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Rashid Sayyid: Hello, everyone, and thank you for joining us today in this UroToday recording. I'm Rashid Sayyid, robotic urology and oncology fellow at USC, and I'm joined today by Zach Klaassen, associate professor and program director at Wellstar MCG Health. We'll be discussing the 2024 key updates to the NCCN prostate cancer guidelines that were published in March of 2024. In this recording, we'll focus on the changes in the recommendations for systemic therapy for patients with M1 CSPC, and specifically, we'll be focusing on the importance of disease volume and timing of metastases.

If we look at the 2023 NCCN guidelines recommendations, we see, essentially, that in the M1 space there's a blanket recommendation for all patients with hormone-sensitive prostate cancer, whereby treatment options include triplet therapy, doublet therapy, they talk about radiation therapy for patients with charted low-volume disease, and also considering ADT in select lower-risk patients. What's notable in these recommendations is that doublet therapy with ADT plus docetaxel is no longer recommended, and the only form of doublet therapy that is recommended is ADT plus an androgen receptor pathway inhibitor.

But what stands out when we look at these recommendations is, really, they're not as nuanced as we would have hoped. One of the things is there's no treatment stratification by either disease volume and timing, which we both know are very important in terms of prognosis, as well as the underlying biology that dictates treatment. If we fast-forward to the current recommendations of 2024, we see that the guidelines very nicely stratified treatment recommendations by both disease volume as well as disease timing. We'll go over these in further detail in the next slide. So, clearly, we're in a new era of recommendations by disease volume and timing.

If we start with the highest-risk group, and this is the patients with charted high-volume synchronous or de novo metastases, really, we have two main treatment options. The NCCN guidelines first recommend considering triplet therapy in fit patients, and that means ADT plus docetaxel with one of the following, being abiraterone or darolutamide, and as well in appropriate patients, considering doublet therapy with ADT plus an androgen receptor pathway inhibitor.

If we next move to the intermediate-risk group, which includes patients with either high-volume disease but with metachronous presentation, meaning they don't present with metastases at presentation and it happens later down the line, as well as the group of patients with low-volume synchronous metastasis, the NCCN panel recommends first considering doublet therapy with ADT plus an androgen receptor pathway inhibitor, and we see listed below is the triplet therapy options. Furthermore, we can also think about, in the low-volume patients, considering prostate external beam radiotherapy for select patients. What the guidelines add here, which was not included in the prior guidelines, was considering also abiraterone based on the PEACE-1 data and docetaxel based on STAMPEDE arm H. So this isn't simply ADT plus prostate radiotherapy, but now when you're treating these patients, you need to think about another layer, which is systemic therapy intensification.

Finally, we have the lowest-risk group with the best prognosis, and that's the patients with low-volume disease and a metachronous presentation, whereby ADT plus an androgen receptor pathway inhibitor doublet therapy is recommended for these patients.

So where does this evidence come from? Why are we recommending triplet therapy for the highest-risk patients with high-volume synchronous disease? Let's take a step back and look at the recent studies that were published. If we look at the ARASENS data, ARASENS was the trial of triplet therapy with ADT plus docetaxel plus darolutamide versus ADT plus docetaxel doublet in patients with metastatic hormone-sensitive prostate cancer. It's important to note that 86% of patients included in this trial had metastatic disease at presentation, so de novo disease. So it's really hard to look at the factor of disease timing, but it's easy to look at low versus high volume.

If we look at the first bullet point here, when darolutamide or triplet therapy was added, patients with high-volume disease had a significant improvement in their overall survival with a hazard ratio of 0.69. If we look here at the top left panel at the Kaplan-Meier curves, we see very nicely the curve split early on, and this trend continues. So this reinforces to us, visually, the benefits of triplet therapy in the high-volume patients.

Conversely, when we look at the low-volume disease patients, you may say, "Well, the hazard ratio is almost the same at 0.68." But two things stand out. First of all, the confidence interval crosses the null value of 1, so at a 95% confidence interval, we can say that this is not a significant finding. The second thing is, if we look at the curves, they really don't split until the very, very end. So that tells us that perhaps some of the benefit we see is spurious and may be artificial and secondary to a lower power issue as opposed to a true survival benefit. Based on that, we can see that the benefit for triplet therapy is clearly in favor of high-volume disease in this study.

Next, let's move on to PEACE-1. As opposed to ARASENS, which was 86% de novo mHSPC, all patients in PEACE-1 had de novo disease. If we see here, it's the same picture as we saw in ARASENS. When we look at patients with high-volume metastatic burden, the addition of abiraterone to ADT plus docetaxel was associated with significant overall survival benefits, again with a hazard ratio of about 0.7. Again, when we look at the low-volume patients, the Kaplan-Meier curves really don't split at all early on, and that's reflected in the hazard ratio of 0.83, with a p-value of 0.66. So now we have two studies that strongly suggest that triplet therapy has the highest survival benefits in patients with high-volume disease.

Next, let's look at the aspect of disease timing, and we get some excellent data from ENZAMET. It's important to note that about 45% of patients in the ENZAMET trial received docetaxel. This was at the treating physician's discretion. So, in some ways, this is a pseudo-triplet therapy trial, and there's a lot we can take from that.

When we look at patients in the synchronous group, meaning those patients who present with metastases at initial presentation, the addition of enzalutamide to ADT plus docetaxel was associated with significant improvements in overall survival, with a hazard ratio of 0.73, and again, we see the curve split early on. Conversely, if we look at patients in the metachronous group, the hazard ratio is 1.1, and the curves are really overlapping. So we see that the synchronous patients benefit the most from triplet therapy with the addition of enzalutamide.

This leaves us with a bit of a conundrum. What about those patients with low volume, meaning they don't really improve or benefit from triplet therapy, and the synchronous that do? So we have really conflicting rationales here. Yet the NCCN does recommend triplet therapy as an option for these patients. So, really, where does the evidence for this recommendation come from? If we look at the subgroup analysis from the ENZAMET trial, focusing on those patients with synchronous disease, meaning those who benefited from adding enzalutamide to ADT plus docetaxel, those specifically with low-volume disease per the CHAARTED criteria had a significant improvement in overall survival with a very meaningful improvement, with a hazard ratio of 0.57. You may see the confidence interval crosses one, but this is likely a factor of a small subgroup size as opposed to a lack of true benefit in this cohort.

Next, we look at patients with low-volume metachronous disease. What stands out is that docetaxel is not a recommendation for these patients. In terms of using docetaxel in the triplet therapy setting, we know that low-volume patients do not benefit, and patients with metachronous disease do not benefit. So it goes without saying that those with both conditions, low-volume and metachronous, aren't going to benefit from docetaxel.

But why do we not even consider docetaxel as a doublet therapy regimen? Just ADT plus docetaxel? Forget about the ARPI aspect? Well, we have recent data from 2023 that was published by Vale et al in The Lancet Oncology that shows us within the context of a meta-analysis that patients with low-volume metachronous really do not benefit from doublet therapy with ADT plus docetaxel. That's in contrast to the other risk subgroups. So, really, especially when we consider the worst adverse event profile of docetaxel, there's not a strong rationale to recommend doublet therapy with docetaxel for these patients.

If we look further into the low-volume synchronous metastasis subgroup, we note that the NCCN recommends considering radiotherapy to the prostate for those with the low-volume synchronous aspect, but also considering the systemic therapy intensification role of abiraterone and docetaxel. The evidence for these recommendations comes from two trials: the STAMPEDE arm H, as well as PEACE-1. I'll turn it over to Zach to go over the evidence from these two trials and discuss why these are a key aspect of the current recommendation for this patient when administering prostate radiotherapy.

Zachary Klaassen: Thanks so much, Rashid, for that great introduction. So let's delve into STAMPEDE arm H, as Rashid mentioned. This was published in The Lancet in 2018. This was a phase 3 RCT of 2061 men with de novo metastatic hormone-sensitive prostate cancer. These men were randomized to either standard of care plus prostate radiotherapy or standard of care alone, and the median baseline PSA for these patients was 97, with 18% of these patients having received prior docetaxel.

In the overall cohort, radiotherapy for these patients did not improve overall survival, with a hazard ratio of 0.92, statistically insignificant, at a 95% confidence interval. However, when we look at this Kaplan-Meier curve on the right, when stratified by metastatic burden, overall survival benefit was noted for the low-volume group—overall survival, 49 versus 45 months in those that received radiotherapy versus those that did not, with a hazard ratio of 0.68 and a statistically significant 95% confidence interval of 0.52 to 0.90.

So what's the key metric? How many metastases are considered low volume? And who is going to benefit from this treatment? There was a subsequent analysis published in JAMA Oncology, a very elegant analysis looking at how many bone metastases on conventional imaging led to a survival benefit. What this study showed was survival benefit decreased continuously as the number of bone metastases increased, with most benefit in three or fewer metastases, as we can see in this figure, but some benefit may be seen with up to seven metastases. So this gives us a little bit of an ability to give a metric to the patient and also led the NCCN to state that a conventional imaging-defined number of bony metastases without visceral involvement may be preferred to define candidacy for treatment of the primary tumor.

Switching gears to PEACE-1, this is prostate radiotherapy for de novo low-volume metastatic hormone-sensitive prostate cancer. This study found that the addition of prostate radiotherapy to standard of care plus abiraterone was associated with a significant radiographic progression-free survival benefit, with a median of 7.5 versus 4.4 years. However, the addition of radiotherapy to standard of care alone was not associated with RPFS benefit, with a hazard ratio of 1.11. Additionally, when we look at overall survival in this analysis, there was no overall survival benefit for the addition of prostate radiotherapy to standard of care alone or standard of care plus abiraterone.

Taken together, what's going on in the metastatic hormone-sensitive space for ongoing clinical trials? This is a relatively new review, a very elegant review from Karim Fizazi, who is the senior author. We see several important trials in this disease space. So in the DRR-deficient population, germline or somatic, we have the Amplitude trial, the TALAPRO-3 trial, and if we look at the PTEN-deficient population, we have the CAPItello trial. Then we have five trials of all-comers for metastatic hormone-sensitive prostate cancer. This includes the ZZ-First trial, CYCLONE-3, PSMAddition, Keynote-991, and the PROSTATEGY trial, which are all looking at patients that are all-comers in the metastatic hormone-sensitive prostate cancer space. So we already have a lot of data. We're going to get continued differentiation, potentially, of treatment options, specifically in some of these patients with germline or somatic mutations, over the next several years.

Let's switch gears and finish with SBRT and metastasis-directed therapy. The NCCN recognizes an expanding role of SBRT in metastatic hormone-sensitive prostate cancer, and they state that SBRT to metastasis can be considered in patients with oligometastatic progression where PFS is the goal. Secondly, SBRT to metastasis can be considered in "appropriate clinical situations." So there's a little bit of discretion by the physician and the patient for treating patients with metastasis with SBRT.

In terms of SBRT for MDT (metastasis-directed therapy), there are four recommendations for MDT outlined by the NCCN. The first one is limited metastatic disease, i.e., oligometastatic, when ablation of these lesions is the goal. There are some phase II trials looking at this: the ORIOLE, STOMP, and SABR-COMET trials. Secondly, in patients with limited progression, i.e., oligoprogression, or limited residual disease on otherwise effective systemic therapy. So really looking at a consolidative approach, again, where progression-free survival is the goal. The notable phase II trial here is the EXTEND trial. Finally, the other two recommendations are in a symptomatic patient where the lesion occurs in or immediately adjacent to a previously irradiated treatment field, and finally, at the physician's discretion for more durable control of pain than achieved with typical palliative regimens used in everyday treatment.

Just briefly looking at some of the key Kaplan-Meier figures from these trials. These are all progression-free survival. In the SABR-COMET trial, this was metachronous metastatic hormone-sensitive prostate cancer and mCRPC. The hazard ratio for the SABR arm versus the control arm was 0.45. In the STOMP trial, metachronous metastatic hormone-sensitive prostate cancer MDT versus observation had a hazard ratio of 0.48 for progression-free survival. Similarly, in the ORIOLE trial, also looking at metachronous metastatic hormone-sensitive prostate cancer, the hazard ratio was 0.40. In the top right, EXTEND, this was synchronous/metachronous metastatic hormone-sensitive prostate cancer and mCRPC. The addition of SABR with ADT to ADT alone had a significant progression-free survival benefit, with a hazard ratio of 0.25.

This is a very active disease space. These are the ongoing trials for MDT. This slide is courtesy of Dr. Tom Zilli from the recent APCCC meeting, and we see a lot of activity in this disease space. Three trials are looking at de novo or metachronous SBRT: the PLATON trial, the PRESTO trial, and the START-MET trial. Then the remaining studies are all in the metachronous setting: the VA STARPORT trial, the RADIOSA trial, ADOPT, PROMETHEAN, DART, SPARKLE, POSTCARD, and RAVENS. These are all SBRT MDT trials, a mix of phase II and phase III, with primary endpoints ranging from CRPC-free survival, PFS, and MFS. We're really going to see some clarity hopefully in the next couple of years as these trials start to read out, and we'll be able to place MDT, specifically SBRT, into the clinical context.

Going back again to this review article from Dr. Fizazi's group, we've spent a lot of time talking about volume, and a little time talking about timing. It's important that volume is easy to detect and easy to count lesions, but we also need to pay attention to the de novo versus recurrent disease status because, truly, these diseases have different biology.

We conclude with this elegant slide from Dr. Fizazi's EAU 2024 talk entitled "A New, Personalized Treatment Paradigm? More Than Just Counting Metastases." He really outlines possible treatment options based on not only volume but also the timing of the metastatic disease. For low-volume de novo metastatic hormone-sensitive prostate cancer, there's a clear role for ADT plus ARPI. There may be a role for triplet therapy, ADT plus docetaxel plus ARPI, specifically for those patients that are young, fit, and have bone-predominant disease, and there likely is a role, as we've seen from several trials, for prostate radiotherapy in these patients.

When we're looking at high-volume de novo metastatic hormone-sensitive prostate cancer, this is really the wheelhouse for triplet therapy, and we may consider prostate radiotherapy as well to prevent genitourinary symptoms as treatment progresses. Finally, for low-volume relapsed metastatic hormone-sensitive prostate cancer, there is scarce data, but ARPI is likely needed for these patients, and certainly, as we've mentioned, SBRT to the metastatic sites, which is being extensively evaluated in clinical trials, will likely play a role for these patients in the coming years.

We thank you very much for your attention. We hope you enjoyed this UroToday NCCN discussion looking at key updates in the metastatic hormone-sensitive prostate cancer setting.