Let us look at the mCRPC in general. What are the unmet needs and what is the current status? This is just an overview of mCRPC. First of all, what is mCRPC? By the way, the terminology will be changing very soon with the PCWG4 criteria. Many of the people here maybe the co-authors on that paper. For now, we will stick to metastatic castration resistant prostate cancer. It is defined as a prostate cancer which progresses despite castrate level of testosterone. We have to make sure that testosterone levels are less than 50 nanograms per deciliter before diagnosing them with mCRPC. What are the unmet needs? It remains incurable. It remains a lethal disease, and there are limited treatment options in later lines of therapies.

Even though we have way more options than we had 10 years ago, those are still quite limited and are mostly associated with relatively modest overall survival benefit. Yes, we do need better options which can induce durable responses in our patients with mCRPC, and it is good that research is happening. Many of that is being presented in the meeting and will be presented in the future meetings. If you look at the survival of patients with mCRPC, and this is an old study, you can see that survival is best in patients with lymph node disease only. As the disease progresses or involves other organs, the survival continues to go down. This is from a large study with patient level data from multiple clinical trials, but it was published quite a while ago. We do not have more recent data, but you can see that patients with liver metastasis have a median overall survival of only 13 months. It is only a year if they have mCRPC and they have liver metastasis.

[00:08:36]

Suboptimal NGS Testing in Metastatic Prostate Cancer

This slide talks about the testing. This paper is by Chadi H. Chehade, who is a resident at the University of Utah, he was our post-doc fellow. This study was done using Flatiron Database, and it was published in JAMA Network Open in 2024. You can see here, out of 12,000 patients we looked at, less than 30% of patients had NGS testing done. If you look at the approval of pembrolizumab for MSI high status, it happened in 2017. TMB high status approval came in 2018. PARP inhibitors were approved in 2019. Five years, more than half a decade after these life-prolonging drugs were approved, less than 30% of patients had testing by NGS testing, and is clearly unacceptable. By the way, median time to receive testing from the diagnosis with metastatic disease is more than a year. I think it was mostly mCRPC. Even patients are being tested, they are tested very late. We had another presentation where a lot of patients were being tested within three months of their deaths, which is clearly not optimal.

Yes, we need to be testing these patients, And testing needs to be more timely. now with the approval of abiraterone plus niraparib combination, I personally think everyone should be tested in metastatic hormone sensitive prostate cancer.

[00:10:15]

DNA Repair Pathways

This is a quick snapshot. Obviously, Dr. Abida is the most knowledgeable person in these DNA repair pathways. I will make it very simple for you. We can actually ignore the mismatch repair pathway, which is not the topic of discussion. This is in the first column of this picture. If you look at the single strand breaks, they are quickly repaired by these enzyme part one and part two, poly-ADP ribose polymerase one and two, by base excision repair pathway. This is a very simple repair mechanism, very efficient.

However, if there is a problem with the single-strand repair, very quickly at the time of next replication, this DNA repair becomes double-strand repair. At that point of time, it is repaired by a process known as homologous recombination repair process. PARP, if they do not do an efficient job of repairing the single-strand break in the DNA, homologous recombination repair kicks in when it becomes a double-strand break, and it repairs the double strand breaks. There is another less efficient and error-prone mechanism of this repair, which is known as non-homologous recombination, and these are quite complicated names out there, we can safely ignore them. But it is sufficient to say that ligase 4 is involved in non-homologous recombination repair. The bottom line is if cells have to repair themselves through non-homologous recombination, Because this is error prone, it leads to accumulation of a lot of faulty DNA points, which is incompatible with cell survival. If you have too much non-homologous recombination going on, cells cannot endure this process for too long and they die.

[00:12:16]

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

This is a simplified version of what I just mentioned. From base excision repair to homologous recombination repair is smoothly conducted by the cellular machinery. However, if you create an issue here, for example in patients who cannot repair, the homologous recombination repair mechanism is deficient, and you somehow inhibit their PARP, the single strand breaks will not be repaired, which will be converted to double strand break. But then homologous recombination repair mechanism is not effective and these cells ultimately die. In those patients with homologous recombination repair deficiency, if we inhibit PARP with PARP inhibitors, that can lead to synthetic lethality of these cancer cells, because they tend to repair themselves by non-homologous end joining, which is not consistent with prolonged survival of these cells.

[00:13:18]

HRR Mutations Occur in 25% of Patients With mCRPC

Now, coming to the prevalence of these mutations, what is the prevalence of these DNA repair gene mutations? These are studies selected based on the number of patients they had, how soon they were reported. For example, one of the seminal studies by Dr. Colin Pritchard and team from Fred Hutch, published about 10 years ago, 11% of these patients with metastatic prostate cancer were found to have germline pathogenic variants in DNA repair genes. It was an eye opener for all of us. Nobody thought 11% of prostate cancer cells have germline defects. Then on the left side, this is the PROFOUND trial data. When we were screening patients of PROFOUND trial, we found that about 30% of these patients have DNA repair mutations. Yes, if you look at number of patients with metastatic prostate cancer we have, 11% have germline mutations, 30% have somatic mutations. This is a huge disease burden based on these prevalence. These are very high prevalence.

[00:14:38]

Prognosis Is Poor for Patients With mHSPC and HRR Mutations

To make it worse, if you look at these DNA repair mutations, if they are present, then the prognosis is actually poor. Again, the first paper is by Chadi Chehade, again, first author and most of the team members here published in Clinical Cancer Research last year. Patients who had DNA repair mutations, they had a shorter time to response to ADT plus ARPI in patients with metastatic hormone sensitive prostate cancer. Another paper was published by Dr. David Olmos and team in Annals of Oncology, Dr. Elena Castro is the, I think, last author in this one. They looked at a multicohort study of mHSPC patients, and again a very similar story. These patients who have HRR mutations, they do not do well. They quickly progress on ADT plus ARPI or I would argue in ADT plus ARPI plus docetaxel chemotherapy. These patients need better treatment options preferably with PARP inhibitors.

[00:15:42]

When to Test: Prostate Cancer Disease States

When to test? What is the right time to test? Until very recently we did not have any reason to test with NGS testing. Everybody should be tested with germline testing. Anyone with locally advanced or metastatic prostate cancer, they need to have germline testing because that, not only has implications on those patients care, but also their families. I have had a 61 year old man who was found to have one of the DNA repair mutations, and both of the daughters were found to BRCA2 mutation, and both daughters had BRCA2 mutations. They were saved because their dad had prostate cancer and had NGS testing done. They had mastectomy and ovariectomy done in a timely fashion. Otherwise, there was a very high chance they would have both developed metastatic ovarian or breast cancers.

What is the right time for NGS testing? Until very recently, we did not have any reason to do NGS testing in metastatic hormone sensitive setting. Now, with the approval of abiraterone plus niraparib combination in metastatic hormone sensitive setting, and we know several more trials like TALAPRO-3 trial, EvoPAR-Prostate01 trial, they will be reporting in the near future, and we will have more indications, more drugs for these patients. According to ASCO guidelines, the best time to test is the first time we see these patients with metastatic prostate cancer.

In PROFOUND trial, 30% of our patients were not eligible for testing because we tested them too late. Original tissue had lost its quality or quantity. In mCRPC setting, it is very difficult to obtain new biopsies. Big centers like in Memorial, in Indiana biopsy is feasible, but in community setting is very difficult for patients to get bone biopsies for technical reasons, for feasibility issues. The best time is when they are diagnosed for the first time, prostate is easily available and they should undergo NGS testing. Primary prostate metastatic tissue anything which is available they should be going tissue testing, and we also order ctDNA testing for most of these patients.

[00:18:01]

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

These are the ASCO guidelines we put together last year. And we can see here this is very simple. Yes, family history is important. But, the bottom line is, all patients with metastatic prostate cancer should undergo genomic testing with both germline and somatic testing. There should not be any ambiguity about this. Of course when they have change of status, although you can chime in during the discussion session, some of these patients may be found to have new HRR mutations at the time of disease progression, or at the time of castrate resistant disease. If not HR mutations, they may have newer targets for ongoing clinical trials. All of these patients should have NGS testing done at the time of disease progression.

[00:18:55]

Current Guideline Recommendations for Somatic (Tumor) Testing

Current guidelines recommend the somatic testing for these HRR genes. You can see all the names here. I will not repeat them. In addition to the HRR mutations, we should also look for MSI high and deficient MMR status and TMB testing, because we have drugs available for all these indications. About 5% of patients, 5.5% of these patients, have other MSI high tumor, 3% or 3.5%, and an additional 1.5% of patients have TMB high mutations excluding MSI high mutations. TMB high can be present without MSI high status. About 5% to 6% of these patients is a very big number, if you look at the prevalence of prostate cancer. In my practice, I do not really necessarily do these point testing anymore. I order NGS testing, which tests for multiple genes, hundreds of genes because tissue is precious. If you start doing point testing, then we often run out of tissue after some time.

[00:20:02]

Sample Sources for Biomarker Testing: Tumor vs Liquid Biopsy

What are the sample source of biomarker testing? I would say anything we can get. My preference is tumor biopsy. That is the gold standard for me. Many of these patients have already started treatment with androgen deprivation therapy. Their ctDNA burden is quite low. I do tumor biopsy for all my patients. These are the advantages and limitations. Obviously, major limitation is the failure rate for new testing is very high, relatively speaking, 30%. Also it is hard to do serial sampling for tumor tissue testing. How many times you can do biopsy of these patients who have predominant bone metastasis? Advantages are the large amount of tissue we get, and is much easier to look for large deletions in tumor tissue.

If you look at liquid biopsy, obviously there are multiple advantages. My older patients do not have to go through those painful biopsies, but they are less sensitive, especially when they are on ongoing treatments because the ctDNA burden may not be high enough to allow a meaningful testing of these patients. The big advantage is that it is just a blood draw. They do not have to do a biopsy again. Then, we have heard about clonal hematopoiesis of unknown significance or CHIP interference, which can happen. We just saw recently that CHIP can cause false positivity for ATM mutation and some of the CHEK2 mutations. Again, there is always a concurrent germline testing which can be done to look for CHIP interference But that is too complicated for this discussion.

[00:21:38]

Germline vs Tumor (Somatic) Testing

Now germline vs tumor testing. Although we have outlined the advantages and limitations, my take on this is everybody should be getting germline testing and tumor somatic testing. It is not, which is better or which should be done in lieu of other, everyone should be getting both germline testing and tumor testing.

[00:22:01]

How Can My Patient Get Access to Genetic Testing?

How can my patient, get access to genetic testing? Some of the large cancer centers have the advantage of having a lot of support nurses, medical assistants, their in-house genetic counselling team. When I talk to our community colleagues in Utah and Wyoming and Montana, many of them are solo practitioners, and they have no access to these high class resources and these expert people in their practices. Of course, there is shortage of genetic counsellors.

There are ways. There are online websites and we have mentioned these websites here, and it is not difficult in your practice if you want to establish one source, I think that is more feasible than trying to keep up with five different sources. In my practice, actually, we stick to one or two sources and we send our patients. We do in-house testing, but patients who are out of town who are coming here for second opinion, we give them these online resources and tell them to talk to their doctors about germline testing if they have not made up their mind to do this testing in my clinic.

Of course, there is a registry, a prostate cancer registry of outcomes in germline mutation for improved survival and treatment effectiveness. It is called PROMISE Registry, and this registry is offering free testing for any of these patients. Feel free to send your patients to this website to explore how they can test for these mutations.

[00:23:42]

Let's Return to Our Question

Let us return to our question now.

[00:23:45]

Posttest 1

Based on the current ASCO guidelines, which of the following describes the recommendation for testing? I think we answered that.

Correct answer is everyone should be testing at baseline with both somatic and germline testing. Then, at the time of disease progression, we should try our best to do somatic testing.

[00:24:24]

Master Class Case Discussion: Optimal Biomarker Testing

We will pass the mic to Dr. Lacuna for some case discussions and we can sit.

Dr. Kristine Lacuna (Memorial Sloan Kettering Cancer Center): Hi, everyone. Thank you for having me. Thank you Decera for setting this event up. We are going to talk about a case here today that goes on the Tar Heels [? 00:24:50] of what Dr. Agarwal has talked about. This is a 66 year old gentleman, PSA of 12 on routine blood test. His medical history includes an MI that occurred 10 years ago. He had a biopsy which confirmed prostate adenocarcinoma with a Gleason score of four plus five. He underwent a radical prostatectomy with pathology that is listed there. He was treated with secondary radiation ADT due to persistent PSA post-surgery in the salvage setting. Quite unusually for this patient, in what we see during his second year on his hormonal therapy, his PSA unfortunately rose to seven and then 16. He had CT scans which showed disease relapse with a pelvic mass infiltrating the bladder and bone metastases.

He was started on treatment with an ARPI enzalutamide for mCRPC with a PSA response, followed by progression of disease only after nine months. He underwent a treatment with docetaxel with stable disease, unfortunately followed by progression of disease after five months. He was referred at that time for a bone biopsy for NGS testing, and unfortunately less than 10% of the tumor content was present, so it was not suitable for NGS. I would like to take the time for the faculty to discuss with the group what they would do next for this case.

I think that you guys can hear me, but basically this is quite a complicated case. I think in terms of this case, there are a few things that are important to note. First, he was diagnosed with very high risk disease, with adenocarcinoma four plus five at diagnosis. Even in the community right at this point, we would be thinking in our minds that maybe we should consider genetic testing for very high risk or high risk disease. In the NCCN guidelines, we are really thinking of metastatic disease. I think that that is changing and moving up further and further along the lines.

There are a few things, I think in this case that are important to bring up. One is that he had pretty aggressive disease even while he was on ADT for his relapse. Which is something to think about. Then another important point is that throughout his treatment course of decisions, he was started on treatments with opportunities to potentially have genetic testing, but he unfortunately had not had that. I will open it up to the group after that summary to see what the questions are, see what you guys would do, and I will just give you guys a few minutes to discuss that.

While the group is thinking about the case, I see some unanswered questions here. One is, can you comment on repeat testing? I think that is important to think about especially as a patient progresses through disease. I think germline testing is a one-time situation, but whenever someone has progression of disease, we should be thinking, are there any new mutations, any new sporadic mutations, that we should be considering because that can offer a potential treatments down the line?

Another question here is I believe the PROMISE registry is now closed. Would you have any additional recommendations? Yes, as of December 30th, the PROMISE registry is closed. I think there is a six month, plus or minus window. Some of the resources I think that Dr. Agarwal mentioned I think are, are quite important to discuss.

As more and more questions come in, what I would like to just talk about is what I would do. There are a few points here. One is that the patient was diagnosed with very high risk disease. Even from the get go I would be thinking, maybe time to get a family history, talk about germline testing. Even at that point. When he was treated with secondary radiation in the setting of salvage he unfortunately progressed. There was some disease badness that we know is going on. That is an unusual situation where we are seeing them develop to castration resistant right from the get go of getting ADT alone.

I think the first point where we could have done something differently here is the patient, at the time that he developed castrate resistant disease, he was started on enzalutamide for mCRPC. I think this was the first point where we know he has bone disease, bone metastases in the mCRPC setting. This would have offered an opportunity to do genetic testing at that point. Genomic testing, both germline and somatic testing, because the patient was started on enzalutamide, but he could have been started on a few combinations with PARP inhibitors, plus an ARPI based on several studies, including TALAPRO-2, MAGNITUDE, especially if there was an HRR or BRCA2 mutation. That is something to consider. That was a missed opportunity.

The second point, I would say, is that he progressed quite quickly after progression of disease with nine months of enzalutamide. He was started on docetaxel and he had somewhat of a response. At that point with the switch in therapy, I again would be thinking about considering somatic testing at that time. Why? Because there could have been new sporadic mutations that were developed and need to be considered in this setting that would have offered potential treatments.

Third, I think this patient was only referred for a bone biopsy at the time that he was pretty late line castration resistance. I think that was unfortunate that he developed such significant disease. It was only at that time that we were testing for somatic mutations. Unfortunately, at that time, he only had 10% tumor content so it was not suitable.

One, I would say we missed the opportunity to test this patient way early on, probably at the time of high risk disease even. Two, if we are seeing that there is not enough tumor content, we should be considering ctDNA testing, as Dr. Agarwal mentioned.

I think that is it. I think we are just going to wrap up and I am going to bring Dr. Agarwal back to the stage to summarize what his group talked about and some of the caveats of this trial and go from there. Thanks.

Dr. Agarwal: Dr. Adra. Before we go to the talk by Dr. Abida, I would like to first discuss what we just discussed during these case discussions session by Dr. Lacuna. By the way, I almost thought you were talking to us. Mic is not working.

Dr. Lacuna: It is an interesting setup.

Dr. Agarwal: We did not realize you were talking to an online audience.

[00:33:06]

Additional Discussion on Biomarker Testing

We were talking about testing and the timing of testing, and should we repeat the testing? When should we really repeat the testing? Maybe Dr. Abida was talking to the trainees here. Maybe you want to summarize what we discussed?

[00:33:27]

Master Class Case Discussion (cont’d)

Dr. Wassim Abida (Memorial Sloan Kettering Cancer Center): We were talking number one. The thing that was missing for this patient, and the main message here, is that this patient had sub-adequate testing on a bone biopsy sample. We were talking about successive NGS from bone biopsies as the lowest of all the tissues that you can biopsy. That has a lot to do with the tumor content in bone, as it is very spotty, as well as processing of bone samples, which are often decalcified and results in degradation of DNA quality. It is not unusual to have failures in NGS in half of bone biopsies, including at expert centers that use PET for target localization.

The options here, number one for somatic testing, let me say, is either a re-biopsy the patient, which of course is a process, we heard it was complicated, or go for the easiest path which is cell-free DNA. Now, this is a patient who is progressing with pretty aggressive disease. He has a higher likelihood of having a decent circulating tumor DNA content in their cell free DNA. It is not perfect as Dr. Agarwal had mentioned before. It may miss some deletions. It is highly dependent on tumor burden, but it is the next best thing when you do not have adequate tissue sample.

The other thing, the other very low hanging fruit, is this patient did not have germline testing. He can have standalone germline testing, which will never miss. It will always identify any known oncogenic germline mutations, and that really complements the tissue testing. It catches half of patients, for example, with BRCA mutations, and some a fraction of patients with microsatellite instability would be Lynch carriers, for instance. Really, germline testing and cell free DNA would be the answer here.

Dr. Agarwal: Thank you very much. Also the topic came up regarding CHIP interference. If you are suspecting and, usually say there is a ATM mutation or CHEK2 mutation, and we are suspecting CHIP, what is the way to figure out it is not CHIP or is a real ATM mutation?

Dr. Abida: That is very tricky. A different labs have different thresholds for calling clonal hematopoiesis mutations. Much of it is from actually sequencing the buffy coat, the white blood cells and there you are going to identify CHIP a lot better. If you do that, if you sequence the buffy coat, you can filter out CHIP mutations. A lot of commercial assays do not do that. They may be calling very low allele frequency mutations. CHIP mutations happen really in certain predominant genes. They really are not known to happen BRCA2 mutations, for instance. That being said, you can have very low allele frequency mutations in BRCA2. It is tricky to give a simple answer to that. ATM and CHEK2 happening at very low allele frequency, you would suspect clonal hematopoiesis mutations. Any mutations that happen in a number of very frequent mutations that happen at very low allele frequency, you would suspect these are sub clonal, not significant. It is hard to give a blanket answer. That is, I think, the challenge of cell free DNA testing. When in doubt, I think if it looks like an actionable mutation, you generally will want to take the option to treat.

Dr. Agarwal: Any other discussion point? Anybody has any questions? The next topic which will be addressed by Dr. Abida, is to evaluate the data on PARP inhibitor combinations.

[00:37:01]

Evaluating the Data: The Rationale for PARPi Combinations

Dr. Abida: Thank you, Dr. Agarwal. Excellent. Thank you very much. It is a pleasure to talk about using PARP inhibitors in practice both as monotherapy and in combination.

[00:37:15]

Let's Begin With a Few Questions

Let us begin with a few pretest questions.

[00:37:17]

Pretest 2

We will ask you to give us your answer, but we will review the answers all the way at the end. This is pre-test question number two. We have a 70-year-old man who presented some time ago with de novo metastatic prostate cancer, and this was a while ago. He was treated with ADT and upfront docetaxel only, no RP. He now develops castration resistance. He has tissue testing performed and is found to have a BRCA2 deleterious mutation. Based on guideline recommendations, what treatment would you consider next for this patient. Would you give him

A. Olaparib alone;

B. Abiraterone and prednisone;

C. PARP inhibitor with abiraterone prednisone; or

D. PARP inhibitor with darolutamide.

We will give you some time to give us an answer on this. Most people answered PARP inhibitor abiraterone prednisone, 92%. Okay, good. We will come back to that later.

[00:38:25]

Pretest 3

Pretest question number three, which of the following statements accurately describes results from the TALAPRO-02 trial of enzalutamide plus talazoparib vs enzalutamide plus placebo, and the resulting FDA approval based on this trial?

A. Is the FDA approval was granted for BRCA1, BRCA2 mutated mCRPC only;

B. Most patients had received an ARPI for mHSPC prior to enrolment;

C. In gene by gene subset analysis, patients with ATM mutations appear to derive an rPFS benefit from the combination; or

D. In gene by gene subset analysis, patients with CDK12 mutations appear to derive an rPFS benefit from the combination.

All right. A bit more mixed here. I look forward to discussing this at the end of the presentation. Most people, 45% answer the last question that CDK12 mutations appear to derive in rPFS benefit from the combination. Next slide.

[00:39:35]

BRCA-Related Synthetic Lethality With PARP Inhibition

I will not dwell on this too much because Dr. Agarwal presented it, but this is the model for PARP inhibitor efficacy in homologous recombination repair deficient tumors. This is a very elegant paradigm of precision oncology, where combining a PARP inhibition in HRR deficient context results in synthetic lethality and cell death. That was really the basis for development of PARP inhibitors in treating specific subsets of prostate cancer before. We will talk about the data right now in specific subsets of prostate cancer.

[00:40:07]

Approvals of Existing PARP Inhibitors in mCRPC

This is really a slide that summarizes all the options we have for using PARP inhibitors either alone or in combination for treating metastatic CRPC. As you can see, we now have a variety of options really six different treatment options, or actually no five different treatment options, either monotherapy or in combination. I will talk about the data underlying these different approvals and where we may lean towards a combination vs an individual drug.

The two monotherapy approvals, the first ones that happened actually, were olaparib, based on the PROFOUND study, and rucaparib based on TRITON2 initially and subsequently TRITON3. Then the combinations that have been approved specifically in first line metastatic CRPC are olaparib with abiraterone, niraparib with abiraterone, and talazoparib with enzalutamide. I will talk about the context where these are approved, whether it is just BRCA1, BRCA2 or across a variety of HR genes.

[00:41:06]

Key Phase III Trials of Single-Agent PARPi in mCRPC

These are the key phase 3 trials of monotherapy PARP inhibitors in metastatic CRPC. As I just showed you, these are olaparib per the PROFOUND study and rucaparib initially per TRITON2, now per TRITON3. I will not go into detail on the data here for these studies, but just to say that these are both Phase 3 randomized studies that enrolled based on genomic status. The PROFOUND study randomized patients who had a variety of DDR gene mutations, predominantly BRCA2, BRCA1, but including a number of other genes, it was a total of 14 actually genes that were allowed based on preclinical data suggesting sensitivity to olaparib or PARP inhibitor monotherapy.

Patients for this study were randomized to receive olaparib vs physician's choice. I just want to stress that the physician's choice was a crossover ARPI only. It did not include the more active drug, which was docetaxel in that setting, it was only a crossover ARPI. What the study did, is it hit its primary endpoint of PFS benefit in the overall population, as well as in the BRCA1, BRCA2. It was strongest in BRCA1, BRCA2, the hazard ratio 0.34, but again vs a crossover ARPI only. There was actually an overall survival benefit ultimately, which is a key secondary endpoint here. The study hit its endpoints and it led to the second PARP inhibitor approval, which was olaparib in across a variety of HR genes.

The FDA actually approved it across all but one of the genes, which is a little bit interesting here. They excluded one gene where it looked like there was a detriment, so that is PP2R2A, even though it was very small numbers.

Then the other study here we are showing the follow up phase 3. Initially the approval was based on a TRITON2 study, but the confirmatory phase 3 study, TRITON3 was a recapper vs physician's choice. It was focused on BRCA2, BRCA1, and ATM as opposed to a broader set of genes. Importantly, the physician's choice here included docetaxel so that was a key difference, and it showed superiority of rucaparib in BRCA2, BRCA1 vs this physician's choice including the subset vs docetaxel. So, it beat out chemotherapy which is really the strongest evidence that you should use a PARP inhibitor instead of chemo, instead of taxane chemotherapy. The hazard ratio here was 0.5. Now, I am not comparing across studies, but again you have to be cautious. This was a hazard ratio vs treatment options that included docetaxel. It was another positive study. Rucaparib was approved in that context. We got two monotherapy drugs. Both were after an ARPI in metastatic CRPC.

[00:43:48]

Rationale for PARPi Plus ARPI Combinations

That is the main distinction between the combination studies which I will discuss right now. The rationale for combinations was number one, earlier use of combination of active drugs. Number two some preclinical data that suggested synergy, not just an additive effect between inhibition of the androgen receptor and PARP inhibition. The hypothesis here was that, or some of the preclinical rationale was that, blocking the androgen receptor actually inhibits DNA repair pathways, so it sensitizes tumor cells, even if they are not inherently HRR deficient, sensitizes them to PARP inhibitors, which obviously are DNA damaging in some way. That was part of the rationale for running these studies, not just in HRR mutated but across solid tumors.

[00:44:33]

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

It formed the basis for this initial phase 3 study, PROpel, which is a study of abiraterone plus olaparib vs abiraterone alone. This was a randomized phase 3 study in first line metastatic CRPC. First line means these patients were predominantly ARPI naive. They had not received Abi, Enza, or any other drug and they were newly CRPC. The study was unselected. It enrolled all comers. It only had an exploratory retrospective analysis based on HRR mutation status. Again, the hypothesis here was that there would be synergy in all comers, and it randomized patients to get the standard care at the time abiraterone alone vs abiraterone plus olaparib. The primary endpoint was rPFS. It had some key secondary endpoints including OS. Then again, key message here is this is a population that does not exist so much anymore, ARPI naive population.

[00:45:26]

PROpel: Radiographic PFS in ITT and BRCA-Mutated Populations

The study did hit its primary rPFS endpoint across the entire population with hazard ratio 0.66. The benefit was greatest in patients with BRCA mutations. Not surprisingly, those are the ones who benefit the most from olaparib. The hazard ratio here was an impressive 0.23.

[00:45:43]

PROpel: Final OS in BRCA-Mutated Subgroup

This is the final overall survival data from this particular study. There was no clear OS benefit across the entire population, it was not statistically significant, but there was an OS benefit when you limit to the BRCA retrospectively identified population. The Kaplan-Meier curves represent that here with a hazard ratio of 0.3 for overall survival. The FDA ended up approving the drug just in the BRCA2, BRCA1 setting here, or the combination I should say BRCA2, BRCA1 first line metastatic CRPC.

The second study, very similar design is the MAGNITUDE study with one key exception. This study used niraparib instead of olaparib. This study was more cautious in the prospective design and essentially had two separate prospective cohorts; one of HR mutated patients that predominantly consist of BRCA2, BRCA1, and a separate HR non-mutated population, completely distinct, to really test out the question of synergy in all comers. It essentially stopped enrolment early because of hitting a futility rule in the HR negative population. That was a completely negative result in the HR negative population. The HR positive population, though, had a positive PFS result. The endpoint was the same. The population was generally the same.

[00:46:51]

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

First line CRPC ARPI naive, and these are the curves for the BRCA positive subgroup, which was the one that benefited the most within the HR positive population. Hazard ratio was 0.55 here, but positive for rPFS.

[00:47:18]

TALAPRO-2: Enzalutamide ± Talazoparib in Patients With Newly Diagnosed mCRPC

In this context, the study was granted FDA approval. Again, abiraterone plus niraparib in BRCA2, BRCA1 mutated first line CRPC. Then the last study here that Dr. Agarwal was the lead on, was TALAPRO-2, which is a similar space. First line metastatic CRPC. A little bit more patients had actually prior ARPI, although the majority did not. It was 6.5% here. The study was run later. ARPIs in CSPC setting were certainly much more common at that point, and it randomized patients to receive either a first line enzalutamide, again the standard of care, vs enzalutamide plus talazoparib.

This study did not have separate cohorts, but it did very, very careful prospective genomic profiling. Actually, the majority of patients had both tissue and plasma prospective profiling. Very well aware of the distinction here between the HR positive and negative population. The genomics was very carefully established and the endpoints were the same, a primary endpoint rPFS, secondary endpoint, key secondary of OS. What this study found, which was actually quite interesting. First of all, the benefit was greatest in the HR deficient population. If you are actually limit to the BRCAs not surprisingly, it is where beneficial is greatest. That is on the right side. The Kaplan-Meier curves with hazard ratio 0.47 across HR negative. It did show benefit across the entire population as well, including the patients without HR mutations that showed an rPFS benefit across that population. That was a very nice to see that.

[00:48:59]

TALAPRO-2 Cohort 2: rPFS by HRR Gene Mutation

The OS and, before I get to OS actually, there was very nice gene by gene analysis in this study, which was published subsequently in a Nature Medicine paper first author Dr. Fizazi. What this showed is probably the first data that was convincing enough that patients with CDK12 mutations, which are 6% of patients with metastatic CRPC, actually derive a PFS benefit from a PARP inhibitor added on to enzalutamide, which you can see here in the Forest plot. This will come back to that second pretest question we will come back to. Patients with ATM mutations CHEK2 mutations do not appear to benefit. So, the confluence of data do not show any substantial benefit for patients with ATM CHEK2 mutations. Of course, the BRCA2 mutations benefit the most. Those are the ones who really do benefit the most from PARP inhibitors, whether alone or in combination. This was a very nice analysis to see because it really showed utility for CDK12 patients for this combination.

[00:49:58]

TALAPRO-2: Overall Survival in ITT and by HRR Mutation Status

This is the overall survival data. Overall survival was positive for the HR deficient population but not statistically significant in the overall population, or in the HR non-deficient population. The FDA ultimately granted FDA approval for the combination of enzalutamide plus talazoparib in a broader set of HR mutated genes, not in all comers, but beyond the BRCA2, BRCA1, and particularly again, the CDK12 is important, 6% of patients here.

[00:50:31]

NCCN Guideline Recommendations for mCRPC

Based on this, the NCCN guideline recommendations here match up very nicely with the data, not surprisingly. In the first line mCRPC context, your rare patient who comes in and is ARPI naive, which is pretty uncommon nowadays, you do see one on occasion, the category one recommendations based on really overall survival benefit are combinations of an ARPI plus a PARP inhibitor. Some of you, I think, heard the breakaway data which supported that today, although we are talking about a much smaller study. These studies are large studies, hundreds of patients. Category one is abiraterone plus niraparib or abiraterone plus olaparib or talazoparib plus enzalutamide, but you heard the discussion from Avenue saying that sequential use is still an option. You have to weigh survival benefit vs toxicity of the combinations.

So, sequential use is also an option, but the category one survival based recommendation is the combinations. Then post an RP, the category one recommendations is still monotherapy. Why? Because we do not know convincingly that a combination is going to be beneficial to a patient. There is added toxicity risk. It is an option though category 2B but the combinations after a patient has already received an ARPI remains to be proven. You heard Dr. Alicia Morgans leading a cooperative study asking that question very precisely. After abiraterone, do you give talazoparib alone? Do you give talo [? 00:51:58] plus enzalutamide? What is the benefit there? That is hopefully going to answer that question.

This is really where we are. You have got monotherapy options. You have got combination options, plenty of options, and it depends on the context. Are the ARPI naive or not? What is the gene combination? A lot of these approvals are just BRCA2, BRCA1 but two of them, two combinations go beyond BRCA2, BRCA1 particularly CDK12 with single out. The only data supports enzalutamide plus talazoparib.

[00:52:27]

AMPLITUDE: Phase III Trial of Niraparib Plus AAP in HRR-Deficient mHSPC

Really, I am almost done. I know, because this is tons of data. I only want to discuss really AMPLITUDE next, and that is the only study in the metastatic HSBC setting that has read out so far. This was a phase 3 trial of niraparib plus abiraterone in HR deficient metastatic HSBC. Now J&J, which has this combination, they had seen the failure in the later study across all comers. AMPLITUDE was a study that was run only in HRR mutated patient population that included BRCA2 and BRCA1. Patients here were newly diagnosed. They had about four months to actually enroll from starting ADT, so they had a nice long window to get the genomic testing done. If they were positive for any one of these genes they were randomized to continue just abiraterone alone, which is standard care or receive abiraterone niraparib. The primary endpoint was rPFS. Secondary endpoints of OS and some other endpoints. Predominantly this was patients with BRCA2 alterations. Just about half of the patients there in both arms.

[00:53:35]

AMPLITUDE: rPFS by Subgroup

The study met its overall PFS endpoint in the entire group. Although the benefits were greatest in BRCA, and actually if you really narrow it down, it was greatest in the BRCA2 population. Ultimately, the overall survival is not mature yet, but leans towards a benefit in the BRCA2 population, which we think will pan out eventually. The FDA granted actually the approval specifically for BRCA2 mutated mCSPC. This was the first PARP inhibitor approval in combination with abiraterone in BRCA2 mutated mCSPC. As Dr. Agarwal mentioned, really argues strongly for doing the genomic profiling as soon as the patient is diagnosed with metastatic disease, or maybe even earlier.

[00:54:19]

NCCN Guideline Recommendations for mHSPC

Then this is the NCCN guideline recommendation for mCSPC, patients newly diagnosed with metastatic disease. The only approval is niraparib abiraterone, and it is a category 2B in this situation because we do not have OS survival benefit although it is trending there for BRCA2 mutated disease.

[00:54:39]

Future Directions of PARP Inhibitors in Prostate Cancer

I have two minutes left and that is enough time to really talk about current and future directions, and then to really summarize the data. Future directions, earlier use of PARP inhibitors in HRR mutant prostate cancer. We see that most active drugs are actually showing benefit when used earlier and earlier. We saw that with ARPI initially. We know that some of the drugs that moved into first line CRPC have shown benefit. The question is what if you move it even earlier. We know already that abiraterone niraparib is effective in BRCA2 mutated mCSPC. There are ongoing trials that looking at partially the same population. I do not know why the name of the study here disappeared, but TALAPRO-3 is the enzalutamide plus talo vs enza study in mCSPC and EvoPAR01. These are all enrolling actually both HR mutant and wild type. EvoPAR01 and AstraZeneca plus saruparib plus ARPI vs ARPI alone. Then you have got really it is moving even earlier in trials in high risk localized HRR mutated prostate cancer.

You have got the NEPTUNE study neoadjuvant olaparib before prostatectomy for BRCA mutated high risk localized prostate cancer. Then you have got a big international study from AstraZeneca randomized, EvoPAR02, which is adjuvant saruparib after RT vs placebo for men with BRCA2 mutated, high risk localized prostate cancer and biochemical recurrent disease. That is a multi-hundred patient international study that is really looking at and trying to cure patients with earlier use of the PARP inhibitor.

Then you have got PARP inhibitor combinations in non-HRR mutated prostate cancer that are really asking the question, is there a synergy? TALAPRO-3 and EvoPAR01 are exploring that question in non-HR mutated. Then you have got really pretty promising path here PARP inhibitor radioligand therapy where we know that there is probably crosstalk and potentially benefit that goes beyond HRR mutated patients. Certainly olaparib and lutetium PSMA, it has been reported to be safe as a combination. Then you have got PARP inhibitors and other DNA repair inhibitors that are still, I would say in phase 1, but with good preclinical rationale, like pol theta inhibitors, where you might actually have synergy as well between these different DNA repair pathways.

[00:56:54]

Conclusion: PARP Inhibitors in Prostate Cancer

That is really a future direction. Just to conclude, PARP inhibitors have changed the treatment landscape of prostate cancer, especially with recent approval in the hormone sensitive setting. The combination of abiraterone prednisone with niraparib is now approved for BRCA2 mutated CSBC or HSBC. The combination of PARP inhibitor in ARPI is appropriate for patients with HR mutant first line mCRPC. The benefit of the combination is really unclear in ARPI treated patients, as opposed to monotherapy, which remains the category one recommendation for patients who were previously treated with ARPI. As in current practice, few patients are ARPI naive when they develop a first line CRPC.

The benefit is greatest in patients with mutations BRCA2 and BRCA related genes like PALB2, for instance. There is no clear benefit from all the studies that have come out so far, I would say leaning towards saying there is no benefit, in patients with ATM and even CHEK2 mutations. There are approvals though, because they were lumped in with the other genes. There is a possible PFS benefit for enza plus talazoparib CDK12 mutant metastatic CRPC. That was my last slide.

[00:58:02]

Let's Return to Our Questions

We will return to the question.

[00:58:04]

Posttest 2

Number one. 74 year old man presented with de novo metastatic prostate cancer treated with ADT and upfront docetaxel. He now has castration resistance, so first line mCRPC, he has tissue testing that shows BRCA2 mutation. Which of these therapy would you give him? I think previously 92% of people had answered the same question. Maybe we can go straight to the poll here. It is 100%. All right. Good. Next slide please. Can we go back one slide? Sorry. I think I advanced it too fast and that is the correct answer. For patients with mCRPC without a prior ARPI, the category one recommendation is really a combination. It is really the one with OS benefit. You could give either abiraterone with olaparib abiraterone plus niraparib. One of these combinations showed an OS benefit, the other one substantial rPFS. You could certainly give sequential use, but again category one is this combination PARPi plus darolutamide probably is effective, but not approved. There was no study really testing it out. It is reasonable to start with abiraterone plus prednisone, but you do not have an approval for olaparib in that context. Next slide.

[00:59:30]

Posttest 3

Then the posttest three. Which of the following statements accurately describes results from TALAPRO-02?

A. The FDA approval was granted for BRCA1, CRPC only;

B. Most patients had received an ARPI for HSBC prior to enrolment;

C. In gene by gene subset analysis patients with ATM mutations appear to benefit; or

D. In gene by gene subset analysis, patients with CDK12 mutations appear to benefit.

Next slide. I am sorry poll. The answer here is 100%. I think the message got through that CDK12 patients appear to derive a PFS benefit here. Very good. I think that was the last slide for my presentation. I will come back to Dr. Agarwal.

Dr. Agarwal: Dr. Lacuna will go through some cases again.

[01:00:26]

Master Class Case Discussion

Dr. Lacuna: All right. Hi, everyone. This is our second case. I will ask Dr. Agarwal, Dr. Abida, and the rest to go to the audience to have some discussions about this case. This is a 57 year old male diagnosed with de novo metastatic prostate adenocarcinoma. Just some features of his disease. Gleason eight. PSA is quite high at 712. He has high volume disease with 10 bone metastases. Underwent treatment with ADT and abiraterone and had a response for 36 months, unfortunately progressed to mCRPC, at which time ctDNA was sampled and showed a pathogenic BRCA2 mutation, which was identified.

The question here for discussion based on all the data that Dr. Abida presented, was what treatment would you choose? The options are olaparib, rucaparib, talazoparib plus enzalutamide, niraparib plus abiraterone, olaparib plus abiraterone, and docetaxel. There may not be one right or wrong answer here. I will open it up for discussion amongst yourselves, and I will be talking to the online audience.

Hi, everyone. If anyone wants to put their questions in the chat that would be helpful here. In terms of this case, I think that there are a few things to consider. One, this patient was diagnosed with de novo disease, and in the mHSPC setting, the patient underwent treatment with a prior ARPI plus ADT, which is what we see in more contemporary times. Again, we have to think about how these studies were designed when Dr. Abida was presenting them. It was at this time, after progression of an ARPI in the setting of hormone sensitive disease, that he was found to have a BRCA2 mutation.

Previously treated with abiraterone in the mHSPC space. Things to think about here. What are some things that we probably would not do? We saw from the data that when someone is presenting in the mCRPC space with a BRCA2 mutation, you really want to think about PARP inhibitor. This patient was treated with prior abiraterone. I think when we are thinking about the options for olaparib plus abiraterone, this was one of the earlier studies that was designed in this study where we looked at olaparib plus abiraterone. There really was not an allowance for abiraterone in the mHSPC setting because that just was not what the times were. In contemporary times, yes, they are treated with ARPI in the HSBC setting, but that is very different now.

Now we think of the MAGNITUDE study which really presented niraparib plus abiraterone. These patients were allowed abiraterone in the mCRPC setting if it was less than four months. Less than 3% of patients were exposed to abiraterone. It is included in the NCCN guidelines that you could consider this potential treatment.

The other option, which is moving along more contemporary times, was the TALAPRO-02 study, where we are looking at talazoparib plus enzalutamide. In this study again, a later study, they did allow and stratified the study for prior treatment with abiraterone in the mHSBC space. You could certainly consider talazoparib plus enzalutamide in this setting.

When we look at single agents, olaparib and rucaparib, olaparib was approved based on the PROFOUND study post-ARPI and rucaparib post ARPI in the TRITON2 and TRITON3 study. Those could also be considered in this setting. I think, when we are thinking about this case, we think about either these single agents post-ARPI, pre or post-docetaxel or in this case where this patient received abiraterone in the mHSPC setting, you could really consider talazoparib plus enzalutamide based on how TALAPRO-02 was designed, as well as MAGNITUDE where we are looking at niraparib plus abiraterone. You really have to think about whether you are going to choose a single agent vs a double agent in the setting of this patient, patients disease, comorbidities, and looking at the OS and PFS benefit that we see there. I think that those are important pieces of information.

I think another thing that we should also discuss is that this patient was diagnosed with de novo disease in the mCSPC or mHSPC setting. And we, again, are seeing another missed opportunity here where we are not seeing genomic testing right from the get go. This is a potential missed opportunity where we could have seen a potential BRACA2 or HRR mutation, and they could have offered themselves treatment based on amplitude, where we are bringing PARP inhibitors in the mHSPC setting. That I think is a potential missed opportunity where the patient was treated with ADT plus abiraterone, where they could have been treated if they had an HRR or a BRCA mutation, BRCA2 mutation specifically, in the approval where they could have been treated with a PARP inhibitor in addition to ADT plus abiraterone in the mHSPC setting based on ANPLITUDE.

I think that is something to think about and, again, when we think about these cases, it is another potential missed opportunity where we could have been testing for this. I think the important thing that this case hones in upon is that probably the most wrong answer is we should not treat them with docetaxel for several reasons. One, showing the superiority of PARP inhibitors for patients with BRCA2 mutations in the studies that Dr. Abida presented, but also a more targeted approach based on either combination or single agent therapies.

With that, I will stop there. Hi, everyone. I am just going to bring everyone back. Bring Dr. Agarwal back to the stage to summarize the discussions amongst the group. I think this was a good discussion. Thanks.

Dr. Agarwal: All right. We can discuss what was discussed during the case. I had a discussion with the group here, and then Nabil, did you have discussion? Maybe Dr. Adra can talk about his discussion point.

Dr. Nabil Adra (Indiana University): Sure. This is a patient with metastatic castration resistant prostate cancer. Who has had prior abiraterone and has a BRCA2 alteration. When we went over the options, one option could be using single agent PARP inhibitor with olaparib. Then the other option could be using enzalutamide plus talazoparib. We went over the pros and cons of which approach to choose. We thought both options are reasonable. It is worth having a discussion about both options. When we look at enzalutamide plus talazoparib on the TALAPRO-02 trial, there are certain population that had abiraterone and hormone sensitivity and progressed and received that combination and benefited. On NCCN that is a category 2B recommendation, I believe. Both of those are reasonable The discussion was that the priority that this patient should get a PARP inhibitor as their next line of therapy, either as a single agent or as a combination with an ARPI.

Dr. Agarwal: Thank you.

Dr. Abida: We discussed really the category one in a patient who had prior ARPI per the guidelines as monotherapy with either rucaparib per TRITON3 or olaparib per PROFOUND the option for the combination exactly. We would not continue the abiraterone. I think that would make no sense. Certainly a crossover to enzalutamide plus talazoparib would be reasonable. Again, that is an unanswered question if they are getting benefit from enzalutamide. That is the question that hopefully will be answered by the randomized study that is currently enrolling.

Dr. Agarwal: Great. We had a discussion Dr. Gabriel Hooper presented the data today in ASCO GU on mCRPC, the line of therapies patients are receiving and what is the most common agent used in mCRPC in the first line, which is ARPI. The discussion brought up by Dr. George Jabril and Tanner Hardy was that in US, which is a high PSA screen country as opposed to, say, one of the countries in South America, Brazil, for example. I was talking to my Brazilian colleagues and PSA screening is not very high. In a high PSA screened country or area, localized prostate cancer is the most common way to diagnose prostate cancer. And these patients have surgery or radiation or both. We do not see those patients, frankly. We are in academic cancer centers. I mostly see metastatic hormone sensitive prostate cancer unless I am seeing locally advanced prostate cancer for abiraterone. Which is going to be delivered by us because they are getting radiation therapy through our radiation oncology colleagues, we mostly see mHSPC, which is only 10% of new prostate cancer diagnoses in the US. 90% are localized prostate cancer. They undergo surgery or radiation or both, and they have biochemical recurrence. I am talking about cases for last 10 years. They have received ADT monotherapy, intermittent ADT, and when they have slowly progressing PSA, they are diagnosed to have CRPC.

That is another very common case scenario in the community where CRPC patients exist without prior exposure to ARPI. That is why in the Flatiron data set Dr. Hooper presented today, that a lot of patients with CRPC were ARPI naive. The first line therapy was ARPI. How many patients got ARPI in first line CRPC? 70%. This is consistent with our own data we presented in AUA last year. How many patients had exposure to ARPI prior to onset of mCRPC? That was 33%. It looks like we have a very different patient population in our clinic. In the real world out there, seen by surgeons and radiation oncologists, they are seeing very localized prostate cancer patients.

Then second discussion was the attrition rate in mCRPC, which is very high. 50% of patients in the real world do not see the subsequent lines of therapies. It is very important that we have these testing results ready in metastatic hormone sensitive setting, or whenever we see them first, so that we do not spend time on figuring out how to test them, when to test them. Sometimes you order the test. The bone biopsy is scheduled four weeks after, five weeks after. Then, as Dr. Adra Mentioned, decalcification can pose a problem. We get the results after two months and there is negative or insufficient tissue. Then we try to do another biopsy. To resolve all of that, we can do biopsy for all these patients upfront, so that we do not have to really worry about having to find a target when they are really having disease progression in a rapid phase, rapid manner in CRPC setting.

How to prevent attrition of patients is to be ready with the test results before they develop mCRPC. Those were the discussions we had.

With that, the next talk and the final talk, thank you for all your patience today. We will start with Dr. Nabil Adra's talk. Mitigating adverse events with PARP inhibitor combinations.

[01:14:10]

Mitigating AEs With PARPi Combinations: Optimizing Patient Quality of Life

Dr. Adra: Thanks, Neeraj. All right. I get to do the fun part with toxicity management.

[01:14:17]

Let's Start With a Question

We are going to start off with a question.

[01:14:20]

Pretest 4

Patient began treatment with a PARP inhibitor plus abiraterone and prednisone eight weeks ago. He now reports fatigue, dizziness, shortness of breath, and a headache. He is diagnosed with grade 3 anemia. 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?

We can skip this part then, 100%. Great.

[01:15:15]

Common Toxicities With PARP Inhibitor Monotherapy

We are going to go over toxicity management here briefly. When we talk about PARP inhibitors as monotherapy, the two main trials we have were the PROFOUND trial looking at single agent olaparib and the TRITON3 trial, which is looking at single agent rucaparib. You can see that anemia is one of the more common side effects with PARP inhibitors. Close to half of the patients who are exposed to PARP inhibitors will develop some form of anemia, and about 20% to 25% of patients will have significant grade 3 or higher anemia that requires intervention. Some of the other common side effects you might experience would be GI side effects like nausea, vomiting, diarrhea, constipation. Fatigue and asthenia is fairly common. And then some liver function test abnormalities. Other cytopenias and elevation in creatinine are less common and usually lower grade.

[01:16:07]

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

When you look at combination treatments, the three main data sets that we are looking at here is PROpel, which is combination of abiraterone plus olaparib. MAGNITUDE which is combination of abiraterone plus niraparib. TALAPRO-2 with enzalutamide plus talazoparib. You can see that with the combination the adverse event profile becomes a bit higher. Anemia remains fairly similar with close to half of the patients having some form of anemia, anywhere between 50% to 70% of patients having anemia. But you can see that grade three or higher now ranges anywhere between 16% to 49%. Certainly something to look at very closely, especially when you are starting patients on PARP inhibitors in the first few months. Those need to be monitored very closely to look for any dose adjustments that are required.

Other cytopenias like thrombocytopenia and neutropenia tend to be lower grade and do not require as much intervention. Cardiac toxicity is something to monitor, specifically, hypertension is a class effect. We see it specifically with niraparib seems to be more common and higher grade as well. Arrhythmias and cardiac failure can occur as well. Fatigue is common side effects with PARP inhibitors and then some GI toxicity. DVT and PE can occur. They are less common, but certainly something that needs to be monitored for in this patient population as well.

[01:17:35]

Dosing Considerations for PARP Inhibitors

These are some of the dosing considerations for PARP inhibitors, which my colleagues have discussed earlier as well. We will go over those fairly quickly. Niraparib's approval is with abiraterone. it is dosed at 200mg daily. You can see the half-life is about 62 hours. There are some interactions that need to be considered. Niraparib should not be administered with CYP3a4 inducers such as enzalutamide and apalutamide. That is certainly a consideration with niraparib. And you can see it has a strong PARP one and two inhibition.

Olaparib is approved both as a monotherapy and in combination with abiraterone and prednisone. The dose remains the same, which is 300mg twice daily with and without food. Half-life is about 15 hours and again avoid potent CYP3a4 inhibitors like enzalutamide and apalutamide. Rucaparib is approved as a monotherapy at a dose of 600mg twice daily, with a half-life of 26 hours. For this particular drug, if you are using warfarin, you really should be watching the INR much more closely as you can see some interactions there. Then talazoparib is approved with enzalutamide. It is given at a 0.5mg orally daily dosing. Has the longest half-life at 90 hours. With this drug you should avoid P-glycoprotein inhibitors and BCRP inhibitors such as drugs like amiodarone or cyclosporin, and so on. Among those, it has the most potent PARP trapping compared to olaparib.

[01:19:11]

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

These are some of the data for dose modifications when those drugs are given as monotherapy or in combination. If you focus on the first two columns with PROFOUND and TRITON2, those are the monotherapy trials with olaparib and rucaparib. You can see that about half of the patients require dose interruption of PARP inhibitor, and anywhere between 20% to 40% of patients require dose reduction, and about 15% to 18% require discontinuation. PE and DVT can occur, but they are not that common but need to be monitored for. Of course, with PARP inhibitors, MDS is something to watch for, and certainly something, even though not common, but certainly something that needs to be monitored for.

In those data sets, about 25% to 30% of patients had requirement for red blood cell transfusion. When you look at the combination with MAGNITUDE, PROpel, and TALPARO-2, you can see that similarly about half of the patients required dose interruption. Then anywhere between 20% to 55% of patients required dose reduction of the PARP inhibitor, and 17% to 22% required discontinuation of the PARP inhibitor. Again, PE and DVT, something to look at. Then MDS and MDS and AML also was reported. Not that common but something to follow.

[01:20:30]

Managing Key AEs and Safety Considerations With PARP Inhibitors

How do you manage key adverse events from PARP inhibitors? Cytopenia is the one that seems to occur most commonly and needs to be monitored most closely, so we usually recommend checking CBC with differential on a monthly basis when you start this treatment. If you see major cytopenias, hold the dose until recovery and discontinue if not resolved after 28 days. This is for higher grade cytopenias. Fatigue can be mitigated with some exercise, massages, cognitive behavioral therapy and obviously you have to rule out anemia and other causes of fatigue. GI you could use prophylactic antiemetics loperamide for diarrhea as needed. Hypertension is fairly common, as we mentioned specifically with niraparib can occur as well. Exercise regular blood pressure monitoring using a low sodium diet and antihypertensives. Then some of the more rare but serious side effects like PE and DVT should be monitored for really closely. We do not recommend prophylactic anticoagulation. Then MDS is specifically important as we move PARP inhibitors as well to earlier lines of therapy, and patients remain on PARP inhibitors for longer, certainly something to monitor for.

These are below the table with the dose modifications of those drugs, and you can view each of those drugs has one or two dose reductions available if needed for toxicity management.

[01:21:55]

Managing Anemia With PARP Inhibitors

Anemia is the most common and the one that occurs typically early. If you experience anemia with PARP inhibitors, really you should evaluate for other causes. If you have grade 3 or higher anemia, that is typically a hemoglobin less than eight or transfusion is required, then the recommendation is to hold the PARP inhibitor. You should also consider holding if you have grade 2, which is hemoglobin between eight and 10, but with quite a bit of symptoms as well. The transfusion of packed red blood cells is usually the next step. Then if hemoglobin recovers to more than nine after a grade 3 event, you can restart the PARP inhibitor, typically at a reduced dose.

[01:22:34]

Strategies for Promoting Adherence to Oral Therapies

What are some strategies to promote adherence to oral therapies? A lot of those regimens can be complicated. We are asking patients to take, in a lot of instances three different pills, abiraterone for example, prednisone, olaparib. Some is with food. Some is without food. It can get complicated. Usually you should explore and address patient needs and preferences. Really motivate patients on the underlying why and the importance of taking those medications on time and on schedule. Simplify those regimens. Make sure there is a caregiver on board, which is extremely important in those patient populations. Work through any financial concerns as well. Usually just ask questions. These are a couple of examples of questions here. How are you taking the drug and how much does it cost. Cost is a big part of patients concerns whenever we are recommending those regimens as well.

[01:23:24]

Let's Return to Our Question

If we go back to our question, we already had 100%.

[01:23:30]

Posttest 4

This patient started on a PARP inhibitor plus abiraterone and prednisone eight weeks ago and now has fatigue, dizziness, shortness of breath, and a headache. Has grade 3 anemia. You transfuse red blood cells, and what would you also recommend for this patient? You can vote again. Do not change your answer.

All right. For grade 3 anemia in a patient on a PARP inhibitor based therapy, you usually recommend holding the PARP inhibitor until that is recovered. Transfuse red blood cells as needed and then dose reduction of the PARP inhibitor. Typically most patients can get to a good dose and remain on it for a long time without further requirements for transfusions.

[01:24:19]

Monitor Class Case Discussions

I will let my colleague go over the case.

Dr. Agarwal: I think we can stay here. It will be quick. Is it okay?

Dr. Lacuna: All right. This is our last case. This is a patient with mHSPC who received ADT plus abiraterone and experiences, unfortunately, progression of disease to mCRPC. Underwent a ctDNA testing, which revealed a pathogenic PALB2 mutation, and through shared decision making decides to begin talazoparib plus enzalutamide. After three months of being on treatment, the patient's PSA does decrease by 30% with a partial response. However, though unfortunately the patient develops grade 2 to 3 fatigue and also quite symptomatic anemia with dyspnea on exertion. Hemoglobin that decreased from 12.8 to 8.9. Grade 1 thrombocytopenia with platelet count of 85,000 and intermittent nausea. How would you think about treating this patient? You discuss amongst yourselves. Let me see if there is any questions on the chat.

Dr. Agarwal: We can do a panel discussion.

Dr. Lacuna: I think some of the things that-

Dr. Agarwal: You can activate our mics. Thank you.

Dr. Lacuna: Are what the question that was brought up by doctor earlier was the grade 2 to 3 fatigue, but really the symptomatic anemia. One of the things that you have to think about is dose reduction and then treating the symptomatic anemia until it improves and then dose reducing afterwards once they improve. That is something to think about. I do not know if you guys had other considerations for this patient as well.

Dr. Agarwal: As, Nabil, you mentioned, anemia happens early during the course of disease. 3.4 months was the time of onset of grade 3 anemia in the TALAPRO-2 trial. Once we reduced the dose so first step is to hold the drug. Symptomatic management. If they are symptomatic, give blood transfusion. But then we reduce the dose. Most patients who reduce the dose were able to go on a cruise control for until they had disease progression.

[01:26:58]

Master Class Case Discussion (cont'd)

What I did, I started doing is to check anemia, check for anemia every month, and look for anyone who is going to develop grade 3 anemia. Because 50% of patients will not develop grade 3 anemia on this combination. I do not decrease the dose upfront. One of the VA doctors called me and asked me, "Should we reduce the dose?" No, because half of the patients will not develop grade 3 anemia and half of the patients who develop, about 44%, I reduced the dose. Once they reduce the dose, they can tolerate it until they have disease progression.

My hypothesis without PK workup is, based on the earlier PKPD study we had with tala-enza, in many patients, talazoparib level goes up in presence of enzalutamide. It is really difficult to assess who is going to develop that high level of talazoparib. My hypothesis is, these are the patients who are developing grade 3 anemia. They have higher talazoparib level than predicted by the initial 30 patient PKPD studies. Decrease the dose and they do very well. One thing I really do is to make sure I get vitamin B12, folate, and iron level for all these patients who are starting docetaxel chemotherapy or any of these cytotoxic agents.

Dr. Adra: I have had a very similar experience. Most of those patients develop this anemia very early on. I actually know it has helped that you set the expectation with the patient that you have about a 50% chance you will have anemia. If it does happen, then we will deal with it. We will check your CBCS monthly. If you have grade 3 or higher we will hold, transfuse, dose reduce. Then the patients have had to dose reduce, almost all of them did very well. Never had to go off drug again, no interruptions until unfortunate progression but a very similar experience as well.

Dr. Abida: There does seem to be a higher toxicity rate with this combination, and it could be because of the drug interaction, even though talazoparib is half the monotherapy dose, 0.5. The anemia rate is grade 3 is almost double. We have to be vigilant about that. And the other thing is of course, when you go to combinations you have to tease out the toxicity. Particularly in this case, the anemia is only grade 2 but it is trending down. I agree with the dose reduction of the PARP inhibitor in this situation. But the fatigue seems out of proportion, grade 2, grade 3, this is a patient that might end up needing a dose reduction of both enzalutamide, which we know we actually do in practice for patients who get a lot of fatigue and foggy memory, as well as the talazoparib. You do have to tease out the toxicities and dose reduce each drug independently based on its toxicity.

Dr. Agarwal: I think you made a very good point. Patients who have not developed grade three anemia yet, but they are on track to develop grade 3 anemia and-

Dr. Abida: Thrombocytopenia.

Dr. Agarwal: We can decrease the dose even without grade 3 anemia. If somebody his hemoglobin has gone down from 15, in Utah we have a lot of patients with a hemoglobin of 14 because of high altitude, and it goes to 10 or 11, there is no reason why a patient will not develop a hemoglobin of nine after two months. I reduce the dose if there is a clear trajectory of decline, every month we are losing one gram percent, I reduce the dose without reaching grade 3, which was not allowed on the protocol. Protocol mandated grade 3 anemia before, and that should not have been the case. We learn with these protocols. TALAPRO-3 does not have that. We expect reduced incidence of grade 3 because we can pre-empt dose reduction or pre-empt grade 3 by dose reduction. Again, we all learn from our patients and with time.