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Rashid Sayyid: Hello everyone and thank you for joining us in this UroToday recording. I'm Rashid Sayyid, the Urologic Oncology Fellow at the University of Toronto, and along with Zach Klaassen, Associate Professor Program Director at Wellstar MCG Health, we'll be discussing the recently amended AUA guidelines discussing advanced prostate cancer. Specifically, in this recording, we'll be touching upon the statements pertaining to mCRPC.

These guidelines were recently published in the Journal of Urology and were amended in 2023 with this modification led by Dr. Michael Cookson.


And in this six-part series, we've discussed numerous aspects pertaining to the evaluation and treatment of patients with advanced prostate cancer. And in this recording specifically, we'll be discussing the statements pertaining to metastatic castration-resistant prostate cancer.


Now, statement #25 pertains to the prognosis of these patients and states that in mCRPC patients, clinicians should obtain baseline labs, for example, PSA, testosterone, LDH or lactic dehydrogenase, hemoglobin, and alk phos levels. And in addition to these labs, they should review the location of metastatic disease as this has important prognostic significance in this setting, looking at lymph node, bone, and/or visceral, also evaluate disease-related symptoms and performance status to inform discussions of prognosis and treatment decision making, and this is a clinical principle.


And why is this important? There are many predictors of increased mortality risk in these patients. And so these include elevated LDH levels, which is kind of a surrogate of worse or higher disease burden, a lower testosterone less than 50, a higher PSA, a shorter PSA doubling time, and a larger metastatic burden. Specifically, patients with visceral metastasis have worse prognosis compared to those with bone only metastasis, which is also worse than those with lymph node metastasis. Naturally, patients with worse performance status and worse disease-related symptoms, for example, bone pain also have a worse prognosis in this setting.


Statement #26 tells us that in mCRPC patients without PSA progression or new symptoms, clinicians should perform imaging at least annually, and this is an expert opinion. And so when we manage these patients, really there are three pillars of follow-up when evaluating mCRPC treatment response and/or disease progression.


So the first one is PSA, which makes sense, and then interval imaging. And you may say, "Well, if the PSA is stable, why do I have to get imaging?" So we have data from the PREVAIL trial which looked at enzalutamide in that pre-docetaxel setting. And in this trial, the investigators demonstrated that about a quarter of patients had radiographic progression without evidence of PSA progression. So if you only do PSA testing without any imaging, you're missing progression in about a quarter of your patients.


What about imaging timing? Now the guidelines tell us at least annually, but the timing should be dictated by PSA response, change in symptoms, or patient preference. And in addition to PSA and imaging, it goes without saying that we need to monitor disease-related symptoms.


Next, statement #27 pertaining to prognosis tells us that in mCRPC patients with disease progression based on PSA progression, radiographic progression, or new disease-related symptoms, having previously received docetaxel and an androgen pathway inhibitor, so in the third-line setting, who are considering Lutetium-PSMA-617, clinicians should order a PSMA PET imaging as an expert opinion.

And why a PSMA PET? The findings of PSMA PET, specifically with the Gallium tracer, have been used to determine patient eligibility in the phase 3 VISION and the phase 2 TheraP trials.

Let's dive into this further. So, what were the PSMA PET eligibility criteria in the VISION trial? In the VISION trial, the findings of the PSMA-11 PET/CT were used to determine eligibility, and these included at least one PSMA-positive metastatic lesion. This was defined as a lesion uptake grade in the liver.


In addition to this one or more PSMA-positive lesions, there should have been no PSMA-negative metastatic lesions, with these lesions being greater than 2.5 centimeters in short-axis diameter, bone metastases with a soft tissue component of at least 1 centimeter in the short-axis diameter, or solid organ metastasis of at least 1 centimeter in the short-axis diameter.


Next, in the TheraP trial, patients had to have two different PET/CTs: the 68 Gallium-PSMA-11 and also the 18F-FDG PET/CT. Patients were required to have high PSMA expression, defined as at least one site with an SUVmax uptake of at least 20, and an SUVmax of greater than 10 at all other measurable sites of metastatic disease. But also importantly, patients should have had no sites of discordant FDG-positive/PSMA-negative disease.


Statement #28 related to prognosis states that in patients with mCRPC, clinicians should offer germline, if not already performed, and somatic genetic testing to identify DNA repair deficiency, microsatellite instability status, tumor mutational burden, and other potential mutations that may inform prognosis and familial cancer risk as well as direct potential targeted therapies, and this is a clinical principle.


We know, based on the data from Pritchard et al., published in 2016, that germline DNA damage response mutations are present in about 12% of patients with metastatic prostate cancer. The most common mutations being BRCA2, CHEK2, ATM, and BRCA1. In addition to them being present in 12%, these mutations are known to portend a worse prognosis in the mCRPC setting, whereby the median overall survival for patients with BRCA2 mutations is about a year and a half, compared to just under three years for patients without any DNA damage response mutations. So it goes from about three years to half at 1.5 years. This is a very important prognostic biomarker, and we'll see later also a very important predictive biomarker as well.


Statement #29 pertaining to treatment states that in newly diagnosed mCRPC patients who have not received prior androgen receptor pathway inhibitors, clinicians should offer continued ADT with abiraterone acetate plus prednisone, docetaxel, or enzalutamide. This was a strong recommendation with evidence level grade A for ABI or enzalutamide and grade B for docetaxel.


We'll see that the next generation of mCRPC patients will evolve based on the treatment that was received in the mHSPC setting. Historically, patients in the mHSPC, or the hormone-sensitive setting, have received only ADT with or without bicalutamide. But increasingly, we'll see patients in the mHSPC setting who will be exposed to androgen receptor synthesis inhibitors such as ABI and ENZA, or docetaxel, or both potentially. So the next generation of mCRPC patients that we'll see filter through the next years will have been strongly pretreated, and that's going to be a very important nuance consideration for physicians treating these patients in the future. But one important thing we need to consider in this first-line mCRPC setting, assuming that these patients were only through with the ADT, is that the choice of initial treatment should be driven by the side effect profile for these patients.


So we see that in TAX-327 with docetaxel, about a quarter of patients in the docetaxel plus prednisone arm had one or more serious adverse events, and roughly 11% discontinued treatment due to these adverse events. So docetaxel is not a benign treatment in this setting. When we think about abiraterone with the COU-AA-302 trial, although we had grade three to four mineralocorticoid-related adverse events and liver function abnormalities with AAP, the agent was generally well tolerated compared to docetaxel and may be a more "benign" drug to give in this setting. And then, similar to abiraterone, in the PREVAIL trial, we see that the most common adverse events associated with enzalutamide treatment were fatigue and hypertension. And so this side effect profile really influenced the AUA with regards to the evidence level they assigned to these treatments, giving grade A to ABI or enzalutamide and grade B to docetaxel.


Now let's delve further into the different treatment options in the mCRPC setting, specifically focusing on the first-line treatment setting. The first agent that demonstrated overall survival benefit was docetaxel in 2004, and this is based on the TAX-327 trial that randomized just over a thousand men with mCRPC to receive mitoxantrone. And we know that mitoxantrone was approved in 1996 by the FDA based on demonstrated improvements in pain and quality of life measures but not survival. And then we had docetaxel 75 milligrams per meter squared every three weeks and then docetaxel given 30 weekly. So we see two different dosing schedules for docetaxel. Then importantly, docetaxel at 75 milligrams per meter squared every three weeks significantly improved overall survival compared to mitoxantrone with a hazard ratio of 0.76. And we note that the weekly docetaxel regimen did not significantly improve overall survival compared to mitoxantrone, and this is why we see that docetaxel given at this dosing schedule every three weeks is administered in practice.


Next, in 2013 we saw the COU-AA-302 trial that looked at abiraterone in the pre-chemotherapy setting, and this trial randomized just over a thousand patients again who were taxane-naive to abiraterone plus prednisone given five milligrams twice daily versus placebo plus prednisone. And importantly, patients in the abiraterone arm had significant improvements in radiographic progression-free survival, doubling from 8.3 to 16.5 months, and also the overall survival benefits with a hazard ratio of 0.75. And we note that for the first time in a clinical trial setting, we saw that the median overall survival for these patients improved to the range of three years, although we note that in real-world practice this is closer to about two years.


Next, in 2014 we saw the PREVAIL trial that evaluated enzalutamide in the pre-chemotherapy setting, and this trial randomized 1700 taxane-naive mCRPC patients to enzalutamide versus placebo. And similar to abiraterone, enzalutamide significantly improved 12-month radiographic progression-free survival with the 12-month rate of 65% versus 14% with placebo. And then we also saw significant overall survival benefits with a hazard ratio of 0.71. Next, we saw Sipuleucel-T emerge based on the results of Kantoff et al. in The New England Journal of Medicine in 2010, and statement #30 states that in mCRPC patients who are asymptomatic or minimally symptomatic, clinicians may offer Sipuleucel-T, and this is a conditional recommendation with evidence level grade B.


What is Sipuleucel-T? It's an active cellular immunotherapy, sort of a therapeutic cancer vaccine, consisting of autologous peripheral blood mononuclear cells which include antigen-presenting cells that have been activated ex vivo with a recombinant fusion protein PA204. This essentially consists of prostatic acid phosphatase, which is used to stimulate the granulocyte-macrophage colony-stimulating factor, or GM-CSF, which is an immune cell activator. So in essence, we are using our own immune cells to activate an immune response against the prostate cancer cells with this drug.


So the IMPACT trial in 2010 evaluated Sipuleucel-T, which was a phase 3 double-blind RCT that randomized 500 asymptomatic or minimally symptomatic mCRPC patients, and it's important to note that these patients had no visceral metastasis in the first-line setting. These patients were randomized 2:1 to Sip-T given IV every two weeks for three doses versus placebo. And impressively, Sip-T prolonged median overall survival by about four months, from 22 to about 26 months, with a hazard ratio of 0.78, as demonstrated in the Kaplan-Meier curve to the right. But it's important to note, although there was an overall survival benefit through Sip-T, there were no significant differences in objective disease progression rates at 3.7 essentially for both arms, and the time to clinical disease progression essentially was null. Additionally, PSA50 reductions, meaning that the PSA response by about 50%, was noted in only 3% of patients, for comparison is only 1.3% in the placebo arm.


And so there are also no significant differences in overall or Grade 3 to 5 adverse events, but immune-mediated adverse events like chills and pyrexia were more common with Sipuleucel-T. So these are very interesting results, and it's important to counsel our patients that although there's documented overall survival benefits, this is not necessarily going to be reflected in their PSA, and it's very important to manage the expectations in this setting. At this point, I'll turn it over to Zach to discuss statement #31 pertaining to Radium-223 in the mCRPC setting and the remainder of statements pertaining to mCRPC.


Zach Klaassen: Thanks so much, Rashid, for that great introduction to mCRPC and those early statements. So let's move to Radium-223. This is a grade B evidence strong recommendation that clinicians should offer Radium-223 to patients with symptoms of bony metastasis from their disease and without known visceral disease or lymphadenopathy greater than three centimeters. With regards to background for Radium-223, this is a targeted alpha emitter that selectively binds to areas of increased bone turnover, evident in bone metastases, and emits a high-energy alpha particle of short range that leads to double-strand DNA breaks and basically has localized cytotoxic effects in the target areas. Because of the short pathway of alpha particles, this minimizes toxicity to adjacent tissues, including the bone marrow, which is in contrast to its predecessor, Strontium-89. This data comes from the famous ALSYMPCA trial from 2013. This was a phase 3 double-blind RCT that randomized 921 patients with symptomatic progressive mCRPC, plus or minus prior docetaxel, just over half of these patients, and no visceral metastases, randomizing them 2:1 to Radium plus best standard of care versus placebo plus best standard of care.


And we see that Radium-223 was associated with significant improvements in median overall survival, 14.9 versus 11.3 months, with a statistically significant hazard ratio of 0.70, which we can see in the Kaplan-Meier curve here on the right. Radium-223 was also associated with prolonged time to first symptomatic skeletal-related event, 15.6 versus 9.8 months, time to increase in the total ALP level hazard ratio, statistically significant of 0.17, and time to serum PSA level increase also statistically significant, hazard ratio of 0.64. Interestingly, and of note, grade 3 to 4 adverse events were seen less frequently in the treatment arm compared to the placebo arm at 56 versus 62%.


The panel does have a couple of comments related to Radium-223 in clinical practice. And basically, because Radium-223 targets bone only and is not associated with a PSA decline in the majority of patients, it is imperative for clinicians to carefully assess the patient on a monthly basis. We need to assess for progression in non-bone sites as this is not infrequent during the six-month period of treatment. And given the lack of utility of PSA measurements in this disease space, the panel recommends obtaining abdomen-pelvis CT imaging and chest X-rays, even in the absence of symptoms, prior to cycle 4 out of 6, to assess for occult disease progression.


Moving to statement 32, this is discussing Lutetium-PSMA, and this is grade B evidence strong recommendation that clinicians should offer Lutetium-PSMA to patients with progressive mCRPC, having previously received docetaxel and an androgen pathway inhibitor, with a positive PSMA PET scan. And this is based on two trials, which we'll discuss, and Rashid briefly mentioned in his part of the discussion, based on the VISION phase 3 trial and the TheraP phase 2 trial.


So looking at VISION, this was in 2021, eligible patients had to be previously treated with a taxane and an androgen receptor pathway inhibitor. The protocol permitted standard of care before randomization, except for patients that received chemotherapy, immunotherapy, Radium-223, or investigational drugs. Patients had to have an excellent ECOG performance status, a life expectancy greater than six months, and as Rashid mentioned, a PSMA positive mCRPC scan with Gallium-PSMA-11. These patients were then randomized 2:1 to Lutetium-PSMA versus standard care alone and they were assessed every eight weeks during treatment and every 12 weeks during follow-up. One of the co-primary endpoints was imaging progression-free survival, and we can see that this significantly benefited Lutetium-PSMA versus standard of care alone, a benefit of 8.7 months versus 3.4 months, and a hazard ratio of 0.40, which was statistically significant.


The other co-primary endpoint was overall survival. This was 15.3 months in the Lutetium-PSMA arm and 11.3 months in the standard of care arm. Again, a hazard ratio of 0.62 at a 95% confidence interval of 0.52 to 0.74.


Switching gears to TheraP, these patients were mCRPC patients post-docetaxel with a rising PSA greater than 20. Again, excellent performance status, as Rashid mentioned, with regards to the imaging, PSMA SUVmax greater than 20 and no FDG positive PSMA negative sites of disease. Randomization was then to Lutetium-PSMA up to six cycles versus cabazitaxel up to 10 cycles. And so we see in this Australian trial that compared to cabazitaxel, Lutetium-PSMA significantly improved PSA progression-free survival, hazard ratio of 0.63, as well as, we can see here in the figure, improvement in PSA50 rate, 66% for Lutetium versus 37% for cabazitaxel.


With regards to overall survival, there was no significant difference in restricted mean survival time between Lutetium-PSMA-617 and cabazitaxel, and we can see that in the figures here at the bottom, specifically this Kaplan-Meier curve with a hazard ratio of 0.97. Moving on to statement 33, cabazitaxel, based on grade B evidence, in mCRPC patients who received prior docetaxel chemotherapy with or without prior abiraterone or enzalutamide for the treatment of CRPC, clinicians may offer cabazitaxel. And there are two key trials in the cabazitaxel setting that we'll discuss, including the TROPIC trial published in 2010 as well as the CARD trial in 2019.


Looking at TROPIC, this was published in Lancet in 2010. This is the first trial that led to approval post-docetaxel in the mCRPC setting, a phase 3 trial of 755 men treated with prednisone who were randomized to mitoxantrone versus cabazitaxel. And we see in the figures on the right, cabazitaxel was associated with improved overall survival, hazard ratio of 0.70, and improved PFS, hazard ratio of 0.74.


Statement 34 related to cabazitaxel, based on grade B evidence, states that in mCRPC patients who received prior docetaxel and abiraterone or enzalutamide, clinicians should recommend cabazitaxel rather than an alternative androgen pathway-directed therapy. And this is based on the CARD trial published in 2019, in The New England Journal of Medicine. This was a phase 3 trial of 255 mCRPC patients previously treated with both docetaxel and either abiraterone or enzalutamide that were randomized to cabazitaxel or an ARPI switch, so whatever ARPI they had not previously received. Based on the Kaplan-Meier curves on the right, we can see that patients in the cabazitaxel arm had significantly improved imaging-based progression or death, with a hazard ratio of 0.54, and also a statistically significant improvement in overall survival, 13.6 months versus 11 months, with a hazard ratio of 0.64 and a 95% confidence interval of 0.46 to 0.89.


Switching gears to the PARP inhibitors and statement 35, clinicians should offer a PARP inhibitor to patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC following prior treatment with ENZA or ABI and/or a taxane-based chemotherapy. Of note, platinum-based chemotherapy may be offered as an alternative for patients who cannot use or obtain a PARP inhibitor, and this is a grade C moderate recommendation. We do note that in patients with mCRPC, defects in DNA repair can occur in up to 30% of men.


Looking at the PROfound trial, this was published in 2020. This is looking at olaparib after progression on ENZA or ABI. This was a phase 3 RCT published in The New England Journal of Medicine of 387 patients with progression on ENZA or ABI that were then randomized 2:1 to olaparib or the physician's choice of enzalutamide or abiraterone. Cohort A was a group of patients that had at least one alteration in BRCA1, BRCA2, or ATM, and cohort B had alterations in any of 12 other pre-specified genes. The endpoints, including the primary endpoint, was imaging-based PFS in cohort A, which you can see on the right here, hazard ratio of 0.34, 95% confidence interval of 0.25 to 0.47, favoring olaparib. Secondary analysis, this was an interim overall survival in cohort A, showed a benefit of 18.5 versus 15.1 months.


In a subsequent report, we see the final analysis of overall survival in cohort A with a hazard ratio very similar to the interim analysis favoring olaparib, hazard ratio 0.69, 95% confidence interval of 0.50 and 0.97. On the right, this is a crossover-adjusted analysis, noting that 67% of patients crossed over to olaparib, and we see that after adjusting for this crossover, the hazard ratio for death was even more impressive for olaparib, with a hazard ratio of 0.42, 95% confidence interval of 0.19 to 0.91.


Statement 36 looks at pembrolizumab, and this is the final statement in the mCRPC section. In patients with mismatch repair-deficient or MSI-high mCRPC, clinicians should offer pembrolizumab as a moderate recommendation, grade C level of evidence. In May of 2017, the FDA approved pembrolizumab for any metastatic MSI-high or deleterious-MMR histology of any disease that had progressed following previous treatments, so this was an agnostic FDA approval six years ago. In a case series of 1,033 patients with advanced prostate cancer, 3.1% had a mutation, and more than half of these treated with anti-PD-1 therapy responded with a greater than 50% PSA decline.


So, in conclusion, for mCRPC, there are multiple first, second, and third-line treatment options for these patients, and sequencing of therapy depends on treatment received in previous disease spaces. It is crucial for genetic testing to further guide this therapy for these patients. As we've seen, many of these options are based on genomics. And finally, PARP inhibitors and radioligand therapy are new therapies approved in the mCRPC setting.


We thank you very much for your attention. We hope you enjoyed this UroToday guideline discussion of metastatic castrate-resistant prostate cancer.