Alicia Morgans:  Hi. This is Alicia Morgans, GU medical oncologist and associate professor of medicine at Northwestern University. I'm very excited to present today my thoughts on how to choose treatments for patients who need therapy in the metastatic CRPC setting after they've received whatever their intensification strategy is in the metastatic castrate sensitive or hormone-sensitive setting.

The learning objectives for today are to understand the rationale for avoiding sequencing of androgen receptor-targeted agents one after another, even when separated in the so-called sandwich method by another therapy in-between. How to consider populations that may experience greater benefit from particular therapies and those who benefit from targeting specific mutations in their either germline or somatic mutations in the tumor, and to recognize the importance of including patient preferences in our treatment choices always, because they are the people that actually have to live with these treatments.

This is an outline of how we'll proceed. We'll talk about how there have been numerous therapeutic options developing over the last number of years in metastatic CRPC. Then we'll discuss the clinical factors that guide my treatment choice, including ensuring that we avoid sequencing androgen receptor-targeted agents, considerations for specific populations, and targeted approaches that may lead to specific treatments for specific patients. Finally, we'll talk about the importance of shared decision-making and then wrap things up.

We know from our NCCN guidelines in the U.S. and also, of course, the EAU guidelines, the AUA guidelines, and others, that there is a great emphasis on really using intensification strategies or combinations of treatments with androgen deprivation therapy, for patients who have metastatic castrate sensitive or metastatic hormone-sensitive prostate cancer. Usually what we want to do at that point is for patients who are fit enough to consider ADT plus docetaxel or chemo-hormonal therapy, or for any patient, you can use ADT plus abiraterone or enzalutamide or apalutamide, and really those discussions in helping patients to choose the right choice are happening all the time and are really much more important than we realized, I think, initially. ADT alone is really not the preferred choice anymore, except for specific patients who don't have the performance status or who have co-morbidities that would not really allow them to live long enough to experience the benefit of intensified therapy.

As we know that we have all of these treatments available for intensification in the hormone-sensitive setting, we also have to think about how those therapies impact our treatment choices when we get to metastatic CRPC. This is a brief schematic trying to outline some of the therapeutic options in metastatic CRPC, and I've listed them with those treatments that we can use in combination with ADT, the metastatic castrate sensitive setting off to the left. When we think about the first line and second line, and certainly we also will think eventually about the third line and fourth line for many, many patients, we have to think about what treatments these patients received in that metastatic CSPC setting, as we make our choices. We can see here that in metastatic CRPC, we have the option for docetaxel, if we haven't used that in the castration sensitive setting, cabazitaxel if we have used docetaxel in the castration sensitive setting, abiraterone or enzalutamide if we have not used prior antigen receptor-targeted agents, sipuleucel-T for specific patients with a low burden of symptoms, radium 223, and for certain patients, PARP inhibitors or pembrolizumab can now be used.

We know that those treatments can be considered in the second line, and the third line, as I mentioned. What are the clinical factors that really guide treatment choice when we have so many options? Well, as I mentioned, several times prior treatments certainly come into play because we usually are going to want to use a novel mechanism of action. That's not necessarily when we're thinking about putting cabazitaxel after docetaxel, because they are different enough that we can still get some activity with cabazitaxel after docetaxel and we know that from clinical trials.  But for other agents, we do really want to think about novel mechanisms of action. We also have to think about which options are available in my practice location and with the folks that I collaborate with. If we don't actually have access to things like radium or sipuleucel-T because of our geography or the collaborations that we have, then those are not necessarily going to be true options for our patients, even if they are options on the NCCN guidelines. Hopefully, we can move to get them into our practice by recognizing the importance that they are in the guidelines hopefully in the future.

We have to think about how is this patient's metastatic disease really distributed? Are there visceral metastases? Is there bone-only metastases? And we also have to understand if that patient's going to be a candidate for things like chemotherapy, which might be a little more intensive in terms of the side effect profile in the beginning. We also have to recognize whether that patient has a small cell or neuroendocrine differentiation because we know that our treatment approaches for those patients are going to be very different and not necessarily target the androgen receptor pathway, but more using a combination chemotherapeutic approach, usually with a platinum and etoposide. We also have to remember, are there targetable DNA repair defect mutations, or does the tumor have high microsatellite instability. These, we have to test on the patient's somatic tumor tissue or in their germline, or we can sometimes use liquid biopsies if we don't have somatic tissue available to us, but we have to do additional testing to find out whether a patient's eligible for those options.

And, of course, we always want to consider clinical trials. As I mentioned, a novel mechanism of action is really the way that I think about sequencing these patients and trying to get something new that the tumor hasn't yet seen. This is important because resistance mechanisms can spread through metastasis to metastasis seeding. We can see on the right a fascinating assessment of the mutations that have developed in several patients over time. You can see that these mutations are actually being shared between different metastatic sites and with the primary, and really can lead to different mechanisms of resistance in different areas, different metastatic sites throughout the body. It's interesting that the similar resistance patterns will often occur in these close geographic proximity areas where metastatic sites are really just sharing those mutations back and forth. As we think about how to hit this tumor next, it's important to think about using something that that cancer has not already seen because they hopefully will not already be resistant to that treatment.

As a general principle, I think that sequencing androgen receptor agents is generally poorly effective. I think we saw this in several studies that were recently reported. We definitely saw in the CARD study that this was not necessarily the best strategy and that cabazitaxel was more effective in terms of prolonging survival than sequencing AR targeted agent after AR targeted agent. To remind everyone, CARD was a study in which patients had received prior docetaxel chemotherapy and had received an AR targeted agent, either abiraterone or enzalutamide for 12 months or less before experiencing progression of the disease. Patients were randomized to the alternate AR targeted agent or cabazitaxel and were followed for radiographic progression-free survival, as well as overall survival and several other secondary endpoints. In this study, we saw that only 14% of patients in that AR targeted agent arm or the control arm had a greater than 50% PSA response to that secondary or targeted agent. That is pretty abysmal.

There was a median progression-free survival of only 2.7 months for that second AR targeted agent. So nearly no response. At the first scan, these patients were experiencing progression of the disease. So this study really focused on people who had 12 months or less of time on an AR targeted agent in the first place. Does that mean that this sequencing of AR targeted agents might work in patients who have experienced longer periods of exposure to androgen receptor directed therapies were good responders? I think the answer is still no. We saw this actually in the control arm of the profound trial. In this setting, we had patients who had progression of disease on an AR targeted agent in the past and many of them, if not most had received at least docetaxel, if not both docetaxel and cabazitaxel. All of these patients had a DNA repair defect mutation, and they were randomized to treatment with the olaparib or with the other AR targeted agent.

There was no restriction on the amount of time that they needed to have been exposed to that AR targeted agent in their prior treatment setting. What we saw was very similar to the CARD study. The median progression-free survival in the control arm that received that second AR targeted agent was 3.55 months. Really emphasizing again in a completely different setting and a completely different trial that sequencing AR targeted agents is not an effective way to go for the most part. We also saw that in multiple other studies, and we can see sort of the graveyard of sequencing AR targeted agents here with multiple studies suggesting really minimal responses and emphasizing that this is not a really successful strategy. So, besides avoiding that, what can we think about for specific populations that might be a good option? Well, Sipuleucel-T is a treatment that is FDA approved in the United States for patients who are minimally symptomatic.

And I think this proceed registry, which was done after the approval of Sipuleucel-T and enrolled patients who were getting the treatment basically through the standard of care, really emphasizes some of the ways that we might better think about using Sipuleucel-T in those populations who might benefit most. Really interestingly, this study looked at outcomes for patients who were African-American and compared them to similar patients who were Caucasian. What they found was that in a PSA matched group, the median overall survival for the African-American patients was 35.3 months as compared to 25.8 months for those matched Caucasian patients. This really suggests that there may be for those African-American patients, a better response than some other patients, which is really actually quite encouraging and certainly something that I think about when I'm treating minimally symptomatic patients who have mCRPC. Additionally, they found that patients who have a bit of a lower PSA seem to have better responses as well, and improved overall survival and a lower PSA in this study actually meant below the median, which was 29.48.

So. we're not talking about levels of two or three. The median, which was the way that they defined lower, was actually almost 30. If patients have a PSA of less than 30, they're still potentially in that group that may benefit. The hazard ratio here for improved survival was 0.52. That's pretty impressive and that was highly statistically significant. Something that I think about when I'm making treatment choices.  Another thing that I think about was some interesting work by a group that was studying radium 223, and this was in an expanded access program that was happening in Europe. What they found in this expanded access program was that patients who were asymptomatic when they entered this program, and at that time, the expanded access program allowed that to happen so that patients could get access to this drug. Asymptomatic patients actually had improved overall survival as compared to men who were symptomatic.

That may be because they were able to tolerate a little more of the treatments, or it might also be because the earlier we use this particular therapy, the better we may do. We actually see that with so many therapies that the earlier in the line that we use that particular treatment, the more effective we see that that drug is. Really just some food for thought about radium. What about targeted approaches? This has been an area of extreme interest, and we've seen several new drug approvals related to this. Well, the TRITON2 study was a study of patients with metastatic CRPC, that enrolled patients who had germline or somatic alterations in their DNA repair genes. These patients had already had progression on an AR targeted therapy and one taxane. We found that these patients had improved progression-free survival. You can see here, a beautiful waterfall plot showing a great PSA response.

We know that this drug, rucaparib used in this study, actually has been FDA approved. At this point, after progression on an AR targeted agent and a taxane for patients with BRCA one or BRCA two mutations. In a profound study, which I've already mentioned, we found the same thing, but in this case, patients were treated with olaparib and the patients treated with olaparib had an improved progression-free and we now know overall survival as compared to treatment with that second AR targeted agent. In May of 2020, we learned that rucaparib was approved for men with BRCA one or BRCA two mutation after progression on an AR targeted therapy and a taxane and Olaparib was also approved in this case for patients who had a DNA or HRR mutation after progression on an AR targeted therapy, whether or not that patient had received prior taxane.

Not to leave anything out, I want to mention pembrolizumab. This was FDA approved for any patient who has microsatellite instability-high or MSI high tumor. Pembrolizumab has been an option for any patient with metastatic CRPC, who has an MSI high tumor and that's about two to 3% of all patients. But if we don't look at the tissue, or if we don't sequence it, we won't actually know. Pembrolizumab, as we know, is a checkpoint inhibitor. As I said, it occurs in about two to 3% of patients, and it can have some pretty pronounced responses with relatively low side effects for patients who have mCRPC, but MSI high tumors. You can see on the right, some of those beautiful regressions of disease during treatment. Finally, I always emphasize the importance of shared decision-making. I think that patient factors should definitely really help guide our treatment choice if not make the ultimate decision.

These are critical because these are the people who are going to be living with the treatments that they're choosing or receiving. Patient preferences, especially in a setting of multiple treatment options like we currently have that may provide similar efficacy but have a very different regimen, side effects, and other toxicities, really need to be incorporated. Preferences could relate to a patient's obligations at work, maybe their past experiences for themselves, or for others who have received certain treatments, their fears about financial toxicity, insurance restrictions, and other things really can come into play and pain and other symptoms that really could prompt palliative treatments like radiation in addition to what we're doing should also be discussed and should also be incorporated into our treatment selection.

Future considerations hold a lot of promise and a lot of excitement. We did learn at ASCO 2020 about the TheraP trial in which patients who had metastatic CRPC and had progression on prior docetaxel in an AR targeted agent were actually randomized to receive lutetium or cabazitaxel. In this, we saw that there was a superior PSA response for patients who received lutetium as compared to cabazitaxel with a pretty tolerable side effect profile for those patients receiving Lutetium. Actually, the cabazitaxel side effect profile is exactly as we've experienced in the past. So nothing concerning there.  But this particular agent, Lutetium, may become a treatment option in the future. We can see in the upper right-hand corner of this slide, the VISION trial that might lead to that approval, if it is successful, in which patients who have already received AR targeted agents and chemotherapies could have been enrolled in this trial. They were randomized to Lutetium versus best supportive care, whatever that was in terms of the investigator or the treating doctor, and those patients were monitored for overall survival.

We don't yet have the results of the VISION trial, but we are hopeful that we'll see that at some point in the near future. If positive, this may make lutetium an option for treatment as well for metastatic CRPC. In summary sequencing and androgen receptor-targeted agents is generally poorly effective. As I mentioned, with several trials, large phase three trials, demonstrating this or phase four in the case of CARD and a change in the mechanism of action after an AR targeted treatment is really critical as we want to really optimize the outcomes for our patients and not waste time with treatments that are not going to work. Existing clinical information may be used to identify populations who may experience a greater benefit from a particular therapy. This can be true in therapies that we've had around for a long time, like sipuleucel-T and radium 223, that we can think about in different ways and identify certain populations who may do even better with these therapies. PARP inhibitors and pembrolizumab can be used in specifically identified patient populations using both the germline and somatic genetic testing so that we can identify who those patients might be.

We have to test in order to use these treatments. So it's important for us to incorporate testing of tumor tissue and germline for the patients in our clinical workflows. We always have to consider patient preferences in our treatment decisions. Thank you so much for your time.