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Rashid Sayyid: Hello, everyone, and thank you for joining us in this UroToday recording. I'm Rashid Sayyid, a Urologic Oncology Fellow at the University of Toronto. Along with Zach Klaassen, Associate Professor and Program Director at Wellstar MCG Health, we'll be discussing the recently amended AUA guidelines for advanced prostate cancer. And in this recording, we'll be discussing the statements pertaining to bone health and future directions. This recent amendment was published in the Journal of Urology in 2023, with this update led by Dr. Michael Cookson.

So, in this series, we'll be discussing two underappreciated, often underdiscussed, aspects of prostate cancer, specifically, bone health, which remains a matter of utmost importance for our patients. And also, we'll be discussing future directions in this field.

So, starting off with bone health, it's important to highlight the factors which increase the risk of bone complications for men with prostate cancer. And a lot of people may know this already, but it's important to highlight different nuances that are often underappreciated in this cohort of patients.

First of all, the median age of onset of this disease is in the late sixties. And so, particularly for patients with advanced disease, this takes time, and so the average age of our patients with metastatic prostate cancer is in the seventies. And we know that men in their seventies are a high-risk population for a physiologic, age-related decrease in bone mineral density. So, first of all, we have the age factor going against these patients.

Next, patients receive ADT as the backbone of treatment for advanced prostate cancer. And ADT is associated with a progressive loss of bone mineral density, and it's not infrequently to the point of osteopenia or osteoporosis. And this increases the fracture risk, even in patients without metastatic disease.

And then the third component is that, in advanced prostate cancer, bones are the most common site of metastasis, which increases the risk of bone fractures.

Statement Number 37 tells us that we should assess the risk of fragility fractures, whereby clinicians should discuss the risk of osteoporosis associated with ADT and should assess the risk of fragility fractures in patients with advanced prostate cancer. This is a Clinical Principle. There are many tools out there, which include the fracture risk assessment tool, which is a validated resource to predict a patient's 10-year probability of hip fracture and a major osteoporotic-related fracture. We can also assess baseline bone mineral density with a dual-X-ray absorptiometry, the DXA scan, that may be considered in men receiving ADT or other systemic therapy. And so, what is a reasonable approach? To assess the osteoporotic risk at baseline using either the FRAX tool or the DXA scan and then at one-yearly intervals thereafter, and then at longer intervals after a longer period of treatment.

Next, Statement Number 38, pertaining to preventive treatment for fractures and skeletal-related events, tells us that clinicians should recommend preventive treatment for fractures and skeletal-related events, including supplemental calcium, vitamin D, smoking cessation counseling, and weight-bearing exercise, to advanced prostate cancer patients receiving ADT, and it's a Clinical Principle. And we have information and guidance pertaining to preventive treatment that comes from the US National Osteoporosis Foundation, which recommends, for these patients, weight-bearing exercises, muscle-strengthening exercises, balance exercises, smoking cessation, reduction in alcohol intake, and adequate calcium and vitamin D supplementation or intake for these patients.

Next, with regards to specific pharmacologic therapies in this setting, bisphosphonates or denosumab, Statement Number 39 tells us that in advanced prostate cancer patients at high fracture risk due to bone loss, clinicians should recommend preventive treatments with bisphosphonates or denosumab and referral to physicians who have familiarity with the management of osteoporosis when appropriate. And this is a Clinical Principle.

The pharmacologic strategies can be thought of as one of three approaches: oral bisphosphonates with alendronate or pamidronate; we have intravenous bisphosphonates, zoledronic acid; and then we have subcutaneous RANK ligand inhibitors, which include denosumab. One important side effect to be aware of is osteonecrosis. And so, this is a rare but serious side effect, and so we should consider dental evaluation prior to starting therapy, preferably using the assistance of a certified dentist.

Now, let's talk about the specific drugs in this setting, bisphosphonates, and denosumab. So, there's a lot of evidence out there for bisphosphonates, with a recent meta-analysis looking at 15 trials that included over 2,500 men, looking at bisphosphonates versus placebo. And it noted that bisphosphonates significantly reduced the risk of osteoporosis with a relative risk of 0.39. And bisphosphonates furthermore significantly decreased the risk of osteoporosis-related fractures with a relative risk of 0.8. It's important to note that the greatest reduction in fractures was with zoledronic acid, with a relatively small number needed to treat of 15 patients.

Next, for denosumab, there was a trial of just under 1,500 men that randomized patients to denosumab given at 60 milligrams every six months versus placebo. It's important to note this is the q6 monthly dose, not the monthly dose. And at 36 months, denosumab significantly increased bone mineral density and decreased the risk of vertebral fractures from 3.9% to 1.5%, and this corresponds to a relative risk of 0.38.

Statement Number 40, bone preventive agents for mCRPC, tells us that clinicians should prescribe a bone-protective agent, either denosumab or zoledronic acid, for mCRPC patients with bony metastases to prevent skeletal-related events. This is a Moderate Recommendation with an Evidence Level Grade of B.

And so, is there any evidence for denosumab versus zoledronic acid in mCRPC? Yes. We have the data from Dr. Fizazi published in The Lancet, 2011, whereby a non-inferiority trial of just under 2,000 mCRPC patients with bone metastases was performed, and randomized patients to denosumab versus zoledronic acid, with a primary endpoint of time to a skeletal-related event. And it was demonstrated that denosumab was non-inferior to zoledronic acid. With regards to this outcome, actually, it was a little better, 21 months versus 17 months. And it's important to note that the rates of hypocalcemia were higher with denosumab, and so it's important to monitor calcium levels. And obviously, we know that zoledronic acid comes at a higher risk of osteonecrosis of the jaw, so we have to balance these side effects and be aware of each and perform the recommended surveillance in this setting.

More recently, we have the CALGB 90202 trial that looked at zoledronic acid in the metastatic hormone-sensitive prostate cancer. We note the previous trials were in the CRPC setting. So, the CALGB 90202 was a phase III RCT of 645 metastatic hormone-sensitive prostate cancer patients who were randomized to zoledronic acid, given at a dose of four milligrams IV every four weeks, versus placebo. And after progression to mCRPC, all patients receive zoledronic acid as is recommended currently by the AUA guidelines.

And so, with regards to the median time to the first skeletal-related event, there was really no significant benefit to zoledronic acid, and also, there was no significant benefit with regards to overall survival. And so, the results of this trial provided the basis for not recommending zoledronic acid routinely in mHSPC patients, although we note that patients with osteopenia or at high risk for fractures should be counseled and considered for such treatment in this setting.

At this point, I'll turn it over to Zach, who'll go over the future directions in this exciting field.

Zach Klaassen: Thanks so much, Rashid. So, we'll conclude our package of AUA advanced prostate cancer guidelines with several future directions as highlighted by the panel. So, there'll be five sections for this, the first of which is the integration of care.

Certainly, multidisciplinary clinics and the resulting multi-modality treatment approaches can optimize several key aspects for a patient. This includes treatment selection, maximizing results, reducing overtreatment, and better managing side effects. Currently, one example given by the panel is that the surgical resection of the primary tumor in the setting of metastatic prostate cancer is considered experimental. So, from a multidisciplinary standpoint, we'll highlight the SWOG 1802 trial, the PI being Brian Chapin, which is a phase three, randomized, controlled trial evaluating standard systemic therapy, plus or minus local control, in men with de novo metastatic hormone-sensitive prostate cancer, and local control being identified as either surgery, radiation, or both, with the physician and the patient being allowed to choose which modality they would like.

The study aim is to address whether local treatment of the primary in the setting of metastatic disease provides an overall survival benefit, and we can see the trial schema here to the right. And, there also are plans for a surgical arm to be incorporated into the STAMPEDE platform. So, this is truly looking at a multidisciplinary approach specific to a question that currently, we do not have the answer to.

The second point is advanced PET imaging and theranostics, and we need to be cognizant of the stage migration that will occur with advanced PET imaging, especially with the vast uptake we've seen over the last couple of years. And what will ultimately determine the role of these PET agents will be trials demonstrating that imaging-improved patient outcomes as a direct result of either earlier intensification of systemic therapies, MDT, and/or prediction of responses to specific therapies. And, theranostics is another area where integrated, multidisciplinary care will be important and will require expertise from medical oncology, nuclear medicine, and radiation oncology.

The third point for future directions is metastasis-directed therapy. We've previously seen that both the STOMP and the ORIOLE phase two trials have shown that MDT to oligometastatic sites delays systemic therapy in patients with metastatic hormone-sensitive prostate cancer. However, there are two issues with the current data. We don't have overall survival data, and we need to further define appropriate patient selection criteria for those that may benefit from MDT. Currently, the standard of care, plus/minus SBRT to metastatic sites, is being assessed in prospective phase three trials. This includes the START MET trial as well as the PRESTO trial. So, hopefully, in the next couple of years, we'll have high-level data to further define which patients may benefit from metastasis-directed therapy.

The fourth point is biomarkers and other systemic therapies. Currently, the most promising biomarkers are those associated with identifying DDR genes, such as BRCA1 and 2, and ATM, and providing evidence for PARP inhibitor use, and MSI-high status providing evidence for immune checkpoint inhibitor use. Of note, though, circulating cell-free DNA may be a future alternative approach to identify DDR alterations, and subsequent reversion mutations could be identified after disease progression. There are ongoing trials that are continuing to explore whether immune checkpoint inhibitors, vaccine-based therapies, or oncolytic viruses may have broader utility in men with advanced prostate cancer.

The fifth point in terms of future directions is unmet needs, and there are several unmet needs in the advanced prostate cancer disease space. First, and importantly, is that Black patients with advanced prostate cancer demonstrate worse outcomes, and understanding the societal and biological underpinnings is a critical area of need for prostate cancer.

Secondly, personalized care with predictive markers for treatment selection based on tumor and host biology has not yet been achieved.

And third, there is a movement toward the identification of prognostic markers and the identification of molecular markers based on immunohistochemistry and genomic signatures, but as of yet, these have yet to yield predictive results.

Fourth, PSMA imaging is indeed changing advanced prostate cancer. And as we learn more about its utility in managing patients, we will soon be able to treat with precision-guided therapy.

Fifth, with the widening utilization of next-generation imaging, the application of metastasis-directed therapy as a standard of care requires definitive trials, two of which we mentioned in the previous discussion.

Sixth, improving responses by treating high-risk patients in a neoadjuvant approach prior to surgery, based on tumor susceptibilities, is also an area of developing interest.

Finally, the last three unmet needs: We need a high-level evidence directed at understanding the optimal sequencing of advanced prostate cancer therapies. We need additional studies and data to guide clinicians and patients in terms of treatment intensification and combinations of therapies. And, finally, we need to improve access to care for those who are socioeconomically disadvantaged, which is a key future goal suggested by the panel.

So, in conclusion, patients with advanced prostate cancer are at significant risk of osteopenia, osteoporosis, and fractures, and clinicians should be cognizant of utilizing bone-protective agents, particularly bisphosphonates and denosumab.

And, finally, there are several crucial unmet needs in advanced prostate cancer, including optimizing outcomes of Black patients and those at a socioeconomic disadvantage, the sequencing of therapies, and increasing the personalization of therapy through the further uptake of genomic testing.

We thank you very much for your attention. We hope you enjoyed this UroToday guideline discussion of the AUA advanced prostate cancer guidelines.