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Rashid Sayyid: Hello everyone, and thank you for joining us in this UroToday AUA Guidelines recording. I'm Rashid Sayyid, the Urologic Oncology Fellow at the University of Toronto, along with Zach Klaassen, Associate Professor and Program Director at Wellstar MCG Health. We'll be going over the recently amended AUA guidelines for advanced prostate cancer. As previously mentioned in prior recordings for this guidelines, this will be a six-part series, and in this recording, we'll be going over the statements pertaining to mHSPC advanced prostate cancer. By way of reminder, this most recent amendment of the guidelines was published in the Journal of Urology in 2023 with Dr. Michael Cookson as the Lead Senior Author.

So, statement number nine, discussing prognosis. Clinicians should assess the extent of metastatic disease, meaning to the lymph node, the bone, and the visceral organs, in newly diagnosed mHSPC patients as a clinical principle. This is quite clear; the need for and the choice of systemic therapy is strongly influenced by the presence and extent of metastatic disease burden. We'll go over the treatment options by presentation and burden in later slides. The panel suggests that patients can undergo conventional imaging or PSMA PET at the time of diagnosis. But as we see in the last statement, treatment recommendations are based on conventional imaging findings. So although PSMA PET may be performed and may detect a higher burden compared to conventional imaging, at the current time, physicians can do either imaging modality at this point. Now, for patients with disease recurrence following primary therapy, conventional imaging, PSMA PET, and Axumin PET are all reasonable options in this biochemically recurrent setting.

Statement number 10 tells us that in newly diagnosed mHSPC patients, clinicians should assess the extent of metastatic disease defined as low versus high volume. And this is based on the CHAARTED criteria. High volume is defined as greater than or equal to four bone metastases, with at least one of these metastases outside of the spine or pelvis, and/or the presence of visceral metastases. And this is a moderate recommendation with evidence Level: Grade B. And so if we look at prognosis based on the CHAARTED criteria, we've demonstrated that the addition of docetaxel to ADT shows an overall survival benefit in the high-volume disease patients, with a hazard ratio of 0.63, but not in the low-volume disease patients, with a hazard ratio of 1.04. Although in the STAMPEDE trial, we didn't really see this distinction. Quite clearly, based on the data from the CHAARTED trial, there is a difference based on the disease volume, and so it's imperative on the physician to define that.

Statement number 11 tells us that clinicians should assess if a newly diagnosed mHSPC patient is experiencing symptoms from metastatic disease at the time of presentation to guide discussions of prognosis and further disease management. And this is a moderate recommendation of evidence Level: Grade B. And so this is quite simply because symptomatic metastatic disease is clearly a poor prognostic predictor based on the available data. And so, an analysis of the SWOG 8894 trial, which is an earlier trial in ADT in the metastatic hormone-sensitive state, demonstrated that the presence of bone pain was associated with worse 10-year overall survival, with a convincing odds ratio of 2.61. So clearly, patients with bone pain are at worse prognostic risk.

Statement number 12 tells us that clinicians should obtain a baseline PSA and then serial PSAs at three to six-month intervals after initiation of ADT in these metastatic, hormone-sensitive prostate cancer patients, and should consider periodic conventional imaging as well, this is a clinical principle. And we know that baseline PSA kinetics afterward, post-treatment initiation, are strongly prognostic of survival options. So again, very important to get these at baseline and then later on.

But PSA alone does not completely predict cancer progression, as some patients may demonstrate cancer growth in the absence of PSA rise. Clear examples of this are patients with poorly differentiated, ductal, or neuroendocrine tumors, as well as mHRPC, who don't have the epithelial cells to produce and secrete the PSA into the serum. So clearly, they can progress without a serum PSA rise. And so, two things: symptom assessment and periodic imaging are both critical to detect disease progression in the absence of a PSA rise.

Now, just looking further at baseline PSA, it's quite intuitive. Higher PSA is most likely reflective of a higher disease burden. And as such, we would expect those with a higher baseline PSA to have a worse prognosis. And this has been corroborated by many studies, one of the most notable ones being a SEER analysis of just under 9,000 patients with treatment-naive advanced prostate cancer that showed that a higher baseline PSA is associated with worse prostate cancer survival. So, if we look at those with a lower PSA, less than 0.6, the hazard ratio was 0.6. So they had about a 40% lower hazard of prostate cancer mortality. And then, as I mentioned, numerous other trials and observational studies have conclusively demonstrated that higher baseline PSA is associated with worse survival outcomes.

Let's talk about the prognostic value of PSA response following treatment initiation. So we talked about baseline PSA; clearly, these patients do worse with a higher baseline PSA. What about the PSA kinetics? So Harshman et al. looked at this in the CHAARTED trial and performed a seven-month landmark analysis in these patients, irrespective of whether they received ADT alone or ADT plus docetaxel. And they demonstrated that PSA response was strongly prognostic of survival outcomes. So patients at seven months with a PSA of 0.2 or lower had a median overall survival of about five months. Comparatively, those with a PSA greater than four had a median overall survival of about two years. So clearly, a big difference, and this is very important in two things: in counseling our patients and then deciding on treatment intensification in these patients with a poor PSA response.

So that was seven-month PSA; can we look at earlier PSA? So a three-month landmark analysis of the TITAN trial, which looked at ADT plus or minus apalutamide for mHSPC patients, demonstrated that PSA decline to 0.2 or less or greater than 50% from baseline was associated with improved overall survival, hazard ratio 0.35, radiographic progression-free survival, and time to CRPC. So we've established two things: seven months matters a lot, and also three months.

But another important question is, with the increased utilization of ultra-sensitive PSA assays, does ultra-low PSA matter, or is it just less than 0.2 versus greater than 0.2? And so, a recent analysis that was presented at ESMO 2023 from this trial showed that among PSA responders, an ultra-low PSA decline, defined as less than 0.02, was associated with significantly improved survival outcomes, be it overall survival, rPFS, compared to those with a good PSA response of 0.02 to 0.2.

So clearly, the better they respond and the earlier they respond, the better their outcomes. So again, very important. And this principle is forming the basis of many future trials that will look at both treatment intensification and importantly, treatment deintensification in those with an excellent early response. And so, very exciting data that will inform future clinical trials and hopefully, practice.

And statement number 13 for prognosis tells us that in patients with mHSPC, clinicians should offer germline testing, and consider somatic testing and genetic counseling. And this is a clinical principle, and I just want to highlight, germline testing essentially looks for inherited mutations. When we look at somatic testing, we look at both inherited and acquired mutations as well.
And one study that's very important was by Pritchard et al., published in the New England Journal in 2016. This was a study that evaluated 20 DNA repair genes associated with autosomal dominant cancer predisposition syndromes in a population of men with metastatic prostate cancer. They determined that the prevalence of inherited, meaning germline, repair mutations was about 12%. So about one in eight patients have these germline mutations.

And so, why does this matter? First of all, for informing personalized treatment decision-making, especially with the emergence of PARP inhibitors. And we'll talk about that in later slides. And also for defining prognosis. We know that BRCA2, for example, is both a prognostic and predictive biomarker in the setting whereby patients with BRCA2 have a worse survival compared to those without any of these defect repair gene mutations. And it's also a predictive biomarker, meaning that they respond better to PARP inhibitors. So clearly, very important given the increased prevalence of these germline mutations, not to even mention the somatic or acquired mutations.

And at this point, I'll turn it over to Zach to go over statement 14, treatment, and the remainder of the statements in this disease space.

Zach Klaassen: Thanks so much, Rashid. So looking at treatment statement 14, based on evidence Level: Grade B, clinicians should offer ADT with either LHRH agonists or antagonists, or surgical castration in patients with metastatic hormone-sensitive prostate cancer. We do know that LHRH agonists or antagonists and bilateral orchiectomy are considered equally effective for cancer control. And really, what we're looking for, regardless of castration modality, is a serum testosterone less than 50. And we do know also that bilateral orchiectomy and GnRH antagonists avoid the testosterone flare, which is observed with LHRH agonists. And these can be useful in select circumstances, such as impending spinal cord compression. There is now an oral GnRH receptor antagonist, relugolix or Orgovyx, which was approved in December 2020. This was following the results of the Phase III HERO trial.

Statement 15 suggests that in patients with metastatic hormone-sensitive prostate cancer, clinicians should offer ADT in combination with either androgen pathway-directed therapy. This may be abiraterone plus prednisone, apalutamide, or enzalutamide, or chemotherapy in the form of docetaxel. And so the next several slides will take us through a historical journey of these trials, starting with the 2013 publication of the GETUG-AFU 15 trial, looking at docetaxel plus ADT. And as we can see here, this was a negative trial. There was no significant OS benefit with docetaxel being added to ADT, meaning overall survival was 59 versus 54 months. Hazard ratio 1.01. But if we fast-forward to 2015, this is the CHAARTED trial; this was docetaxel also plus ADT, and docetaxel in this trial improved overall survival from 47 to 57 months. However, as we can see on the right-hand side of this slide, this was limited to patients with high-volume disease having an OS benefit of 17 months versus no overall survival benefit in low-volume disease patients.

2016 showed the STAMPEDE trial looking at also docetaxel plus ADT, and this showed that the addition of docetaxel to ADT improved overall survival from 43 to 59 months. But contrary to the CHAARTED trial, survival benefit was observed in both high and low-volume groups, which was important as we move forward into the late 2010s, having the approval of docetaxel for ADT for all patients with metastatic hormone-sensitive prostate cancer.

Next year, after the STAMPEDE trial, was the LATITUDE trial. This looked at abiraterone, plus prednisone plus ADT. And we can see here based on the overall survival curve to the right, an early and consistent splitting of the curves favoring ADT plus abiraterone plus prednisone. This improved OS in patients with de novo high-risk metastatic prostate cancer, 53.3 months from 36.5 months. Statistically significant hazard ratio 0.66, 95% confidence interval, 0.56 to 0.78.

STAMPEDE also looked at abiraterone, plus prednisone plus ADT. And we see here again that both high-risk and low-risk patients, this was statistically significant, benefiting the combination treatment arm, both with the hazard ratio statistically significant of 0.54.

Looking ahead to the ENZAMET trial, this was enzalutamide plus ADT, published in 2019. This looked at the addition of ENZA to ADT, versus ADT plus the non-steroidal anti-androgen. And this improved overall survival, hazard ratio of 0.70, 95% confidence interval of 0.58 to 0.84. And in ENZAMET, there were 45% of patients that were also planned for early docetaxel use.

Also, the same year looked at the ARCHES trial, again enzalutamide plus ADT, showing an improvement in overall survival. Again, median overall survival was not reached in the combination arm, with a hazard ratio favoring enzalutamide plus ADT of 0.66, 95% confidence interval of 0.30 to 0.81. And again, 17% of patients in this trial had previously received docetaxel chemotherapy.

The TITAN trial looked at apalutamide plus ADT, also published in 2019, and we saw again, a positive trial. Apalutamide plus ADT improved overall survival. Median overall survival not reached in the combination arm, versus 52.2 months in the placebo arm, with a hazard ratio of 0.65, at a 95% confidence interval of 0.53 to 0.79.

This takes us to statement 16, again related to treatment. And this is stating that in selected patients with de novo metastatic hormone-sensitive prostate cancer, clinicians should offer DT in combination with docetaxel and either abiraterone acetate plus prednisone, or darolutamide. So this is the triplet therapy that has been evolving over the last couple of years.

And so, this is based on the ARASENS trial published in 2022, ADT, plus docetaxel plus darolutamide. And this triplet therapy improved overall survival in metastatic hormone-sensitive prostate cancer patients, 86.1% of whom had de novo disease. And the hazard ratio for this triplet therapy versus chemotherapy plus ADT was 0.68, with a 95% confidence interval of 0.57 to 0.80.

The PEACE-1 trial looked at ADT, plus docetaxel, plus abiraterone plus prednisone. And this addition in patients with de novo metastatic disease demonstrated a 25% OS improvement, with a hazard ratio of 0.75, 95% confidence interval, 0.59 to 0.95. So this is the triplet therapy. Both of these options are available for our patients.

So in conclusion, the extent of metastatic hormone-sensitive prostate cancer should be assessed for high- and low-volume status. Secondly, patients with metastatic hormone-sensitive prostate cancer should be considered for somatic versus germline testing, in order to potentially guide personalized therapy. As we've discussed over the last several slides, there are several doublet and triplet therapy options available for these patients. And treatment intensification should be standard of care for the majority of metastatic hormone-sensitive prostate cancer patients.

Thank you very much for your attention. We hope you enjoyed this UroToday AUA Guideline discussion of metastatic hormone-sensitive prostate cancer.