As many of you are familiar with, as you take care of prostate cancer patients, prostate cancer is very heterogeneous. There are many ways to get to advanced disease. Ultimately, in this talk, we are talking about mCRPC, which unfortunately remains incurable and is the cause of death for patients who die of prostate cancer. Of course, there is many routes to get here. The majority of patients that we will all take care of present with locally advanced, local or locally advanced disease, and receive definitive therapy, either surgery or radiation. Then, unfortunately, a fraction of these patients will recur and develop more advanced disease. Alternatively, there can also be patients who present with de novo metastatic disease who start systemic therapy right away, then start on that journey to reach metastatic castration resistant prostate cancer, potentially a little earlier.

[00:07:16]

Treatment Options Across Prostate Cancer Disease States

We have a multitude of therapies approved across the spectrum of prostate cancer. Talking specifically about more advanced disease. We have androgen receptor pathway inhibitors approved in M0 or non-metastatic castration resistant prostate cancer. Once we get into the castration sensitive setting, we have four androgen receptor pathways improved. With de novo disease, we also have triplet regimens including taxane chemotherapy regimens for two of the ARPI combinations. Then getting into the CRPC space, is where we have some of our targeted and novel agents like radioligand, as well as PARP inhibitors, both as monotherapy as well as combination regimens. We are going to get into that data in more detail in the coming slides.

[00:08:07]

mCRPC: Unmet Needs and Current Status

Why do we care about mCRPC and what is our definition of it so that we are all on the same page? It is prostate cancer that progresses clinically, radiographically, or biochemically despite the patient having castrate levels of serum testosterone, so defined as less than 50 nanograms per deciliter. Even though we have all of the therapies that I just showed you on the slide before, androgen receptor pathway inhibitors, chemotherapy, immunotherapy, targeted therapy, now radioligand therapy, it still remains incurable. Patients as they get farther and farther along in the disease course, do you have limited treatment options and ultimately will succumb to their disease. Research and recent approvals are directed towards understanding the inter-individual patient and tumor heterogeneity, as well as biology to personalize the treatment.

[00:09:05]

Optimizing Germline and Somatic Testing for mCRPC Is a Significant Unmet Need

To personalize the treatment, first of all, it is really important to talk about optimizing germline and somatic testing for mCRPC. This is showing some data from a chart review. De-identified real world cohort of 500 patients who had newly diagnosed and actively treated mCRPC. They looked at how many patients got germline and somatic testing. As you can see, less than 60% of patients actually received homologous recombination repair mutational testing. Even though a third of the patients who did get the testing screened positive for having an HRR mutation, only two thirds of those patients actually received a PARP inhibitor, which is on label for HRR mutations. As you can see in this real world analysis, a large proportion of patients did not receive germline or somatic testing, and only a third of patients who were eligible for targeted treatment actually received this treatment. We definitely still have some work to do in terms of optimizing who gets testing.

[00:10:16]

NCCN Guidelines: Recommended Treatment of mCRPC

It is important because it is part of our NCCN guidelines both in the pre-androgen receptor pathway inhibitor space, in the post-ARPIU but pre-chemotherapy space, and then also in the post-post space. Although here we are focusing more on the monotherapies rather than the combination regimens, and we will get into some of this detail.

[00:10:38]

Patient Case Presentation

We are going to illustrate it with a patient case presentation. A 66 year old black man with a history of localized prostate cancers, treated with radical prostatectomy. He has Gleason four plus four grade group four prostate adenocarcinoma. Unfortunately, he has extracapsular extension and he also has a positive margin on surgical pathology. He develops a biochemical recurrence about a year after surgery with PSA rising, with a doubling time of three months. I will hold right there just in case I spoke a little too fast.

[00:11:15]

Patient Case Presentation (cont'd)

All right. Continuing on with the patient's case, he undergoes conventional imaging. It is negative for evidence of recurrent disease. His testosterone is normal, so he is castration sensitive. He started on treatment with enzalutamide for non-metastatic disease in the setting of rapid PSA doubling time.

Unfortunately, his PSA starts to rise over the next several months. He gets standard imaging that now does reveal metastatic disease. At this time, he is diagnosed with mCRPC.

[00:11:55]

Pretest 5

Which of the following would you recommend as the next best step for this patient?

1. Undergo cryotherapy for pelvic lymph node recurrence consistent with mCRPC;

2. Pursue olaparib plus abiraterone for mCRPC;

3. Explore options for clinical trial enrollment and standard treatment through reputable sources of information for patients; or

4. Pursue surgery to remove retroperitoneal nodes that appear involved in the PSMA PET scan.

Speaker 3: Poll is open. Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr. Reizine: All right. Excellent. We have some people doing localized therapy as well as looking at next generation targeted systemic therapy. Then also, of course, exploring clinical trial options. Excellent.

[00:13:09]

Poll 6

Before we move on if you do not mind scanning this QR code to type in the chat, what factors specifically weigh in to the answer that you just submitted for next steps with this patient?

Speaker 3: Thank you, Dr. Reizine. As you said, you can scan the QR code and text in a response, or also alternatively, we have a polling box open where you can just simply type in your answer and Dr. Reizine you can move forward. We will just leave that polling box open for a few more seconds.

[00:13:41]

PARP Inhibitors

Dr. Reizine: Excellent. On topic with one of the answer choices that we just had, we are going to first talk about PARP inhibitors.

[00:13:54]

BRCA-Related Synthetic Lethality With PARP Inhibition

A little bit of background. PARP repairs single strand DNA breaks. When PARP is inhibited through an inhibitor, the single strand breaks can collapse into double strand breaks. BRCA1 and BRCA2 are genes that repair double strand DNA breaks through homologous recombination. Normal cells who have active BRCA1 and BRCA2 can repair these via BRCA mediated repair. If a patient has BRCA mutant cells, they cannot. That is the definition of synthetic lethality and why we preferentially know and expect that patients with BRCA mutant cancers will respond to PARP inhibitors.

[00:14:39]

Rationale for PARPi + ARSI Combination

There are a number of mechanisms of action for rationale for why there may be synergy or, at least, additive improvements in terms of results from PARP inhibitor and androgen receptor signaling combinations. PARP inhibitors may attenuate the resistance mechanisms that patients develop to androgen receptor signaling inhibitors. Androgen receptor signaling inhibitors may actually upregulate PARP and thus induce PARP inhibitor sensitivity by having more of the target available. PARP inhibitors may actually downregulate AR target genes, which lead to resistance, and androgen receptor signaling inhibitors may downregulate HRR genes, thus inducing a BRCAness phenotype for patients who may actually respond better. As you can see, there is a number of different mechanisms that have led to why this is a combination strategy.

[00:15:38]

Approvals of Existing PARP Inhibitors in mCRPC

As a result of that, we have numerous FDA approvals in the CRPC space for both monotherapy regimens as well as combination regimens. It is a little confusing because the FDA indication is biomarker selected. For some of the therapies or combination therapies, it is just BRCA1 or BRCA2 mutated CRPC, and for others it is other HRR alterations. We will go through some of the data that led to these approvals.

[00:16:14]

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

The first combination that was developed was based off the PROpel study. This was a double blind, randomized phase 3 study. Patients with mCRPC who were previously treatment naive for CRPC, and had not been treated with prior abiraterone were enrolled. There was no screening for HRR mutations, but they were tested with next generation sequencing afterwards. Patients were stratified by their site of metastases, and whether or not they received a taxane in the castration sensitive space. Then they were randomized to receive olaparib plus abiraterone and prednisone versus placebo plus abiraterone and prednisone. The primary endpoint was radiographic progression free survival and crossover was not permitted. Key secondary endpoints included overall survival, and you can see that, in less than a third, about a quarter of patients received prior docetaxel. Really no one had received androgen receptor pathway inhibitors in this patient population.

[00:17:22]

PROpel: rPFS in Asymptomatic/Mildly Symptomatic Disease

It did meet its primary endpoint in terms of an improvement in the combination regimen of improving radiographic progression free survival with a hazard ratio of 0.59.

[00:17:37]

PROpel: Safety

Overall, in terms of safety, you can compare the orange, which is the combination, to the gray which is the placebo plus abiraterone. You can see that overall there is slightly increased adverse events in the combination arm, as to be expected. Most commonly and significantly is anemia. This was primarily managed through dose modifications and transfusions when needed. Then venous thromboembolism, including pulmonary embolism, needs to be monitored for, although fortunately for the patients, most of the time these were asymptomatic.

[00:18:14]

TALAPRO-2: Enzalutamide ± Talazoparib in Patients With ND-mCRPC

The next combination regimen that we would want to talk about is enzalutamide plus talazoparib. This was also approved in the mCRPC population based off a double blind, placebo controlled, randomized phase 3 trial. I am going to highlight some of the design differences that were different and the same compared to the PROpel regimen, which we just discussed.

This was also patients with newly diagnosed mCRPC, except these patients were actually prospectively assessed for HRR gene alterations. Patients were stratified whether they were deficient or non-deficient or if it was unknown based off of the testing. They were also stratified by if they would received prior abiraterone or docetaxel in the castration sensitive prostate cancer space. You can see study population slightly different and stratification factors certainly different. The primary end point was the same. It was radiographic progression free survival with a key secondary endpoint of overall survival. Then patients received the combination regimen of talazoparib plus enzalutamide or they received placebo plus enzalutamide.

[00:19:28]

TALAPRO-2: Efficacy Outcomes

It did meet its primary and key secondary endpoint of improving radiographic progression free survival for the primary endpoint, and then also the overall with a hazard ratio of 0.66. Then the combination met the overall survival secondary endpoint with a hazard ratio of 0.7. This was maintained at follow-up of two years.

[00:20:00]

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

The third and final combination regimen that is approved that we are going to discuss is niraparib and abiraterone. This was evaluated in the MAGNITUDE trial which, once again, was a double blind randomized phase 3 trial, but it was different than the prior two studies. The similarities are that once again, this was castration resistant prostate cancer. They could not have received prior treatment except for a brief amount of less than four months of abiraterone. Then patients were prospectively evaluated for HRR mutations, and then were actually placed into different cohorts depending on if they had HRR mutations or they did not have them. Then they were subsequently randomized to the combination versus the placebo plus abiraterone arms. You can see even more prospective stratification. Once again the primary endpoint was radiographic progression free survival. That is consistent across all three of the clinical trials.

[00:21:10]

MAGNITUDE: Final OS Analysis in BRCA + Subgroup

This did meet its primary and secondary endpoints of improved overall survival, particularly in the BRCA1 and BRCA2 subgroup analysis. Those patients did benefit from the combination regimen leading to the FDA approval. Once again, looking at safety, pretty similar to the other regimens that we were discussing. There is a little bit of increased adverse events in the combination arm, as is expected you can see that in the orange. Overall, it was pretty manageable with dose modifications.

[00:21:46]

Conclusion: PARP Inhibitors in Prostate Cancer

In conclusion, there is a clear role for PARP inhibitors in mCRPC. We have a number of FDA approvals in this space. With which HRR mutations, though is where things get a little bit more confusing. Clearly, there is a benefit with BRCA2. These patients do worse otherwise, and they clearly have an improved overall survival with PARP inhibitor treatment. Likely BRCA1 as well as PALB2 and maybe CDK12 also benefit. Some of the other HRR mutations were really getting into very small numbers when you look at how many patients were actually enrolled on the trials. It can be a little bit more difficult to evaluate the actual benefits. I think that it really needs to be a case by case basis.

However, it is important to test. If you do not test, we will never know if the patient has an HRR alteration to make this therapy a possibility for them. Certainly if it is a germline alteration that can be relevant for their families. And then use in earlier disease stages is currently being evaluated. The last combination regimen that we just spoke of niraparib and abiraterone is actually now approved in the castration sensitive space based off the AMPLITUDE trial.

[00:23:10]

Targeted Radiation: 177Lu-PSMA-617 and Beyond

All right. We are going to move on to targeted radiation. Specifically, we will talk about PSMA-617 and beyond.

[00:23:20]

ALSYMPCA: Efficacy of Radium-223 in mCRPC

The first radioligand therapy that was approved in prostate cancer is actually radium-223, based off of the ALSYMPCA trial. This is an alpha emitting particle. It is a calcium mimetic. It homes to regions where new bone matrix is being laid down, and it showed improved overall survival and reduced skeletal complications in men with symptomatic CRPC who had bony mets. Because of this, it was FDA approved back in May of 2013.

[00:23:56]

PEACE-3: Enzalutamide ± Radium-223 in mCRPC

We have some updated data on radium-223 in a combination regimen in the CRPC space that was just recently presented through the PEACE-3 trial. This was an open label randomized phase 3 trial. Patients with CRPC. They were stratified by prior docetaxel use and whether they received bone protective agents as well as prior abiraterone. Then they were randomized to receive enzalutamide alone or to receive enzalutamide plus radium-223. This did meet its primary endpoint of improving radiographic progression free survival with the combination regimen compared to enzalutamide alone. Key secondary endpoints include overall survival as well as skeletal events, very important in this patient population.

[00:24:51]

PEACE-3: Fracture Rates by Mandating Use of BPAs With Enzalutamide ± Radium-223

Very importantly, with this regimen, as many of you may remember with the combination of radium-223 and abiraterone from the ERA 223 trial, without a bone protective agent, fracture risk is increased. This trial was halted and amended to mandate bone protective agents. The cumulative fracture risk actually is low for patients who receive the combination therapy or enzalutamide if they are on adequate bone protecting agents.

[00:25:24]

Key Ongoing Trials Assessing Radium-223 in mCRPC

Radium-223 is having a little bit of a renaissance, I would say. Its initial approval was in 2013, but we have a number of very exciting trials ongoing that are looking at sequencing with chemotherapy, like the RAPSON trial or combination with chemotherapy, like the DORA trial, looking at sequencing with ARPIs and docetaxel. How does it fit into the upfront management of patients with advanced disease? Then, very excitingly, the AlphaBet trial, which is looking at radium and alpha emitting particle and lutetium PSMA, a beta emitting particle, hence the AlphaBet name, combination together. Then looking at it in other combination strategies with immunotherapy such as nivolumab.

[00:26:16]

Evolution of PSMA-Based Radioligand Therapy Phase III Trials

Now we are going to move on to PSMA-based radioligand therapy. There has been a number of phase three trials that have either reported out or have reported some results. Starting first with the phase 3 VISION trial, looking at the most advanced patients. And then also we will talk a little bit about PSMAfore and the ECLIPSE study. As you can see, the data is going earlier and earlier into the disease space, into the castration sensitive, as well as even in the localized space.

[00:26:50]

Phase III VISION: 177Lu-PSMA-617 + SoC vs SoC Alone

First we have to start with the landmark phase 3 VISION study, which was an international open label, randomized phase 3 trial. This evaluated patients with mCRPC with PSMA positive disease on PSMA PET CTs. They had to have received prior androgen receptor pathway inhibitor as well as taxane. They were then randomized to receive lutetium PSMA plus standard of care versus protocol permitted standard of care, best supportive care. The co-primary endpoints were radiographic progression free survival as well as overall survival.

[00:27:32]

VISION: Efficacy of 177Lu-PSMA-617 + Best SoC in mCPRC

The VISION trial met both of its co-primary endpoints, improving overall survival with a hazard ratio of 0.62, and improving radiographic progression free survival with a hazard ratio of 0.4, leading to its FDA approval in March of 2022 for patients who have PSMA positive CRPC who have been treated with an androgen receptor pathway inhibitor, as well as taxane chemotherapy.

[00:28:05]

PSMAfore: 177Lu-PSMA-617 vs ARPI in Taxane-Naive PSMA + mCRPC

We have additional data and additional indication for this trial that was as a result of the PSMAfore study. This also looked at patients with CRPC, but in this case patients were taxane naive, although they should have progressed on one prior androgen receptor pathway inhibitor. Similarly, they had to have PSMA positive disease. They were then randomized to receive lutetium PSMA versus the control arm which was an androgen receptor pathway switch. If the patient was on abiraterone previously, they got enzalutamide and vice versa enza to abi. Crossover was permitted and occurred at a very high rate. The primary endpoint was radiographic progression free survival. Key secondary endpoint of overall survival.

[00:28:55]

PSMAfore: rPFS and OS

It did meet its radiographic progression free survival with the significant improvement hazard ratio of 0.49 compared to the androgen receptor pathway inhibitor. Overall, survival, certainly the lines cross multiple times. Probably because of the crossover that did occur with the study. Irrespective, the FDA did expand the indication to include adults who have CRPC that is PSMA positive, that have been treated with androgen receptor pathway inhibitor, and are considered appropriate to delay taxane based chemotherapy. That is the specific language that the FDA uses.

[00:29:38]

ECLIPSE: 177Lu-PSMA-I&T vs SoC in mCRPC

I wanted to briefly talk about the ECLIPSE trial which has met its radiographic progression free survival endpoint. This is an open label randomized phase 3 trial. It is looking at patients with mCRPC, previously could have received ARPI, and in this case very similar to the PSMAfore study, but looking at a different radioligand molecule lutetium PSMA INT. Very similar setup as the PSMAfore, as I mentioned, with the control arm being androgen receptor pathway inhibitor switch with crossover permitted. As I mentioned, this study has met its radiographic progression free survival endpoint and we are awaiting other data.

[00:30:29]

Multiple Current Pathways to the Onset of mCRPC

As we started out, there is multiple ways to get to advanced CRPC. This is showing one of the earlier figures in this presentation in a slightly different way. Showing that patients can progress from localized disease, locally advanced prostate cancer may be receiving intensified treatment with radiation and systemic therapy, and then also presenting with de novo advanced disease and being eligible for either a doublet or triplet regimen, but ultimately developing castration resistant prostate cancer will occur.

[00:31:08]

Other Targeted Radionuclide Therapeutic Approaches Under Investigation in mCRPC

We are evaluating other radioligand therapies in this space. One of the most prevalent and notable to talk about our other alpha emitting particles called the actinium-225 labeled antibodies. I have three listed here that are currently being developed. The major difference between alpha and beta: alpha particles are heavy particles with low penetration and very high ionizing power, whereas beta are very light and have medium penetration. I think of alpha particles as bowling balls and beta particles as baseballs in terms of their mechanism of action and amount of tissue penetration and damage that they can cause.

[00:31:54]

Posttest 3

All right. We are on to our posttest question here. You will recognize this question from before. Which of the following most accurately identifies the current approved indication for lutetium PSMA 617 therapy in patients with mCRPC based off the PSMAfore trial? We can open up the poll.

A. Newly diagnosed with bone only disease;

B. After progression on at least one androgen receptor pathway inhibitor;

C. After progression on at least two; or

D. After previous ARPI and taxane therapy.

Speaker 3: Poll is open.

Dr. Reizine: All right. Do we show these results as well?

Speaker 3: Yes. There was one more response coming in. I can see someone. There we go. All right, we will close the poll and share the results.

Dr. Reizine: Most of you got that it is after one androgen receptor pathway inhibitor and patients who are appropriate to delay taxane chemotherapy. There is the answer and the very recent approval of just this past year expanding the indication of lutetium PSMA in CRPC.

[00:33:34]

PI3K-AKT-mTOR Pathway Inhibition

We are going to move on to some more biology of prostate cancer, in particular focusing on PI3K, AKT-mTOR pathway. The PI3K AKT-mTOR signaling pathway, I am sure you guys are familiar with this. it is often overactive in cancer, including prostate cancer. It causes increased cell growth and survival. PTEN is a really important tumor suppressor gene. It is important for many cancers, including prostate cancer. Its main job is to turn off this pathway, the PI3K-AKT signaling pathway. It prevents AKT activation. When you have PTEN deficiency or PTEN loss, it leads to overactivation of this pathway. As a result, capivasertib is an oral pan-AKT inhibitor that has been developed to hopefully combat this mechanism of cancer progression.

[00:34:34]

CAPItello-281: Abiraterone ± Capivasertib in PTEN-Deficient mHSPC

It has been evaluated in several studies, most recently, and the one we are going to highlight, is the CAPItello-281, which is a study of abiraterone with or without capivasertib in PTEN deficient metastatic castration sensitive prostate cancer. This was a double-blind, placebo controlled, randomized phase 3 study. Patients had de novo hormone sensitive prostate cancer. They also had to have PTEN loss, and this was determined by immunohistochemistry testing for PTEN expression within the prostate cancer cells. Patients were then randomized to receive the combination of capivasertib plus abiraterone versus placebo plus abiraterone, with a primary endpoint of radiographic progression free survival.

This did meet its primary endpoint and was just recently presented at ESMO, although we are awaiting further data. So, it is an exciting strategy that we are excited about in certain biomarker selected prostate cancer patients.

[00:35:43]

EZH2 Inhibition

Moving on to EZH2 inhibition.

[00:35:47]

Mevrometostat: Epigenetic Therapy via EZH2 Inhibition

EZH2 is an epigenetic regulator that silences gene expression. It condenses chromatin and represses gene transcription. EZH2 is overexpressed in CRPC as well as other cancers, and associated with a poor prognosis. Mevrometostat is a selective EZH2 inhibitor that has been developed in this disease space. Epigenetic reprograming from mevrometostat makes tumor cells more dependent on AR signaling, maybe increasing sensitivity to AR directed therapy, which of course is our standard. That gets to the preclinical efficacy of the combination strategy.

[00:36:36]

Multipart, Phase I Trial of Mevrometostat

Mevrometostat is being evaluated, and it was first evaluated in this open label dose escalation, dose expansion phase 1 trial looking at not just prostate cancer, but also looked at small cell lung cancer as well as follicular lymphoma. For prostate cancer, of course, it was looked at in combination with enzalutamide versus enzalutamide alone. This was patients with CRPC who were randomized to receive the combination versus enzalutamide alone. As you can see, it did meet its primary endpoint of, first of all, being tolerable from a phase 1 perspective from the side effect profile, but also meeting its radiographic progression free survival improvements with a hazard ratio of 0.5.

[00:37:21]

Enzalutamide ± Mevrometostat in mCRPC: Safety

Looking at the safety. Again, the orange is the combination regimen, the gray is the enzalutamide alone. You can see that toxicity is slightly higher in the combination regimen as to be expected. I think it is really well shown on this tornado plot that there is more toxicities with the combination. However, fortunately, most of these were grade 1 to 2, except for asthenia, diarrhea, and anemia, which had some grade 3 or higher events.

[00:37:55]

Key Ongoing Phase III Trials of Mevrometostat in mCRPC

There is a number of ongoing trials looking at mevrometostat in mCRPC. The biggest difference between those is how much treatment they have had. MEVPRO-1 allows prior abiraterone exposure but not enzalutamide, otherwise looking at a CRPC patient population. MEVPRO-2 is a less treated patient population. Patients have to be androgen receptor pathway inhibitor including abiraterone naive to go on to this study. So, less pretreated patient population.

[00:38:33]

CYP11 Inhibition

Next we are going to move on to CYP11 inhibition.

[00:38:37]

Opevesostat: Mechanism of Action

Everyone is familiar with abiraterone which, of course, is a CYP17A inhibitor, inhibiting partial adrenal steroid synthesis, including androgen synthesis, which is the major mechanism of action. As you can see, opevesostat is a CYP11A1 inhibitor. I call it super abi in my head. I do not know if I am allowed to do that, but that is how I think of it, because it is definitely going a couple of steps upwards of where abiraterone's mechanism of action is. As you can see, can render the patient completely adrenally insufficient. This agent needs to be given with dexamethasone and fludrocortisone.

[00:39:22]

CYPIDES Phase II Trial of Opevesostat in mCRPC: Unconfirmed Best PSA Change

The CYPIDES was a phase 2 trial of opevesostat in CRPC, and you can see that, looking at both patients who had AR ligand binding domain mutations, it really seemed to have quite a nice waterfall response here. With the PSA 50 response of more than half of the patients meeting it, whereas it is not quite as effective in AR ligand binding domain wild type patients.

[00:40:01]

CYPIDES Phase II Trial of Opevesostat in mCRPC: Safety

In terms of the side effects, overall pretty well tolerated. The most common ones are listed here. Adrenal insufficiency, as I mentioned, a significant and on target side effect that needs to be monitored. Of the majority of adverse events, most of them were grade 1 to 2. The drug certainly, you need to prepare for it and counsel patients on it, but can be monitored.

[00:40:33]

Key Ongoing Phase III Trials of Opevesostat in mCRPC

There is a number of phase 3 trials looking at this in CRPC. Once again, these studies are different based off the treatment history of the patients. 003 is a later line CRPC setting. Patients have to have progressed on an androgen receptor pathway inhibitor, and at least one taxane. As the OMAHA-004 trial is earlier line CRPC. Patients could only have received one prior androgen receptor pathway inhibitor, and no prior taxane is required. Patients can be taxane naive or could have refused taxane.

[00:41:15]

PROTAC: Protein Degraders Targeting AR

All right. Moving on to more exciting novel agents and mechanism of actions are protein degraders targeting AR.

[00:41:25]

BMS-986365: PROTAC Protein Degrader Targeting AR

First going to start out with this BMS molecule. The study that first established the safety and the dosing, phase 1 study in progressive CRPC. This is a first in class dual AR degrader as well as antagonist. It really inhibits AR by two different ways, and you can see that PSA responses were seen at the twice a day dosing regimens. The maximum tolerated dose was not reached.

[00:42:01]

Phase I Trial of BMS-986365 in mCRPC: PSA Response by AR Status and Dose; rPFS by AR-LBD Status

As you can see here, they are looking at AR ligand binding domain mutation status. You can see that a PSA response is observed regardless of whether there is an AR ligand binding domain mutation. I think this is because, once again, this medication irreversibly degrades AR while also directly antagonizing it, so it can overcome other forms of androgen receptor pathway resistance like AR gene amplification and AR overexpression.

[00:42:41]

ARV-766: PROTAC Protein Degrader Targeting AR

In contrast, ARV-766 is a novel, potent, pure protac AR degrader. It is a bifunctional molecule. How it works? Tt brings together the protein that you want to eliminate, which is the transcription factor AR, and binds it to an E3 ubiquitin ligase. The E3 ligase tags the target protein with ubiquitin, and then it is sent to the proteasome and degraded through the cell's machinery. This drug is specifically targeted to clinically relevant and prevalent AR ligand binding domain mutants which are associated with poor prognosis and CRPC.

[00:43:23]

Phase I/II Trial of ARV-766 in mCRPC

As you can see from the phase I/II trial, from the dose escalation and cohort expansion, the PSA response was really quite excellent in patients who have AR ligand binding domain mutations that are targeted by this protein, by this agent.

[00:43:46]

Next-Generation Immune-Directed Therapies: Bispecific T-Cell Engagers and CAR T-Cell Therapies

All right. Moving on to, I believe the last therapy, which is immunotherapy in prostate cancer, which is very exciting.

[00:43:56]

Next-Generation Immunotherapy

As many of you are aware, prostate cancer is thought to be a cold tumor, and immunotherapy by immune checkpoint inhibitors, unfortunately has not worked so well. That is probably because we had not found the right targets. A lot of the these novel therapies and next generation of therapies are looking at prostate specific targets that are highly expressed. Examples of these are KLK2 antigen which is produced by prostate epithelial cells. It is really enriched in prostate tissue. STEAP1 and STEAP2 is also quite prevalent in CRPC even if the patients lost PSMA expression. DLL3, you may know this from small cell lung cancer or neuroendocrine cancers, and it can be quite prevalently expressed in neuroendocrine or small cell prostate cancers as well, which is an aggressive prostate cancer associated with really poor outcomes. You can see this is a non-exhaustive list of bispecific antibodies as well as T cell engagers, CAR T cell agents that are being developed focusing on these prostate specific markers.

[00:45:19]

Evolving Era of Cell Surface Targeting: Under Investigation

Again, this is a non-exhaustive list, but you can see that we are really getting into the era of cell surface targeting, specifically of the prostate cancer. We have obviously talked about PSMA. There is antibody drug conjugates as well as all of these other agents targeting B7-H3. We mentioned STEAP1 and DLL3. Then a number of these other cell surface markers that you may recognize from other tumor types that are being developed and leveraged in prostate cancer.

[00:45:55]

Conclusion

In conclusion, there are numerous novel agents targeting cell surface proteins on the horizon for patients with CRPC. These act via different mechanisms of action that you may be familiar with from other tumor types, like ADCs, CAR T cell therapies, as well as bispecific T cell engagers and radioligands. Watch out for clinical trial enrollment of these. These are really exciting agents in both the refractory and heavily pretreated patients as well as moving earlier and earlier. Of course, the logistics of administering and making sure that there is equitable access to these agents that will have to be considered as these agents are being developed further down the line.

[00:46:45]

A Final Survey

We have a final survey now. We have made it. I am doing okay on time.

[00:46:51]

Posttest 4

How confident are you with educating your colleagues and patients on the mechanism of action and rationale for utilizing newer combinations with PARP inhibitors and/or androgen receptor pathway inhibitor signaling?

Speaker 3: Poll is open. Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr. Reizine: Oh, great. Confident. Somewhat confident. Very confident. That is wonderful.

[00:47:35]

Patient Case Presentation

All right. Going back to the case. We remember this case from before of the man with localized prostate cancer with some high risk features, developed biochemical recurrence. Standard imaging was negative started on enzalutamide and then unfortunately develops metastatic CRPC.

[00:48:01]

Posttest 5

Which of the following would you recommend as the best next step for this patient?

1. Undergo cryotherapy;

2. Pursue olaparib plus abiraterone;

3. Explore options for clinical trial enrollment and standard treatment through reputable sources of information for patients;

4. Pursue surgery to remove the retroperitoneal lymph nodes.

Speaker 3: Poll is open. Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr. Reizine: All right. Excellent. Most people looking at clinical trial enrollment. Hopefully that means that you guys are just as excited as I am about some of the novel agents that are being developed for CRPC. We did not know if he had a BRCA1 or BRCA2 mutation, which is what olaparib and abiraterone is approved for. That is why that answer is incorrect. If he had that, then that would definitely be an option.

[00:49:22]

Poll 7

Do you plan to make any changes in your clinical practice based on what you learned in today's program?

1. Yes;

2. No; or

3. Uncertain.

Speaker 3: Poll is open. Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr. Reizine: Yes. Great. Yes or uncertain. I will take it.

[00:50:03]

Poll 8

Okay. Are you going to have another type in poll? Yes. You do. Excellent.

Speaker 3: Yes. Once again, you can scan the QR code and text in a key change you would likely make in your practice, or once again, the polling box is open and we will leave the polling box open for a few more seconds. Dr. Reizine, you can go ahead and move forward.

[00:50:35]

Interactive Decision Support Tool: mCRPC

Dr. Reizine: This is the final slide before the question and answer session. Just showing this additional resource if you want to dive more into some of the data that we talked about in terms of learning from many of these experts and thought leaders in terms of this interactive decision support. Definitely recommend it if you want to learn more about what we talked about today.

Program Moderator: Thank you, Dr. Reizine.

[00:51:12]

Question and Answer Session

We are taking any questions you may have now for Dr. Reizine. Please use the Q&A function in Zoom to submit your questions. While you do so, I would like to point out the links in the chat panel. Dr. Reizine, do you have another slide there in your deck?

Dr. Reizine: I do not think so.

[00:51:32]

Thank You For Attending Our Program!

Program Moderator: There we go. Yes. There are also some QR codes on the screen. One of these will lead to the downloadable slide deck from today's presentation, and then the other for the program evaluation. To complete that and claim your credit for attending, you will need to log in to or create a DCE account, that is Decera Clinical Education. We would encourage you to claim your credit within 30 days, as credit for today's program will expire after this 30 day time frame. Dr. Reizine, I do see a few questions that have come into Q&A. Are you able to see those? If not, I can read those out to you.

Dr. Reizine: If it is okay, I will just open up my questions here. All right. I see three questions here. Is that what you see? I can go ahead and answer those. The first one is how might AKT inhibitors alter frontline strategies? I think this is a great question. The CAPitello-281 study that we looked at is actually a frontline study because it is de novo metastatic castration sensitive prostate cancer. It is looking at a new triplet regimen. Looking at ADT plus abiraterone plus capivasertib in biomarker selected, so PTEN deficient, tumors. As I mentioned the radiographic progression free survival was met. We are awaiting additional data like overall survival as well as safety. The feasibility of testing for the biomarker PTEN loss is also something that has to be considered. It is not available everywhere and it is not standardized. I think, if this gets moved forward into the front line setting for advanced prostate cancer, we certainly need to figure out what is the biomarker and how are we going to test it, so that we can really pick the correct patients. Because it is not without side effects, of course. I do think it is an exciting strategy, and I think it is good to molecularly stratify and target prostate cancer patients.

When do you favor radium-223 versus PSMA targeted therapy? That is another great question. Radium-223, if you remember, it is a calcium mimetic. It only works at sites of bony turnover. For patients who only have bony disease, osseous disease, if they have any visceral disease or lymph node disease, unfortunately, radium-223 is not going to go there. The PEACE-3 strategy, if you opt for that, that was looking at ARPI naive castration resistant prostate cancer patients. Of course, enzalutamide will work. I think that could be a strategy for patients with CRPC. Generally, if I see very high PSMA avidity on the PSMA PET scan and particularly if there is visceral disease like lymph node or liver or lung, I am opting for lutetium PSMA treatment. Just because I know that will be a more homogeneous response.

Which patients do you prioritize for bispecific or CAR-T trials? This is another excellent question. I am very excited about the immunotherapy regimens that are coming to prostate cancer. So far, it has only been tested in pretty refractory pretreated patients. I do think, though, that if we can show tolerability, efficacy, and feasibility of these agents earlier on, they may be beneficial even in the pre-taxane space. Patients who have not yet been exposed to chemotherapy have an intact immune system. Hopefully, they would really mount an immunotherapy response. I think there are clinical trials ongoing that are evaluating some of these bispecific T cell engagers compared to chemotherapy. I am very eagerly awaiting those trials and enroll to those whenever I can to see if we can move a chemo-free regimen even earlier.