but they seem to benefit. CDK12, initially I was on the fence, but I am much more convinced, and it is good news that PARP inhibitor in combo work for CDK12 patients because this is aggressive cancer typically. On the other hand, the initial hope that CDK12 may predict for immunotherapy to work is not there. Or rarely, let us say.

 

So again, we keep learning. So again, I can understand both agencies, one being more restrictive and trying to protect patients from getting a toxicity if they are not getting efficacy, not even speaking about cost, but on the other hand, because we are learning, providing a broader approval can actually make doctors using the drug when they learn that actually X alterations is predictive.

 

Rana McKay: Yes. Well, thank you so much for sharing. I do not know, Dr Agarwal, if you have anything to share, highlight?

 

Neeraj Agarwal: So my take on this is monotherapy with PARP inhibitors has different efficacy from the combination therapy of PARP inhibitor plus ARPI. And you talked about the preclinical rationale, so the way I look at this, if I have a patient who is ready to start enzalutamide in my clinic and who has any homologous recombination or peer mutations, I will bring up enzalutamide plus talazoparib treatment in the discussion. And we will see the data. And this is online, I was just checking, I was not checking my text, I was making sure the abstract is online.

 

So Dr Stephanie Schavitz[? 1:39:37] is presenting the data from TALAPRO-2 trial gene by gene analysis. And I can tell you, of course, these are subsets of 400 patients. So there were 400 patients on the HRR mutation positive cohort. And if you look at the ATM mutation only, and of course I have not seen ATM mutation responding to olaparib in most patients. There are some patients who respond beautifully, but most patients did not respond. But I was surprised to see the data. And this, I am just reading off the abstract, which will be presented in 2 days, that ATM mutation benefit response rate, 75% vs 33%; radiographic PFS 30 months vs 18 months, and overall survival 45 months vs 39 months. These are absolute data and these are quite striking to me personally when I have not seen ATM mutation responding to single agent PARP inhibitors. So this is very intriguing, I would say.

 

If you look at CDK12 mutation, Dr Fizazi mentioned the response rate 63% vs 22%, radiographic PFS 19 months vs 13 months, overall survival 36 months vs 22 months. combination of enza-tala vs enza. And this, I am just reading off the abstract right now.

 

So these data are very intriguing and it makes me think there is something beyond going on when you combine PARP inhibitor plus ARPI, especially in the context of enzyme-tala. So I have, it was not too long answer, but.

 

Rana McKay: No, thank you for that. Thank you so much for your attention. All right, I am going to call up Dr Agarwal, who is going to take us home.

 

[01:41:37]

 

Managing PARPi-Associated AEs in Prostate Cancer

 

Dr Neeraj Agarwal (University of Utah): All right. So last one is usually the time when we are ready to go home or go to our hotels. So I will try to make it as interesting as possible. The bottom line is managing PARP inhibitor associated adverse events in prostate cancer can be done with timely dose modification and timely recognition of toxicities. So as long as we are following the patients, maybe every 2, every 4 weeks, they do not even have to come to the clinic. We can call their cell phones or home phones. We can do the lab test monthly through the local labs. And just by doing that, we know which of these patients are going to develop grade 3 or more side effects, hold the drug, and then restarting the drug after resolution of grade 3, 4 side effects is all we need for PARP inhibitor therapies.

 

The rare patients who develop, life-threatening side effects, MDS or AML, most of the trials have very small number, less than 1%, less than 0.5% patients developing those side effects. Comparing that to many other therapies we use in our clinic for MCRPC, docetaxel, cabazitaxel, carboplatin, managing side effects of PARP inhibitor is pretty straightforward.

 

[01:43:10]

 

Patient Case: 66-Yr-Old Man With Anemia

 

So I would start with a case, 66-year-old men with anemia. And this patient has a relatively long history, but bottom line, started PARP inhibitor with ARPI combination 4 weeks ago. Now reports the symptoms of anemia: fatigue, dizziness, shortness of breath, headache. He is diagnosed with grade 3 anemia, and you have the hemoglobin level right in front of you from baseline of 9.4. 9.4 is pretty low anyway. And by the way, based on our experience, we have learned that patients who have anemia at baseline, they are more likely to develop grade 3, 4 anemia.

 

So always make sure that these patients are thoroughly evaluated for why they have anemia. Many patients, especially who are vegetarians, can have vitamin B12 deficiency. A lot more common in India, where I am originally from, than US, but it is quite common. Many patients have iron deficiency. Many patients have many other issues which can cause anemia. And if anemia is present at baseline, they are more likely to develop grade 3, 4 anemia later. So the bottom line is check the work, do the work-up, make sure they do not have any other problems, and if they have baseline anemia, I follow them more often, maybe every 2 weeks.

 

[01:44:28]

 

Pretest 4

 

So the pretest is, in addition to transfusing packed red blood cells, which of the following would you recommend for managing this patient's grade 3 anemia in your current practice? So 4 months after starting this ARPI PARPI combination, patient develops grade 3, 4 anemia. What do you do? These are the 4 options. Please take the poll.

 

[01:45:13]

 

Wow, we do not need this session. So hold PARP inhibitor until resolved and then restart at the reduced dose. And I think the same concept applies to pretty much all cancer therapies. There is nothing new. And my colleagues, many of them are general medical oncologists, they deal with so many more combination therapies, toxic therapies, and for them it is, I find them more actually comfortable managing PARP inhibitor toxicity than a prostate cancer oncologist who may not use that much chemotherapy.

 

[01:45:50]

 

Common Toxicities With PARP Inhibitor Monotherapy

 

So these are the common toxicities as Dr Fizazi and Dr McKay have already explained. GI toxicity, hematologic toxicity and fatigue. And these are the 3 major toxicity classes and others are quite common. So if you look at hypertension, it may be a little more common with niraparib, but the bottom line is hematologic toxicity, decrease in the blood counts after 2 or 3 or 4 months, and then you stop it. They improve.

 

Nausea, vomiting, much less common than many chemotherapies we use. So if you look at nausea and vomiting, I never let any of my patients leave my clinic on Olaparib without anti-nausea medications. They are going to call you with nausea and vomiting, bottom line, optimize anti-nausea medications and if they are not well controlled, decrease the dose, they do fine.

 

Fatigue is more likely a side effect of an ARPI in this case. These patients are starting enzalutamide, abiraterone, fatigue is way more commonly associated with them. But exercise is the number 1 intervention I use for my patients with fatigue.

 

[01:47:00]

 

PARP Inhibitor Combination Regimens: Common TEAEs and/or TEAEs of Clinical Interest

 

So this is the overall profile. I am not going to go through each one of these numbers, but the bottom line is cardiovascular side effects may be more common with niraparib. So I will let you go through these figures while I grab my bottle of water. So we can see the liver enzyme elevations are very uncommon with these patients. DVT, PE a little bit more common than control, but absolutely, they are not very high.

 

[01:47:46]

 

Dosing Considerations for PARP Inhibitors

 

So what are the dose considerations of PARP inhibitors? First of all, let us look at how many times these patients have to take the medications if they are taking these PARP inhibitors. Rucaparib, twice daily, Olaparib twice daily, Niraparib once daily, talazoparib once daily. So I tell my patients when they are starting this, you will be taking a pill once or twice daily, and I will be reducing the dose if you have intolerable side effects. So we will take a break and restart.

 

And there is lot of very pertinent information on this slide deck. So I suggest keeping this, storing this on your laptop or phone or 1 of the folders. And really, this really helps me with patient counseling. So the drug interactions, how they are metabolized or what are the half-lives, which is really helpful when I am told that the patient needs to start a drug, which is going to interact with 1 of the PARP inhibitors. If I know a patient is on a PARP inhibitor with a long half-life, I will tell the local physician or whoever is calling me, not to start the other drug within that timeframe. So this, keep this slide with you, this really helps me with my own management of patients.

 

[01:49:11]

 

Dose Modifications and Key AEs With PARP Inhibitors as Monotherapy and in Combination Regimens

 

And if you look at the dose modification schedule, literally basic principles of oncology. So anytime you have grade 3 or 4 side effects or intolerable side effects, grade 2 nausea can be intolerable. It does not have to be grade 3 nausea. Vomiting even once is intolerable to me. So if a patient has intolerable side effects or grade 3 or 4 side effects, I have a rule in my clinic, stop the drug, wait for side effects to resolve, restart the drug at a lower dose, and that usually works out very well.

 

[01:49:46]

 

Managing Key AEs and Safety Considerations With PARP Inhibitors

 

So again, repeating the same thing in a different way, how do I manage these side effects? Monitoring, monitoring and monitoring. So my nurse calls the patients 7 days after. We, by the way, we tell the patients to message us if they have any issues, so they can message us through MyChart, through many other platforms all of us use. So if we do not get a message from them, we usually call them every, you know, so often. And this can be done on trials by study coordinators. This can be done by medical assistants, who are one of the most important pillars in my clinic, in our clinics, or nursing staff or even we tell the patients to send us a message.

 

But cytopenias or hematologic toxicity, I tell them to do local CBC every month. They do not have to come to the clinic. I do not have them come to the clinic every 15 days or 20 days or 28 days. They can do it locally. Fatigue and the bottom line exercise, and then massage and cognitive behavioral therapy. And of course we need to rule out other causes of fatigue, which is anemia.

 

The gastrointestinal toxicity, I do not see a problem in oncology clinics because so many other drugs are causing GI side effects that most of the oncology clinics are extremely well tuned to take care of GI side effects. And some rare side effects, MDS, AML, they are so rare. I have not really seen a single case of MDS or AML so far despite training the patients with PARP inhibitors on the PERFORM trial since 2014. But they happen. And how do we recognize them? If anemia is not improving despite stopping the PARP inhibitor, that is a reason to think about doing a bone marrow biopsy.

 

And then of course, hypertension can occur more commonly because of the partner drugs, abiraterone, enzalutamide. If that happens, I control them with those modifications or blood pressure medications.

 

[01:51:58]

 

Managing Anemia With PARP Inhibitors

 

And this is the same thing, same story. I will not repeat this. If grade 3 anemia happens, and by the way, in the TALAPRO-2 trial protocol did not technically allow. A protocol does not require patients to reduce the dose. A protocol says that nobody will reduce the dose. So a lot of patients develop grade 3 anemia or more, almost half of the patients, and half of the patients had grade 1/2 anemia at baseline. And what we did, we stopped the medicine and reduced, restart the talazoparib at reduced dose. Only 8% patients, 8% of patients had to discontinue talazoparib for anemia. So those discontinuation rates are very low with these PARP inhibitors.

 

[01:52:49]

 

Strategies for Promoting Adherence to Oral Therapies

 

And again, these are the strategies for promoting adherence to oral therapies. Nothing unique to PARP inhibitors, this applies to basic principles of oncology. So that is it.

 

[01:52:58]

 

Now, let’s go back to our question

 

Now let us go back to the question. Let us see if I did a good job.

 

[01:53:02]

 

Patient Case: 66-Yr-Old Man With Anemia

 

In addition to transfusing packed red blood cell to this patient, what else you will do? Please go ahead.

 

[01:53:28]

 

All right, I got passing marks. All right, I think – oh, there's another one. Are we done? It is oscillating.

 

[01:53:50]

 

Posttest 4

 

Okay, so there is the rationale, and rationale is if grade 3 anemia happens, we have to rule out other etiologies, vitamin B12, iron, folate, and then reduce the drug. Next, please.

 

[01:54:07]

 

Poll 6

 

Do you plan to make any changes in your clinical practice based on what you learned in today's program? Yes or no? And you, they do not have to give the answer right now.

 

[01:54:23]

 

Poll 7

 

Now please take a moment to enter one key change that you plan to make in your clinical practice based on this education. One change. It could be anything. Management of anemia, workup of anemia, PARP inhibitors, anything. Whether you like the food outside. I am just kidding. It is a clinical practice question.

 

[01:54:51]

 

Panel Discussion and Audience Q&A

 

All right, panel discussion. So I will – there are some questions here. There are lot of questions here actually, but most of them came early on. So let me ask Dr Fizazi.

 

Karim, how do you really look for MDS and AML? Those are the most life-threatening complications. I always worry that I am not recognizing them. See if I am not seeing them, there are 2 possibilities. Either they are not happening or I do not know how to look for it.

 

Karim Fizazi: I think they are rare. And so far, mostly so good. With PARP inhibitor use in phase III trials, we saw really low numbers. It is not only you or me, it is across the board. I think the key question for us will, whether using PARP inhibitor for longer duration will actually be associated or not with an excess in MDS and leukemia. CRPC unfortunately remains a lethal disease. So typically when we treat patients with a PARP inhibitor, it is for 6 months, a year, year and a half, something like that. Not very long. And this is maybe why we haven't seen so many MDS/leukemia events in all the patients until now.

 

The key question is really going to be now that we have trials testing these agents in castration-sensitive disease, and because castration-sensitive disease now, or at least metastatic CSPC, means a novel survival of probably 6 years, 7 years, something in this range, is that going to be leading to more m MDS/leukemia if you are using a PARP inhibitor for 2 years, 3 years, 4 years, etc? And of course we do not know.

 

In the trials, I think the decision was made to carry on with a PARP inhibitor until progression, while you may argue that capping to, I do not know, 2 years, 3 years might be safer. So of course data will tell and depending on what we will find, we will probably have either to do what was done in the trial or maybe to cap the duration. But I think this, this will be very important.

 

Neeraj Agarwal: So capping the duration of PARP inhibitor if they are going on for too long?

 

Karim Fizazi: It may be. We do not know. But again, we will know, we will have first data this week or during this congress with AMPLITUDE and I guess TALAPRO-3 will follow and then the AZ trials as well. So we will know soon. Which again is very important clinically.

 

Neeraj Agarwal: Great. Thank you. Fatigue. question for Dr McKay. Fatigue is so common with both enzalutamide and talazoparib, abiraterone and olaparib. How do you know which drug to stop when somebody's having fatigue? Do you reduce the dose of both drugs? Do you discontinue both drugs? How do you know which is causing fatigue?

 

Rana McKay: You know, I think fatigue is a very multifactorial complex, and I think teasing out to try to figure out what is going on in that patient's life that could be driving the fatigue is really important when we talk about sort of dose modifications and dose reductions. Are they not getting enough sleep at night? Are they on a lot of narcotics to control their pain? And actually trying to understand what is the context in which the fatigue is happening is critically important. If somebody is having significant, you know, grade 3 fatigue, that is impacting them, I actually stop both drugs and give us, like, let the patient recover and then we can make modifications.

 

You know, when I think about what exactly to modify, if it is a BRCA2 mutated individual, we know that sensitivity has been linked to PARP dose and PARP exposure and I try not to muck with that too much, I have to say. But I always try to understand what is going on with the patient. You know, recommending exercise. Sometimes we do stimulants. You know, I am not a big keen player on that, but I actually think exercise is huge for our patients. So, but it is a challenging question of sort of which one do you adjust and how.

 

Neeraj Agarwal: And I just want to add, if I see no other side effects of a PARP inhibitor and only fatigue, I tend to blame the fatigue on the ARPI rather than PARP. But again, there is no one way.