NCCN 2024 Prostate Cancer Guideline Updates: Progressive M0 CSPC Management - Rashid Sayyid & Zachary Klaassen

April 3, 2024

Rashid Sayyid and Zach Klaassen dive into the 2024 updates of the NCCN prostate cancer guidelines, specifically addressing the treatment and monitoring of progressive M0 CSPC in patients post-maximal pelvic therapy. Highlighting the critical nature of identifying high-risk patients, they introduce the major shift in recommendations based on the EMBARK trial results, which supports considering enzalutamide with or without leuprolide in specific high-risk cases. This key addition marks a significant change in managing patients with M0 hormone-sensitive prostate cancer, previously limited to monitoring or ADT alone. Through meticulous examination of historic and recent studies, they underscore the necessity of stringent risk stratification to enhance patient outcomes, emphasizing the PSA doubling time as a pivotal factor.


Rashid Sayyid, MD, MSc, Urologic Oncology Fellow, Division of Urology, University of Toronto, Toronto, ON

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Well Star MCG, Georgia Cancer Center, Augusta, GA

Read the Full Video Transcript

Rashid Sayyid: Hello, everyone. And thank you for joining us in this NCCN guidelines update recording. I'm Rashid Sayyid, a urologic oncology fellow at the University of Toronto, and along with Zach Klaassen, associate professor and program director at Wellstar MCG Health, we'll be going over the 2024 key updates to the NCCN prostate cancer guidelines. Today we'll be discussing the pros related to the treatment and monitoring of progressive M0 CSPC in patients who have received maximal pelvic therapy.

So, just a brief outline, these are the current recommendations by the NCCN pertaining to the management of patients with M0 hormone-sensitive prostate cancer. Essentially, briefly, these are patients that receive treatment in the form of radical prostatectomy and/or radiotherapy, and their PSA is rising, but conventional imaging doesn't show any evidence of metastasis. These are patients which we call progressive M0 CSPC. And currently, the recommendation, the preferred management for these patients, is still monitoring, but other options, and we'll discuss these further, include ADT and, in select patients, the use of enzalutamide with LHRH agonists. Typically, these patients are followed up with a physical exam and PSA every three to six months, and then if there are any symptoms or rising PSA, imaging is performed, and then based on whether they progress or not, you'd treat them still based on the M0 treatment paradigm, or you look at whether they are M1 and then they receive the appropriate treatment. But we'll be discussing this further, and what is the evidence that informs these recommendations by the NCCN.

And so the major take-home message in this subgroup of patients is, how do we identify those patients at high risk of recurrence? And so if patients are high-risk, obviously you want to be more aggressive both in terms of surveillance and in terms of management. And so this is the first question. Who are these high-risk patients? And so there are a couple of very important studies that have been published over the last couple of decades that really inform this question. And so the first study that we'll be discussing is the Pound data that were published in JAMA in 1999. This is data out of Hopkins. It's a retrospective cohort study of about 2,000 men who underwent radical prostatectomy between 1982 and '97, and these patients were followed up for a median of about five years. Importantly, none of these patients had received neoadjuvant therapy, and then none received adjuvant ADT until there was evidence of gross distal metastasis. And the primary outcome for the purposes of this analysis was metastasis-free survival.

The actuarial MFS for these 2,000 men was about 82% at 15 years following radical prostatectomy, which means that about 18-20% of them had metastases. For the most part, 80% did not have metastasis. And so in total, there are about 315 men who developed biochemical recurrence. And of these 315, 11 received early ADT, so they were excluded from this analysis, leaving about 304 men. Of these 304 men who developed biochemical recurrence, 103 developed subsequent metastatic disease at a median of eight years after biochemical recurrence. So this is very important data for patients asking about biochemical recurrence, "How much longer do I have before I develop metastases?" The answer, based on this historical data, is about eight years.

And so the next question is, well, really what are the factors, the clinical factors, that are going to predict the occurrence of metastases? And we're going to start from left to right looking at these very important Kaplan-Meier curves. So the first one is the pathologic Gleason score. It's the Gleason score assigned at the time of radical prostatectomy. And we see quite clearly the separation of the Kaplan-Meier curves with worse metastasis-free survival outcomes in the Gleason score eight to 10. So that's the first one, the pathologic Gleason score. The second thing is, well, does it matter if patients recurred earlier or they recurred later on? Yes, it appears that patients who recur within two years have worse outcomes compared to those who recur much later on, so they have more indolent disease courses. So that's the second hint. The third hint is PSA doubling time. So does it matter if a patient's PSA doubles in about five to six months versus those whose PSA doubles two to three, four years down the line? Again, the answer is yes. The kinetics of the PSA matter greatly in this setting.

So we have three hints to inform treatment and management decision-making in these patients. The next data that we're looking at comes from Freedland et al. that was published in JAMA in 2005. The first question is, well, do we have any clinical or pathologic variables that predict the development of metastases? The next question is, do we have the same variables that predict prostate cancer mortality? And so to inform this question, the authors conducted a retrospective cohort study of 380 men who also underwent radical prostatectomy at Hopkins between '82 and 2000. And all patients, all 380 men, had evidence of biochemical recurrence with a calculable PSA doubling time with a median follow-up of about 10 years. And the primary outcome here, as opposed to metastases in the prior study, is prostate cancer-specific mortality.

And so out of the 379 patients, 66 patients died of prostate cancer, and that's about 17%. And very similar to the initial analysis that looked at predictors of metastases, pretty much the same predictors of metastases predicted prostate cancer mortality. So we have the pathologic Gleason score, seven or lower versus eight to 10, time from surgery to biochemical recurrence, less than three years versus more than three years, and then the PSA doubling time, and this was divided into quartiles, and we'll talk about this further later on.

Again, this is reflected in these Kaplan-Meier curves whereby we see that patients who have biochemical recurrence within three years of surgery have worse outcomes compared to those in the upper curve that have it greater than three years after surgery. The second variable is the pathologic Gleason score. Clear separation; we see here in the dark black curve pathologic Gleason scores eight to 10 do worse than those who have Gleason seven or less. And then again, with PSA doubling time, when it's divided into quartiles, we see that in the PSA doubling time less than three months group, we see a very distinct and aggressive decrease in the Kaplan-Meier curve, suggesting that prostate cancer mortality occurred much more commonly in these patients.

And so this is also informing a risk table whereby we looked at the risk of recurrence after surgery, be it greater than three years versus less than three years, and also looking at PSA doubling time. And so this is essentially a more sophisticated two-by-two table and then also incorporating Gleason score. So we have three different variables that we talked about. And then based on these different measures, we could calculate a risk table that predicts prostate cancer-specific mortality. So a patient comes into the clinic. You calculate the PSA doubling time. You're aware of their Gleason score and how soon they recurred after their treatment. And you plug these in. And then based on these three different variables, you can inform the patient of their risk of prostate cancer-specific mortality. And importantly, this is specific to patients who had radical prostatectomy, and we cannot generalize these tables to patients who had radiotherapy.

And then the same group pretty much looked also at PSA doubling time in further detail. So they also used the same cohort of the 379 men from Hopkins who underwent radical prostatectomy between '82 and 2000, and all patients here had biochemical recurrence with a calculable PSA doubling time. Now the median follow-up, as opposed to 10 years, is 11 years, which reflects the increased maturity of this cohort. The primary outcome was, again, prostate cancer-specific mortality. And now, when they looked specifically at the outcomes based on PSA doubling time, again, it was very clear that the prostate cancer mortality outcomes were worse in those who had a PSA doubling time of less than three months. But the main limitation here is the sample size is quite small, and the outcomes here only account for about 13% of prostate cancer deaths. We also saw that prostate cancer mortality was quite high in patients who had a PSA doubling time between three and nine months and similarly to those who had a PSA doubling time of less than 15 months.

What's important is when we think about patients who have a PSA doubling time of less than 15 months, this could be less than three, three to nine, or 10 to 15, 90% of all outcomes occurred in this cohort. Conversely, when we look at the group that had a PSA doubling time greater than or equal to 15 months, their competing cause of mortality, meaning heart disease or deaths from a different malignancy, etc., they had a higher risk of dying from other causes than prostate cancer. So this really informs that these patients really have other competing risks that we need to account for, and it sways us away from offering these patients very aggressive treatment. And this is also very important for clinical trial design. When thinking about treatment intensification, as Zach will talk about later on, do we include all patients? Or do we limit this to patients who have a shorter PSA doubling time, less than 15 months or ideally less than nine months, as we'll see in the EMBARK trial later on? And so this was very important data by Freedland et al. that was published in JCO in 2007.

And if we look at this further and we look at the raw numbers here, essentially, we see that for patients with PSA doubling times of less than 15 months, be it less than three, three to nine, or nine to 15, we see that the number of prostate cancer deaths was higher than those not caused by prostate cancer. And this was consistent until we reached the PSA doubling time of greater than 15 months, where the trend kind of turns and flips, whereby we see that the deaths not caused by prostate cancer are almost double those caused by prostate cancer. So very important data again, confirms that the balance tilts in favor of other competing causes of mortality in patients who have a relatively indolent cohort as reflected by a PSA doubling time of 15 months or greater.

And so pre-2023, and we will talk about why that matters, how were these patients treated? The biggest thing that we knew is that the key risk factor is a PSA doubling time of less than nine months in terms of predicting both metastasis and prostate cancer-related mortality. And the treatment options in this setting really were dictated by the PSA kinetics. So if you had a slow PSA doubling time, meaning greater than 15 months, monitoring was the unanimous treatment or management decision taken in this setting. Conversely, if you had a faster PSA doubling time, ADT was a consideration here, but there was a lot of variation in terms of what is your PSA cutoff for starting ADT. Do you just start it as soon as you see a pretty quick PSA doubling time? Do you wait until they reach a certain cutoff? There's a lot of uncertainty in this setting. And then another option here is intermittent ADT, as we'll discuss later on.

But the major limitation is that we didn't really have guidance from phase three trials in this setting. And another important consideration is that there was no data with regards to treatment intensification with ARPIs, such as abiraterone, enzalutamide, darolutamide, etc., because we know that these agents keep moving up the treatment paradigm. They're pretty much established in both the doublet therapy or the triplet therapy treatment paradigms for patients with metastatic hormone-sensitive prostate cancer. And so naturally, the progression of these drugs is to test them in earlier settings in patients who have non-metastatic hormone-sensitive prostate cancer. And so very important considerations. And at this point, I'll turn it over to Zach, who'll discuss what's new in this treatment paradigm and what is the data that informed these changes in the NCCN guidelines.

Zach Klaassen: Thanks so much, Rashid, for setting that context for the key discussion of this NCCN update. And again, to highlight, this is a new section of the NCCN guidelines with regards to M0 castrate-sensitive prostate cancer after maximal pelvic therapy. As Rashid mentioned already, before the EMBARK trial, monitoring or ADT were our treatment options. And we're really going to focus the remainder of our discussion today on this important addition that, in certain circumstances, enzalutamide with or without leuprolide may be a consideration for these patients. And this is based on the discussion from the phase three EMBARK trial, which was published in the New England Journal of Medicine in October of 2023. The senior author was Neal Shore. The first author was Steve Freedland.

So, this trial design, as seen here, involved 1,068 patients that were randomized 1:1:1 to enzalutamide monotherapy versus enzalutamide combination therapy with leuprolide or leuprolide alone. You can see here that regardless of whether these patients were in any of these treatment arms, at 36 weeks, if a PSA was less than 0.2, a unique trial design aspect for EMBARK was that if they hit this cutoff, treatment was suspended and re-initiated if the PSA started to rise. If the PSA never got to 0.2, they remained on treatment until treatment toxicity or progression of disease. The primary endpoint for EMBARK was metastasis-free survival in the group comparing enzalutamide combination versus leuprolide alone. Key secondary endpoints were enzalutamide monotherapy versus leuprolide alone in terms of metastasis-free survival, as well as overall survival. And the remaining key secondary points are listed here at the bottom right of the slide.

In terms of key inclusion criteria for EMBARK, obviously, these patients had prostate adenocarcinoma. They had to have biochemical recurrence after local therapy. And they had to have these key high-risk features. The reason we spent time setting up EMBARK with the historic studies is to really identify the key high-risk features among patients with biochemical recurrence. As Rashid mentioned, this is PSA doubling time less than or equal to nine months, or at a PSA equal to or greater than two above nadir in those receiving radiotherapy or equal to or greater than one among those receiving a radical prostatectomy plus or minus salvage radiotherapy. These patients also had to have a serum testosterone greater than 150 and excellent performance status with an ECOG of zero to one.

This is the metastasis-free survival primary endpoint of enzalutamide plus leuprolide versus leuprolide alone. You can see enzalutamide plus leuprolide in red and leuprolide alone in blue. It's important to note that the median metastasis-free survival was not reached in either of these arms. At the landmark study point of 60 months, or five years of follow-up, the metastasis-free survival rate was 87.3% in the enza plus leuprolide arm and 71.4% in the leuprolide alone arm, with a hazard ratio benefiting enzalutamide plus leuprolide of 0.42 and a 95% confidence interval of 0.30 to 0.61.

The key secondary endpoint was MFS in the enzalutamide monotherapy versus leuprolide arm. And this is enzalutamide monotherapy in orange and the leuprolide alone in blue. Again, both of these arms did not reach median metastasis-free survival. The 60-month landmark analysis showed 80% of patients were without metastases in the enzalutamide monotherapy arm and 71.4% in the leuprolide alone arm, with a hazard ratio favoring enzalutamide monotherapy of 0.63 and a 95% confidence interval of 0.46 to 0.87.

We look at secondary endpoints. This is looking at the combination of enza plus leuprolide versus leuprolide alone. On the left of a hazard ratio of one is enzalutamide plus leuprolide, favored. And we see that generally all of these secondary endpoints, including a trend towards overall survival, PSA progression, first use of new anti-neoplastic therapy, distant metastases, resumption of any hormonal therapy, etc., all favored the combination therapy with the one caveat that there was no difference in the first deterioration in the fact P total score, so amongst these secondary endpoints favoring the combination arm versus leuprolide alone.

Secondary endpoints for the enzalutamide monotherapy versus leuprolide alone generally favored the enzalutamide monotherapy arm in terms of metastasis-free survival, PSA progression, first use of neoplastic therapy. However, we do see that leuprolide alone was better for the resumption of any hormonal therapy, which we'll discuss further. And so we see some benefit here, but maybe not quite as clear-cut as the combination of enza plus leuprolide versus leuprolide alone.

So this is an important slide because it looks at the percentage of patients who suspended treatment. And so remember when we talked about the trial design at 36 weeks. There was an assessment of PSA less than 0.2 at week 36. And so when we look at the percentage of patients that stopped treatment, it was over 90% in the enzalutamide combination, 85.9% in enzalutamide monotherapy, and 67.8% in the leuprolide alone arm. So how long did these patients stay off of treatment? This is important data when we're talking to our patients. In the combination arm, they were off treatment for roughly 20.2 months, in the leuprolide alone arm, 16.8 months, and in the enzalutamide alone arm, only 11.1 months for enzalutamide monotherapy.

So when we look at the effect of treatment on serum testosterone, we see that at the time of treatment suspension, so this is at 36 months, there was a super physiological increase in testosterone which continued during the break, as well as when treatment was resumed. And we see predictably that at the time of treatment suspension, the testosterone is low for the other two arms in terms of leuprolide alone or enzalutamide combination, and then subsequently, over the time of the suspension or the time of the break-in therapy, the testosterone goes up, which then decreases again at the resumption of therapy. So we see a unique aspect here with enzalutamide monotherapy that the testosterone does not decrease whether on treatment suspension or resumption of treatment.

When we look at adverse events, there are several important points to note here. So at the very top, any adverse event, grade 3+ or higher, we see roughly similar rates here for all of these patients, 50% roughly for grade 3+ or higher, and any grade, nearly 100%. When we look at treatment adverse event rates, very similar between these three arms, roughly 80% or higher for any grade versus anywhere from 8.8 to 17.6 for grade 3+ events. And then I want to jump down to some of these other adverse events and discuss them in more detail, particularly fatigue. We see grade 3 adverse events that are not too bad, 1.4 to 4% for these three arms, but even amongst the enzalutamide monotherapy, so the patients that are not getting true hormone deprivation or androgen deprivation, we still see 46.6 any-grade events for fatigue.

Now the last three here, gynecomastia, nipple pain, and breast tenderness, are all important to discuss with regards to enzalutamide monotherapy. The rates are quite low for the combination or leuprolide alone, but we do see 44.9% any-grade gynecomastia, but only 0.3%, grade 3+ gynecomastia. With regard to nipple pain, again, this is an enzalutamide monotherapy phenomenon, 15.3% any grade, as well as breast tenderness, 14.4% any grade.

What's important in terms of the NCCN guideline updates for 2024 is that in terms of M0 maximal therapy for castrate-sensitive prostate cancer, this also translates into some other parts of the update, including PROS 10, which looks at radical prostatectomy with PSA persistence and recurrence. And if we look at 2023, we see that there's no huge change with life expectancy less than five years. This is going to be patients that get observation. For those that have a life expectancy more than five years, we're going to risk-stratify these patients. We're going to get imaging. Depending on if their imaging is positive or negative, they're going to get EBRT plus or minus ADT. And when they progress, they're going to go to systemic therapy for castrate-sensitive disease.

When we fast-forward to 2024, in terms of this update, all of this is very similar until we get to the point of progression where staging becomes important again. So, studies that are negative for distant metastases and not candidates for maximal pelvic therapy, we can continue to monitor these patients. But where EMBARK also affects these patients is for those that are negative for dis-met, maximal pelvic therapy, they may be candidates for M0 CSPC treatment with EMBARK. And certainly, again, when these patients are scanned and they're positive for dis-mets, they're going to be treated as M1 CSPC patients.

Similarly, for changes to PROS 11, this is radiotherapy recurrence, when we look at 2023, again, no major differences for life expectancy less than five years. These patients are going to be observed until the time of progression. But in those with a life expectancy more than five years, they're going to get risk-stratified again. They're going to get imaged. They may get a biopsy of their prostate. And there's a whole host of local therapies that we may offer these patients. And then at the time of progression, they're going to be categorized as either castrate-sensitive, M0 CRPC, or M1 CRPC. When we look at 2024, similar to the radical prostatectomy updates, all of these options are similar between the two years, but when we get to progression, again, they're going to be restaged and very similar to the radical prostatectomy update, for those patients that have negative for distant metastasis on imaging with maximal pelvic therapy already given, they may be candidates for M0 CSPC treatment intensification based on the EMBARK trial data.

So, in summary, for patients with progressive M0 CSPC after maximal pelvic therapy, which is either radical prostatectomy or radiotherapy, options continue to include monitoring or ADT alone. Patients should be very stringently risk-stratified to identify those that are high risk for mortality, and these are primarily patients with a PSA doubling time of less than or equal to nine months. And based on the phase three EMBARK trial, which was published in 2023, enzalutamide with or without leuprolide is an option for patients with high-risk criteria, including PSA doubling time of less than or equal to nine months and a PSA greater than or equal to two above nadir after radiotherapy or greater than or equal to one after prostatectomy with or without salvage therapy, and those that are not considered a candidate for pelvic-directed therapy.

We thank you very much for your attention. We hope you enjoyed this 2024 NCCN prostate cancer guideline update focusing on M0 castrate-sensitive prostate cancer.