Christopher Wallis: Hello, and thank you for joining us for a UroToday discussion, of NCCN Clinical Practice Guidelines in Oncology. Today we're focusing on the prostate cancer guidelines of February 2021, with a focus on nuances in advanced prostate cancer, including neuroendocrine disease, bone and visceral metastases, and treatment sequencing. I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto. With me today is Zach Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia. Again, this is the outline for today's discussion. In the context of bone metastases, we'll highlight a variety of data that has been published over the last few decades. Now, this is the initial study which led to bone targeting agents in advanced prostate cancer from the zoledronic acid prostate cancer study group. This trial was initiated and enrolled men with a CRPC and asymptomatic or minimally symptomatic bone metastases.

These men were then randomized to receive zoledronic acid 4 milligrams, zoledronic 4/8 milligrams or placebo. As you can see here in the Kaplan-Meier curves, we see that zoledronic acid 4 milligrams every three weeks reduced the rate of skeletal related events from 44% to 33%, a difference which was statistically significant. However, no difference in overall survival was seen. Now bisphosphonates of which zoledronic acid is, one function by inhibiting osteoclastic bone reabsorption. While further studies have shown that zoledronic acid did not reduce skeletal related events in castration sensitive disease, it is therefore not recommended until patients progress to mCRPC based on the data highlighted in the previous slide. Further, other bisphosphonates, including oral agents, have not been shown to be effective while zoledronic acid has been, and so zoledronic acid remains the preferred bisphosphonate choice in advanced prostate cancer. Zoledronic acid every 12 weeks has been studied and may be non-inferior to every four week dosing, providing some measure of convenience to patients.

The TRAPEZE randomized clinical trial assessed combinations of treatment, including docetaxel alone, docetaxel with strontium 89, docetaxel with zoledronic acid, or docetaxel with both agents. This trial was conducted among just under 800 men with bony metastatic and CRPC, and the outcome of interest was clinical progression-free survival defined as pain progression, skeletal related events, or death. No bone directed therapy that is strontium 89, or zoledronic acid, or of the combination, was associated with improved overall survival. However, in adjusted models, strontium improved clinical progression-free survival and zoledronic acid improved the time to skeletal related events and decreased the total number of skeletal related events. An alternative bone health approach is the use of denosumab. This is a RANK-ligand inhibitor, which functions to block osteoclast maturation, function and survival. As a result, it serves to decrease bone resorption. In this clinical trial denosumab was compared to zoledronic acid among 1900 men with mCRPC in a randomized, double blind, placebo-controlled fashion.

As you can see here, the absolute incidence of skeletal related events were similar between these two arms. However, denosumab delayed the median time to event by approximately three and a half months. In a non-inferiority analysis, the authors found a significant result. Additionally, in a superiority analysis, this was also statistically significant. However, rates of spinal cord compression, need for radiotherapy, and pathologic fractures are similar between the two arms and these are the most clinically meaningful of skeletal related events. When we look at the toxicity of these two approaches, you can see that any adverse events are similar in both arms, notably hypocalcemia, arthalgias, and osteonecrosis of the jaw occur at relatively similar rates between the two treatment approaches. It does however, warrant mention that osteonecrosis of the jaw is typically limited to those with pre-existing dental problems. Denosumab was further examined to prevent or delay the spread of disease to the bone in patients without metastatic disease, and while this was evident with the delay in metastasis of four months compared to placebo, no overall survival benefit was seen, and as a result, the FDA has not approved denosumab in this indication.

Further bone health recommendations from the NCCN panel can be summarized as follows. Denosumab every four weeks or zoledronic acid every three weeks is recommended in men with mCRPC and bone metastasis to prevent or delay skeletal related events. The optimal duration of therapy is unclear. However, it is clear that oral hygiene, baseline dental examination, and avoidance of dental surgery while on therapy is key for patients receiving these agent to avoid osteonecrosis of the jaw. Further, supplemental calcium and vitamin D are recommended for patients while on therapy. Monitoring a renal function is required to guide dosing of these agents, particularly for patients receiving zoledronic acid. Denosumab can be given in patients with renal failure, but increases the risk of both hypocalcemia and hypophosphatemia. An alternative consideration in terms of bone targeting agents is the use of radium-223, a category one treatment option for patients with symptomatic disease without visceral metastasis. Now we're going to step over to other considerations in the nuances of patients with advanced prostate cancer and Zach will take over at this point.

Zachary Klaassen: Thanks Chris. So next we'll talk about small cell and neuroendocrine prostate cancer, and this is a de novo rare and very biologically aggressive disease. And what we see is that treatment induced small cell neuroendocrine prostate cancer is most common in up to 17% of those with metastatic CRPC. This entity's associated with a shorter overall survival when accounting for prior therapy, then those with adenocarcinoma, and it does not co-exist with DNA repair mutations. So we'll go over a clinical scenario to sort of examine how small cell and neuroendocrine prostate cancer can manifest and how to treat it. In this clinical scenario it's a tumor that's non-responsive to ADT, associated with metastatic disease, especially when a low PSA is seen despite a large metastatic burden and visceral disease. This also has increased risk in those with Gleason grade group five disease. So when we see these patients in the clinic with low PSA, high volume disease and not responding to energy deprivation therapy, the next step is biopsy of an accessible metastasis site. Treatment for these patients is typically cytotoxic chemotherapy, which may include cisplatin and etoposide or carboplatin and etoposide, or docetaxel and carboplatin.

Based on data in the Small Cell Lung cancer Literature, specifically the IMpower133 trial, we may consider atezolizumab with etoposide, and this is listed in the NCCN Guidelines for Small Cell Lung Cancer. Next we'll talk about visceral metastases. Visceral metastases is defined as those occurring in the liver, lung, adrenal gland, peritoneum, or brain, and importantly this does not include the soft tissue or nodal disease. For these patients abiraterone acetate is a category 2A recommendation and in general, data is relatively sparse, particularly in the third line of therapy and beyond for visceral metastases patients. And finally, we'll talk about sequencing of therapy and CRPC. This is essentially the holy grail of advanced prostate cancer treatment and ongoing research. So with regards to the guidelines, we can see here in several of our sessions we've had discussed in the NCCN Guidelines, there is many different types of treatment available for M1 CRPC and depending on whether the patients had prior docetaxel or prior novel hormone therapy, these options are listed as follows in the table on the right. Importantly, no chemotherapy has shown overall survival benefit after cabazitaxel.

Many of these agents have shown palliative benefits, and finally prednisone dexamethasone may provide palliative benefit in the post chemotherapy setting. Looking further at treatment sequencing combination regimens at this time remain experimental, and there's been no survival benefit demonstrated with increased toxicity being noted with these combined regimens. Previous literature has shown that following abiraterone enzalutamide, there is no randomized data comparing taxane to novel hormonal therapies with the caveat being that the CARD trial, which we've discussed as well previously, included patients following docetaxel and abiraterone or enzalutamide. However, data does suggest some degree of cross resistance and previous randomized phase two data suggests that abiraterone followed by enzalutamide may be more efficacious than enzalutamide followed by abiraterone. We'll discuss AR-V testing in this setting, as this has become more common. This may allow for appropriate selection of treatment with a lack of response to abiraterone or enzalutamide and not associated with differential effect to taxane based chemotherapy.

This paper on the right is from Dr. Share's group from 2016 in JAMA Oncology we did at a Memorial Sloan Kettering Cancer Center, and we can see that on these two figures that the effect of docetax or taxane-based chemotherapy is better in the AR-V positive setting than compared to AR signaling inhibitors. And this may be test based on CTCs using RNA-based PCR or immunohistochemistry staining. Looking further at this trial, you can see here that looking at the multi-variable analysis, that in the AR-V7 positive setting taxane versus an antigen receptor has a significant hazard ratio of 0.24 and a 95% confidence interval of 0.10 to 0.57, whereas in the AR-V7 negative setting, when looking at taxane versus an antigen receptor inhibitor, there's no difference with a hazard ratio of 0.92. So it's really the treatment recommendations for these patients with AR-V7 mutation versus negative versus positive is in patients with negative AR-V7 taxane and AR targeted therapy are likely equivalent, whereas if AR-V7 is positive, overall survival improves among those who receive taxane-based chemotherapy.

However, important to note that AR-V7 is present in only 3% of patients prior to therapy, so it's not useful for selecting patients and in the first line setting. So to summarize these nuances in metastatic prostate cancer, as Chris discussed bone metastases include bone targeting agents delaying skeletal related events but do not improve overall survival. This can either be treated with denosumab q4 weeks or zoledronic acid q3 weeks and important to recommend supplementing calcium and vitamin D in these patients. As we just discussed a small cell neuroendocrine prostate cancer carries a poor prognosis and is typically treated with cytotoxic chemotherapy. For visceral metastases there's poor data in terms of survival benefit for many treatment options. However, abiraterone acetate is considered a category 2A recommendation, and really these patients should be enrolled in clinical trials. And finally treatment sequencing, there's little data to guide which treatment we should be utilizing, when, however, this is the subject of many ongoing trials, and as we discussed the AR-V7 status may be helpful following first line abiraterone or enzalutamide therapy. Thank you very much. We hope you enjoyed this discussion on the nuances in metastatic prostate cancer, as highlighted in the NCCN Prostate Cancer Guidelines.