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CME / ABIM MOC

Metastatic Castration-Resistant Prostate Cancer: Updates From the 2022 European Annual Meeting

  • Authors: A. Oliver Sartor, MD; Tanya Dorff, MD; Joe O’Sullivan, MD, FRCR, FFRCCSI, FRCPI
  • CME / ABIM MOC Released: 10/26/2022
  • Valid for credit through: 10/26/2023
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Target Audience and Goal Statement

This activity is intended for oncologists, nuclear medicine specialists, radiologists, urologists, and other clinicians who care for patients with mCRPC.

The goal of this activity is for learners to be better able to understand the latest clinical data on mCRPC presented at the 2022 European Society of Medical Oncology (ESMO) Congress in Paris, France, and to incorporate the data into clinical practice.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Key clinical trial data for the treatment of mCRPC reported at a major oncology medical meeting
  • Have greater competence related to
    • Incorporating emerging data from a major oncology medical meeting into the treatment paradigms for patients with mCRPC
  • Demonstrate greater confidence in their ability to
    • Stay abreast of evolving areas of interest for mCRPC therapies reported at a major oncology medical meeting


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Faculty

  • A. Oliver Sartor, MD

    Professor of Medicine
    Medical Director
    Tulane Cancer Center
    C. E. and Bernadine Laborde Professor of Cancer Research
    Tulane University, School of Medicine
    New Orleans, Louisiana

    Disclosures

    A. Oliver Sartor, MD, has the following relevant financial relationships:
    Consultant or advisor for: Advanced Accelerator Applications (AAA); Astellas Pharma, Inc.; AstraZeneca Pharmaceuticals LP; Bavarian Nordic; Bayer HealthCare; Blue Earth Diagnostics, Inc.; Bristol-Myers Squibb Company; Clarity Pharmaceuticals; Clovis Oncology; Constellation; Dendreon Corporation; EMD Serono, Inc.; Fusion; Isotopen Technologien Meunchen; Janssen Pharmaceuticals; Merck & Co., Inc.; Moyvant; Myriad; Noria Therapeutics, Inc.; Novartis Pharmaceuticals; Noxopharm; Pfizer Inc.; POINT Biopharma; Progenics Pharmaceuticals, Inc.; Sanofi; Telix; TeneoBio; Theragnostics
    Research funding from: Advanced Accelerator Applications; Amgen, Inc.; AstraZeneca Pharmaceuticals LP; Bayer HealthCare; Constellation; Endocyte; Invitae Corporation; Janssen Pharmaceuticals; Lantheus; Merck & Co., Inc.; Progenics Pharmaceuticals, Inc.; TeneoBio
    Stock options from: AbbVie, Inc.; Cardinal Health; Clarity Pharmaceuticals; Clovis Oncology; GlaxoSmithKline; Lilly; Noria Therapeutics, Inc.; United Health Group
    Owns stock (publicly traded) in: AbbVie, Inc.; Cardinal Health; Clarity Pharmaceuticals; Clovis Oncology; GlaxoSmithKline; Lilly; Noria Therapeutics, Inc.; United Health Group

  • Tanya Dorff, MD

    Associate Professor of Medicine
    Department of Medical Oncology & Therapeutics Research
    Section Chief, Genitourinary Disease Program
    City of Hope
    Duarte, California

    Disclosures

    Tanya Dorff, MD, has the following relevant financial relationships:
    Consultant or advisor for: Astellas; AstraZeneca Pharmaceuticals LP; Exelixis, Inc.; Janssen Pharmaceuticals; Seagen Inc.

  • Joe O’Sullivan, MD, FRCR, FFRCCSI, FRCPI

    Consultant Clinical Oncologist
    Kingsbridge Private Hospital
    Clinical Professor
    Professor of Radiation Oncology
    Queen’s University Belfast
    Belfast, Ireland

    Disclosures

    Joe O’Sullivan, MD, FRCR, FFRCCSI, FRCPI, has no relevant financial relationships.

Editor

  • Davecia R. Cameron, MS

    Medical Education Director, Medscape, LLC

    Disclosures

    Davecia R. Cameron, MS, has no relevant financial relationships.

Compliance Reviewer

  • Leigh Schmidt, MSN, RN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Leigh Schmidt, MSN, RN, CNE, CHCP, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.


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CME / ABIM MOC

Metastatic Castration-Resistant Prostate Cancer: Updates From the 2022 European Annual Meeting

Authors: A. Oliver Sartor, MD; Tanya Dorff, MD; Joe O’Sullivan, MD, FRCR, FFRCCSI, FRCPIFaculty and Disclosures

CME / ABIM MOC Released: 10/26/2022

Valid for credit through: 10/26/2023

processing....

Activity Transcript

Chapter 1

Oliver Sartor, MD: Hello, I'm Dr Oliver Sartor, and I'm the C.E. and Bernadine Laborde Professor of Cancer Research and Medical Director of the Tulane Cancer Center at Tulane Medical School of New Orleans. I'm very pleased to be able to present this segment titled "Radiopharmaceuticals for the Management of [Metastatic Castrate-Resistant Prostate Cancer]" and the latest data from ESMO 2022. I'm going to be covering four abstracts.

One of them is going to be PSMA Lutetium-177 after Radium. I'm going to be presenting FDG-positive/PSMA pet-negative Prevalence in Metastatic CRPC. I'm also going to be presenting the 0.2002, which is the PSMA Lutetium-177 Initial Results from the SPLASH Trial. And also, briefly a presentation on the VISION Trial with Radiographic Progression-Free Survival Correlating With Overall Survival. So, let's get underway.

The first one is going to be something called the RALU Study. And this is going to be lutetium in patients with prior radium. And what we did was to look at, I say we because I'm one of the authors here, is a retrospective medical chart review from individuals who had received radium and then went on subsequently to receive the PSMA lutetium. And we looked at a couple of factors. Number one, how do these patients respond? Number two, what was their survival? And number three, what was their AE profiles? So when we began to look at this, we divided the patients into two groups, those who had radium, docetaxel, then lutetium. And we also looked at those who received docetaxel, radium, and lutetium, so two different sequences. In addition, we looked at some patients who did not receive any of the docetaxel.

Now these were heavily pretreated patients. Essentially all the patients have been treated with abiraterone, enzalutamide. Majority had been treated with a taxane. So, these are heavily pretreated patients. What did we find for efficacy? First, we found that the PSA changes from baseline had a response rate, and that's 50% PSA decline or more, of 42% for those receiving the PSMA lutetium. And that's very similar to the 46% that we saw in the VISION trial. It would appear as though there really wasn't a lot of difference between those individuals who got lutetium in the VISION trial versus those who got lutetium after radium. We also looked at overall survival, and overall survival indicated that there was a median survival in the RALU trial of 13.2 months, quite analogous from the VISION trial, which is 15.3 months.

And then we looked by these treatment sequences. Remember we had docetaxel, radium, lutetium and then radium, docetaxel, lutetium and there really wasn't much difference. We also looked at AE profiles and there really wasn't a great deal to talk about. So, our conclusion is that PSMA lutetium after radium 223 appears to be safe and effective and that's the RALU study.

Next, we're going to be moving on to a study that was called the 3TMPO Imaging Study. And this is a prospective multicenter PET-imaging trial that looked at a hundred patients with metastatic CRPC and all these patients had at least three metastases with conventional imaging. They ran both a gallium-68 PSMA/PET scan and an F18 FDG/PET scan within 10 days of one another and then looked at various patient characteristics. What they were interested in is trying to find who had PSMA PET-negative and FDG PET-positive lesions. And these individuals were heavily pretreated, but they had some that were not.

And what was interesting was they found that the number of lines of treatment, and ADT is excluded here, but if you had two or more lines of life-prolonging treatment, that'd be something like abiraterone and docetaxel for instance, then there was a much higher probability of having an FDG PET-positive at PSMA PET-negative lesion. They also looked at the location of the metastatic disease and those individuals who had visceral disease were much more likely to have FDG PET-positive/PSMA PET-negative lesions. So, the bottom line is that these lesions which are PSMA-negative/FDG PET-positive increased with lines of therapy and probably in those with visceral disease. And there's a question about whether things like the PSMA lutetium therapy may be as effective for those who have FDG PET-positive lesions that are PSMA PET-negative. So we have to learn more about treatment, but nevertheless lines of therapy results in an increase in the percentage of patients who have these FDG-positive lesions.

Now moving on the SPLASH trial and what we'll say is that the SPLASH trial is looking at PSMA I&T lutetium 177, this is not PSMA 617 lutetium 177, in a prospective randomized trial. And this is going to be done in metastatic CRPC in those individuals who've received some form of second-line hormonal therapy such as abiraterone and enzalutamide and they could have allowed the docetaxel, but it had to be at least one year before. So, these individuals are going to be getting PSMA I&T lutetium 177 times four cycles or an alternative hormone with rPFS as an endpoint. And in this presentation at ESMO, what they did was look at a lead-in dosimetry cohort and they found that rPFS was about 11.5 months. Those individuals having a 50% decline in PSA, or more was about 42%. And if they looked at objective response rates, it was about 60%. Now this is a small number of patients so we can only really talk about a total of 27 patients. But, what I think that the SPLASH trial is likely to be positive on this rPFS, I think it's likely to be better than the abiraterone or enzalutamide that it'll be compared to. So this is an interesting trial, Phase III, pay attention to it coming forward.

The last abstract I'll be presenting very quickly was done by Michael Morris and he looked at the VISION trial, which is a Phase III trial with PSMA 617 lutetium 177 and looked at the correlation between rPFS and OS. And the bottom line is that it was strongly positive that if we looked at the PSMA 617 arm that the correlates were somewhere between 0.71 and 0.76 between rPFS and OS, depending on exactly how you looked at the data. But what I'll say is that rPFS and OS correlated in the VISION trial.

So in summary four abstracts, PSMA lutetium can follow radium 223 safely and likely with preserving efficacy. Number two, FDG PET-positive lesions that are PSMA PET-negative increases with lines of therapy for those with advanced prostate cancer. The SPLASH trial is very likely to be positive for rPFS. And this is the one using PSMA I&T lutetium 177 and rPFS correlates with overall survival in the VISION trial. Thank you very much for your participation today.

Chapter 2

Tanya Dorff, MD: Hello. I'm Dr Tanya Dorff, an associate professor in the Department of Medical Oncology & Therapeutics Research and section chief of the Genitourinary Disease Program at City of Hope. Today, I'm happy to present this segment, titled "Second-Generation Antiandrogens for [Metastatic Castration-Resistant Prostate Cancer]," and the latest data from ESMO 2022. Today, we'll cover three abstracts looking at androgen receptor-targeted agents in combination and in sequence.

The first abstract is a phase 2 study of ZEN-3694 with enzalutamide and pembrolizumab in mCRPC. This ZEN-3694 is a bromodomain inhibitor, or what's called a BET inhibitor. Bromodomain proteins involve epigenetic reading involving histones and promoting gene transcription. So, specifically in prostate cancer, inhibiting BET has been shown to impact expression of androgen-regulated genes, which could help address resistance to androgen receptor- targeted agents, such as abiraterone or enzalutamide. So in this study, combining it with enzalutamide has good rationale.

The ZEN-3694 is a BET inhibitor, which has shown safety in phase 1 studies. The main toxicity has been thrombocytopenia previously, but there's not really been an MTD. So in this study, two different cohorts of prostate cancer patients were enrolled. Cohort A involved treatment-emergent neuroendocrine due to differentiated prostate cancer, or what is sometimes referred to as "small cell neuroendocrine prostate cancer." Then, cohort B was mCRPC that remained in an adenocarcinoma histology. So a little bit of a complicated design, and this is a triple combination.

There were 33 patients enrolled. Median age was 71. About a third had visceral metastases, and about half had had one prior androgen receptor-targeted agent exposure. The other half had had two or three. We know that about 18% had alterations in DNA repair deficiency, and 27% had androgen receptor mutations, which should be potentially susceptible to this BET inhibitor.

So the results show a pretty good PSA decline. So about 39% of patients had a 50% decline in PSA or a 50% response, and this was seen across prior androgen targeted agent exposures, whether it was abi, enza, apalutamide, or a combination.

In terms of side effects, there was not as much thrombocytopenia seen as in the phase 1 study, but there were some grade 3 elevations of liver enzymes and grade 3 rash. Now, of course, this is being utilized in combination with pembrolizumab, so i can be a little bit tougher to separate out what was due to the BET inhibitor versus a contribution from the pembrolizumab. But 37% of patients had to reduce the dose of the ZEN-3694, and then some patients did come off study for toxicity. There was a depiction of an exceptional responder, really nice to see improvement in the bone scan, as well as a drop in PSA to zero that has been ongoing for many months. So some encouraging preliminary efficacy, and the, again, the major side effects seem to be more along the GI spectrum of side effects. In this particular study, there was a bit of thrombocytopenia, but nothing that reached grade 3 levels.

So, in conclusion, ZEN-3694, combined with enzalutamide and pembrolizumab, documented safety. It documented some preliminary efficacy, but we can't really yet tease apart which part of the combination is really working here or whether there's synergy. And so we really need to follow the study for further data to be presented in the future.

The second abstract we'll look at is CABASTY. So this was a phase III trial randomizing older patients with mCRPC to cabazitaxel at the standard dosing, or what I would argue is maybe high dose, 25 milligrams per meter squared every three weeks, or to this modified dose of 16 milligrams per meter squared given every two weeks. Both arms got G-CSF support. The hypothesis here is that people are a little bit worried about using cabazitaxel, particularly in older patients, because of toxicities and, specifically, febrile neutropenia.

So docetaxel dosing has been looked at in prior studies, and there's the potential to use this 50 milligram per meter squared every two week dosing of docetaxel. So that's where the investigators thought they would explore a different dose and dosing strategy for cabazitaxel. So all the patients had been treated with docetaxel and at least one androgen receptor targeted agent. They all had a geriatric questionnaire performed at baseline, and there was a stratification based on this, although it wasn't an entry criteria per se. Those who had a high score on the G8 geriatric assessment were seen by a geriatrician.

The primary endpoint was incidence of grade 3 or higher neutropenia with the secondary endpoints of overall survival and progression-free survival, as well as other response characteristics. The randomization was successful in that the populations on the two arms looked very similar. There were about a hundred patients in each arm. About half were over 75. So this is a good representation of a truly geriatric population, and the youngest patients were 65. The oldest was 96. There were about 19% of patients who had visceral metastases and 80% with bone. So this looks like a really standard prostate cancer population, very little prior use of radium-223, but again, prior AR targeted agents and docetaxel.

The primary endpoint was very, very positive. So febrile neutropenia was significantly lower. It was 5% in the modified dosing, the 16 milligrams per squared, versus 63% with the full dose, or what I would say is high dose, 25 milligrams per meter squared. This, remember, is in the context of both arms getting G-CSF. Now, the main critique here is that G-CSF adds cost, and many of us actually use a dose of 20 milligrams per meter squared, which we often feel comfortable using without G-CSF support when we do it every three weeks. Importantly, the secondary endpoints turned out fine. There was no difference in progression-free survival or overall survival.

So if we do want to use this modified dosing to reduce the risk of neutropenia in our geriatric patients, we should see similar efficacy. Dose reductions were much less frequent when you use the lower dose, only 12% of patients compared to 47% of patients at the full dose, and fewer grade 3 adverse events. There were still some deaths on each treatment arm, just reminding us that chemotherapy is a treatment that not every patient can tolerate. Selection of patients is very important, and, of course, close monitoring and support is important.

The final abstract we'll take a look at is KEYLYNK-010, which was a study of pembrolizumab plus olaparib compared to abiraterone or enzalutamide in mCRPC. So [in] this study, the patient population all had prior androgen receptor-targeted agents, and they essentially used the other drug that the patient had not been exposed to as the control. There was a two-to-one randomization for pembrolizumab plus olaparib, which was dosed at 300 milligrams twice a day, or standard dosing of abi or enza.

The primary endpoints were radiographic progression-free survival or overall survival. The primary endpoints were actually negative in this study, with the survival curves completely overlapping. Median progression-free survival was relatively short, only about four months on both arms, and overall survival, about 15 months. So the big criticisms of the study were whether there was really enough rationale or clinical preliminary data to support this combination.

DNA repair-proficient cancers might respond to PARP inhibitors combined to immunotherapy, but there's just not enough work, maybe, that's been done to establish which populations should be targeted by these types of combination, or in what phase of the disease, or really whether there's synergy between these two agents. It does seem like BRCA-mutated patients in this study benefited the most, not surprisingly, since we know they can benefit from olaparib. Again, that asks the question whether the combination really contributed much.

So, in conclusion, patients with metastatic castrate-resistant prostate cancer still lack treatment options that yield durable remissions. This BET inhibitor is of high interest. It looks to be quite effective, but obviously, they'll have to be benchmarked against other emerging agents. Immunotherapy remains very disappointing with checkpoint inhibitors, such as in the KEYLYNK-010. We still can use sipuleucel-T, and we're awaiting those more powerful T-cell strategies, such as CAR-T and bispecifics.

Finally, balancing quality of life with survival prolongation or longevity remains a key focus for us, and it's challenging in our older population. So the CABASTY trial provides an option for modified dosing of cabazitaxel at 16 milligrams per meter squared every two weeks, which should reduce neutropenia and other serious complications. Thank you for your participation.

Chapter 3

Joe O’Sullivan, MD: Hello, I'm Professor Joe O. Sullivan, a consultant clinical oncologist at the Northern Ireland Cancer Center in Belfast. And I'm also professor of radiation oncology at Queen University Belfast. Today I'm delighted to present this segment entitled "Novel Therapies for the Management of [Metastatic Castration-Resistant Prostate Cancer]," telling you about some of the latest data from the ESMO Congress 2022.

So let's start with the phase two trial of sacituzumab govitecan in patients with metastatic CRPC. This is a drug which targets the Trop-2 protein. This has been used in breast cancer and Trop-2 is highly expressed in advanced prostate cancer. So this was an open label phase 2 trial, patients with metastatic CRPC progressing on ASRI's and stratified according to prior chemo versus chemo naive and really just try to evaluate the safety and efficacy of this SG drug. The primary endpoints were six month radiographic progression free survival, and also the PSA 50% response rate.

And there was also a separate analysis linked with this study looking at Trop-2 expression in prostate cancer biopsies associated with genomic markers of ASRI resistance. And this was analyzed on previously curated cohorts of over 600 patients and from the PROMOTE study. This paper describes a study with 47 patients progressing on ABI or ENZA treated with SG 10mg per kg on day 1, 8 and 28 of the cycle until radiographic progression are unacceptable toxicity. So in this interim analysis, first of all, it was seen that Trop-2 is expressed in more than 85% of patients with metastatic CRPC and also it's as associated with luminal and basal subtypes of prostate cancer.

Interestingly, the expression of Trop-2 did not vary in the presence of AR genomic alterations, but it also did correlate with AR splice variants in the PROMOTE trial. Therefore, this indicates that this Trop-2 protein is likely to have a high value as a therapeutic target in metastatic CRPC. So what about the results presented at the ESMO meeting?

Well, they described 20 patients enrolled at the time of the interim analysis. You could see the median age of 68 as you would expect in a group like this. And the median baseline PSA was 45; 30% have had previous docetaxel. And all patients had prior exposure to AVI or ENSA.

Looking at the results, while the results so far, the six-month radiographic progression free survival rate was 64% in chemo naive and 59% in the total 20 patients.

There were no PSA responses greater than 50%, which is a bit disappointing, I think. And looking at the safety data overall, I think relatively high rates of grade three and above toxicity, especially grade three and above neutropenia with eight patients experiencing grade three or above neutropenia. Conclusion from the presentation at ESMO was that SG has clinical activity in metastatic CRPC, patients progressing post ARSI based on six months radiographic progression-free survival. They describe PSA stabilization being important and analysis of tissue and liquid biopsies ongoing to try and understand predictive biomarkers. But I would say overall disappointing efficacy results. But of course, this is just an interim analysis.

So the second paper I want to talk about is interim safety analysis of nivolumab and Ipilimumab in molecularly selected patients with metastatic CRPC. So this is a single arm, phase two trial, which aiming for 75 molecularly selected MCRPC patients and the trial design is as such. So four cycles of Ipilimumab plus NIVO, and then staying onto maintenance NIVO at a flat dose of 400 mg in total in the run-in trial, it's 3mg/kg of the NIVO and 1mg/kg of IPI. Inclusion criteria, patients with metastatic CRPC, but they must have at least one of the following molecular subtypes. So micro satellite instability and or mismatch repair deficiency, high tumor mutational burden that's greater than seven mutations per mb or BRCA2 inactivation or BRCAness signature or CDK 12 inactivation or a tandem duplication TDS with good performance status.

They were divided into patients naive of previous immunotherapy and also whether or not they had measurable disease or not. So patient A and B were immune checkpoint naive patients. And group A3 were patients with previous exposure to immune checkpoint blockade. Primary endpoint disease control at six months. Most of the groups were either microsatellite instability or BRCA2 inactivation. The vast majority of the patients, almost 90% had grade group 4 or 5.

in the waterfall plot, the responses are divided according to which molecular subtype the patient belong to. BRCA mutation, CDK 12, microsatellite instability or indeed mismatch repair. And in the patients getting good PSA responses, it's dominated by the mismatch repair and microsatellite instability. I mean, these are very early results for just 25 patients. And I think that the spider plot also shows you that the best results, at least biochemically, are happening in the mismatch repair and microsatellite instable patients. Looking at the safety side of things, the swimmers plot showing the greater than grade 3 treatment occurring adverse events and also showing discontinuations due to toxicity. The main greater than grade 3 toxicities were diarrhea, pneumonitis, liver toxicity, and skin toxicity.

But overall, I think pretty well tolerated for immune therapy. Conclusion of Dr. Van Rope was that IPI NIVO showed an acceptable safety profile in this interim analysis of metastatic CRPC patients. Discontinuation rates due to toxicity were numerically below what was previously reported for IPI NIVO and patients continue to be enrolled in this trial. Expected results in 2025. The final paper then was an oral presentation by Kareem Fizazi looking at preliminary phase 2 results of the CYPIDES trial. This looks at ODM-208 in metastatic CRPC patients. The working hypothesis ODM-208 is a CYP11A1 inhibitor. So it blocks steroid production a little upstream from where abiraterone blocks steroid production at the CYP17 part of the process. So this blocks at an upstream level, so it blocks all downstream steroid production. The idea being that even metastatic CRPC patients retain some dependence on steroids.

So looking at the phase 2 expansion, this was an open label study to explore safety and efficacy of ODM-208 at the proposed dose of 5mg BD treated along with dexamethasone 1mg/daily and fludrocortisone 0.1mg/daily as well. And patients had to have a mutation of the AR-ligand binding domain. So very importantly, these patients were molecularly chosen, screened 390 patients and about a 20% positivity rate in these advanced very heavily pretreated patients, all of whom received ABI or ENZA, almost all of whom received previous docetaxel and or cabazitaxel. So looking at the suppression of steroid, unmeasurable levels of steroid hormone levels were achieved in almost all patients. So the drug did what it's supposed to do. The waterfall plot showing the best PSA response, I think is quite interesting, particularly when you think about the extent of pre-treatment. So good rates of PSA, 50% reduction here.

Looking at again, the response based on duration of treatment, it would appear the treatment duration is prolonged in many of these late stage patients. And also seeing some resist responses here demonstrated on the right. From the safety perspective, grade 3 and above AEs occurred in 67% of patients. Most commonly anemia, fatigue, muscle spasm, tumor pain. Four patients withdrew due to AE. That was sepsis, hypercalcemia, and six deaths occurred. But these were mostly explained by prostate cancer and general deterioration of health. So concluding of the CYPIDES 2 trial, phase two trial, the working hypothesis could complete steroid block by ODM-208 be effective. It would appear that there is anticancer activity as demonstrated by PSA and also resist responses. Response rate greater than 50% of PSA is quite impressive.

There are some late stage patients remain hormone dependent, so I think it looks like ODM-208 is a promising future treatment option. Really concluding remarks, implications of these emerging studies for clinical practice. I think no immediate change, but I think it's really exciting and reassuring that molecular subtypes of advanced disease may well have targeted therapy, which can prove efficacious. And I think we are moving into the precision medicine era in metastatic CRPC. Thank you for your participation and please go on to view the other activities in this series.

This transcript has not been copyedited.

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