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Rashid Sayyid: Hello everyone, and thank you for joining us for this UroToday AUA guidelines recording. I'm Rashid Sayyid, a Urologic Oncology Fellow at the University of Toronto. And along with Zach Klaassen, an Associate Professor and Program Director at Wellstar MCG Health, we'll be going over the recently amended AUA guidelines looking at advanced prostate cancer.

This will be a six-part series. And in this recording, we'll be discussing advanced prostate cancer epidemiology and touch upon the statements for early evaluation and counseling of advanced prostate cancer patients. These guidelines were recently amended in 2023 and were led by Dr. Michael Cookson. So as previously mentioned, this will be a six-part series, and again, we'll be discussing the epidemiology and the guideline statements about early evaluation and counseling of these patients. Before we delve into the epidemiology and the guideline statements, let's just talk about some semantics with regards to these guidelines.

First of all, we need to be aware of the strength of evidence definitions. So when it's a Grade A level of evidence, that refers to evidence coming from high-quality, randomized controlled trials, or exceptional observational studies. When the evidence is Grade B, this refers to evidence from RCTs with some weaknesses or moderately strong observational studies with consistent findings. Then, Grade C refers to evidence from RCTs with serious deficiencies or limitations, or the evidence coming from observational studies that are of poorer quality, meaning they have a smaller sample size or there are inconsistent results.

Furthermore, when we talk about a strong recommendation, this is essentially a directive statement that action should or should not be undertaken because the net benefit or net harm is substantial. Now, when we say a moderate recommendation, that's because the net benefit or net harm is moderate. And then when we say it's a conditional recommendation by the AUA, essentially this is a non-directive statement that's used when the evidence indicates there is no apparent benefit or harm, or when the balance between benefits and risks/burden is unclear.

So let's delve into the advanced prostate cancer epidemiology. We know that prostate cancer is the most common solid organ malignancy in the United States and remains the second-leading cause of cancer deaths after lung cancer. It's estimated that in 2023, almost 300,000 incident cases will occur and just over 30,000 deaths will happen. So it's a good number to remember when considering this disease: 300,000 diagnoses, then about 10%, just over 30,000 die from this disease.

We also know that there's a racial disparity whereby the incidence of prostate cancer is 70% higher in Black men compared to white men. Furthermore, the prostate cancer mortality among these Black men is at least twice higher than that of men in most other groups. There are many potential reasons underlying this disparity and can be related to disparities in screening, access to care, and treatment.

It's also important to note that the incidence of de novo metastatic disease has been increasing by about 5% per year since 2013. And this is likely related to the United States Preventive Services Task Force recommendations against prostate cancer screening in 2012. Now, this was reversed in 2016 and was given a Grade C, meaning you should discuss that.

But as we know with clinical implementation, there's often a lag between when the recommendations are amended and how clinical practice is affected. Also, another possible reason for this increase in de novo metastatic disease that we've observed is related to improved imaging sensitivity. And we'll be talking about that in further detail.

Despite the increase in the incidence of metastatic disease, the overall survival outcomes for these advanced prostate cancer patients continue to improve, given the emergence of novel treatment options in both the metastatic hormone-sensitive or castrate-sensitive, as well as the resistant settings. And so we will delve into these with a lot more detail in the further recordings.

But just as a brief overview, if we look at the currently approved agents in the MHSPC space, and these are obviously in addition to ADT, we see that we've had now essentially five agents or combinations approved. So in 2016, we had docetaxel. This is not specifically FDA approved, but there is level one evidence based on the CHAARTED, STAMPEDE, and [Inaudible] trials. Although the [Inaudible] trial is negative, and we'll talk about that further.

We also have abiraterone that emerged in February 2018 based on the results of LATITUDE and the STAMPEDE trials as well. Then in September 2019, we saw the approval of apalutamide and then enzalutamide in December 2019 based on the results of ENZAMET and ARCHES. And more recently, in August 2022, we saw triplet therapy with darolutamide and docetaxel based on ARASENS. And also, we have another option of abiraterone and docetaxel based on the results of the PEACE-1 trial.

This is even more impressive in the MCRPC disease space where we see numerous agents that have been approved. So if we look back to 1996, we see that the only agent at that time approved was mitoxantrone, and this was based on a quality of life pain benefit without an overall survival benefit. Then in 2004, we saw the first agent with an OS benefit in this disease space with docetaxel, and since then we've seen numerous agents approved in this space, which include Sipuleucel-T or Provenge.

We have cabazitaxel, the second line, and then also later on in the third line, we saw that with the CARD trial, abiraterone, enzalutamide, both pre- and post-docetaxel, radium-223 in 2013, pembrolizumab, which was a tumor agnostic approval for MSI-H tumors. We also saw in 2020 the emergence of the PARP inhibitors with olaparib and rucaparib, and then later on in 2022, we saw Lutetium.

In 2023, we had combinatorial agents with PARP inhibitors and the ARPIs, olaparib, abiraterone, talazoparib, and enzalutamide for specific subgroups of prostate cancer patients.

So quite clearly, it's a quickly evolving disease space; it's often very hard to keep up. And essentially this is the objective of this review in order to recap all these agents and provide a contemporary overview of these agents in this disease space. At this point, I'll turn it over to Zach, who will go into more details about the disease states covered in these guidelines, go over the initial guideline statements.

Zach Klaassen: Thanks so much, Rashid. So as Rashid mentioned, let's discuss the disease states that are going to be covered in these AUA guidelines. So biochemical recurrence, otherwise known as rising PSA state without metastatic disease after exhaustion of local treatment options, and so rising PSA in the absence of visceral mets, is basically one of these very difficult disease spaces.

We'll talk about this, and this is after local therapy. This could be salvage XRT after radical prostatectomy or salvage radical prostatectomy, salvage local ablative therapy after external beam radiotherapy. Metastatic hormone-sensitive prostate cancer, it's important to note that this is conventionally imaging-defined, and this is typically broken down as de novo or synchronous or recurrent or metachronous.

And finally, castration-resistant prostate cancer, this is typically broken down by non-metastatic CRPC. This is a rising PSA despite adequate castration with negative conventional imaging, as well as metastatic CRPC, which we'll go through in great detail in this guideline package.

Several guideline terminology and definitions to highlight. So biochemical recurrence, this is defined as a rising PSA following primary therapy after radical prostatectomy. This is a PSA of 0.2 with a repeat confirmatory value of 0.2 or higher. For XRT, this is nadir plus two, and this is the Phoenix Criteria definition. When we look at hormone-sensitive prostate cancer, this is defined as prostate cancer not yet treated with ADT or still responsive to ADT. And this may be in the absence of clinical radiographic progression or a rising PSA of greater than two above nadir.

With regards to castrate-resistant prostate cancer, this is disease progression despite ADT with castrate testosterone less than 50, or ideally less than 20, and this includes a continuous PSA rise greater than two recorded one week or more intervals, progression of pre-existing or new radiographic disease, and/or clinical progression with symptoms.

Looking at high-volume metastatic disease, this is based on the CHAARTED criteria. This is visceral metastasis and/or four or more bone metastases with one or more outside of the vertebral column and pelvis. Low-volume metastatic disease describes metastatic disease that does not meet any of the high-volume criteria. And this is important because the distinction does suggest different prognosis and treatment selections, such as radiotherapy to the prostate for low-volume disease.

When we talk about high-risk metastatic disease, previously the CHAARTED is by high-volume. This is high-risk disease. This is the LATITUDE definition, and this must include two of three high-risk features, including Gleason greater than or equal to eight, greater than or equal to three bone lesions, or measurable visceral metastasis.

Finally, when we talk about PSA doubling time, this is the number of months required for PSA values to increase twofold. This can be estimated using numerous calculators. You can see here listed as the Memorial Sloan Kettering Cancer Center nomogram. And this requires more than or equal to three values measured greater than or equal to four weeks apart to be able to get a true PSA doubling time. For purposes of the guidelines, conventional imaging is described as a CT scan, an MRI, or a bone scan.

With regards to radiographic considerations, as mentioned previously, the purpose for this guideline, the clinician should be considering metastatic disease, which is identified on conventional imaging. Studies inform clinical practice and are largely predicated upon the use of conventional imaging, many of the trials that we'll go through. And while newer imaging modalities such as PSMA PET CT scan have improved the sensitivity and performance, there remains uncertainty about how these image-directed therapies will impact oncologic outcomes.

There's no question that the therapeutic landscape is evolving, and it includes many combinations of systemic therapies with or without local therapies, imaging advances, germline, somatic gene testing, and without a doubt, a multidisciplinary approach to these patients is needed and should be required. You can see here a long list of team members that should be included. This includes urologists, medical oncologists, radiation oncologists, a GU-specific pathologist, radiologists and nuclear medicine physicians, as well as genetic counselors, palliative care physicians, holistic specialists, and primary care providers.

When looking at performance status and predicted life expectancy, it's important to look at these for these patients and to individualize clinical decision-making. We do know that performance status is strongly associated with overall survival in men with MCRPC, and historically, clinical trials have excluded patients with poor performance status. Of note, performance status is no longer included in the classification of disease states in this iteration of the AUA guidelines. It's important to not only assess this initially but also ongoing throughout the care of these patients during their disease and prostate cancer journey.

With regards to clinical trial enrollment in appropriate patients, clinical trial options should be discussed with the patient and their family. This should be done in a shared decision-making process based on eligibility and access. And it's important that not only in the late-stage MCRPC but in all stages of prostate cancer treatment, particularly in the advanced prostate cancer setting.

So, let's discuss early evaluation and counseling, and this is taking us to statement one from the guidelines. This is based on clinical principle in patients with suspicion of advanced prostate cancer and no prior histological confirmation, clinicians should obtain tissue diagnosis from the primary tumor or site of metastasis when clinically feasible. Although the diagnosis of prostate cancer may be clear, there are potential advantages of biopsy in this setting.

So first of all, this allows us to identify somatic mutations for personalization of treatment. This may include PARP inhibitors or Pembrolizumab based on their genetic profile. It may allow us to identify neuroendocrine differentiation and tissue evaluation prior to initiating systemic therapy is important as the treatment may alter the histologic architecture. Of note, if the patient cannot tolerate or refuses biopsy or if there's no accessible tissue for biopsy, treatment may proceed in the absence of histologic confirmation.
Statement two is also based on clinical principle, and this states that clinicians should discuss treatment options with advanced prostate cancer patients based on life expectancy, comorbidities, patient preference, and tumor characteristics. As we discussed earlier in this presentation, this should be in a multidisciplinary setting when available.

Statement three is also based on clinical principle. This states that clinicians should optimize pain control or other symptom support in advanced prostate cancer patients and encourage the engagement with professional or community-based resources, including patient advocacy groups, many of which are available at our cancer centers across the country. There's no question that our treatment does have side effects such as pain, urinary symptoms, and sexual functions. Providers should avail themselves of these resources in the community, such as in-person and online support groups, palliative care professionals, and mental healthcare professionals who can provide additional support and improve the quality of life during prostate cancer survivorship for these patients.

So in conclusion, advanced prostate cancer comprises a wide-ranging, heterogeneous population, and this has become a multidisciplinary disease space and should encompass multiple specialties in care. Evaluation should include a biopsy of the prostate or metastatic site if technically feasible, as this may allow for precision and personalized medicine. Finally, symptom support and pain control are key elements of treating advanced prostate cancer patients.

But thank you very much for your attention. We hope you enjoyed this AUA guideline discussion for UroToday.