A lot of things have happened in the management of prostate cancer over the last decade or so. Perhaps it’s the recognition that treatment intensification remains and perhaps is now the standard of care for every patient who develops advanced disease. So my talk really related to the standard practices throughout the United States and certainly practices that I believe should be standard throughout the world, that is that when you see a patient with de novo metastatic disease and/or someone who has undergone surgery, radiation or either or develops systemic disease objectively then the standard of care is no longer suppression of testosterone. We do suppression of testosterone by giving patients either taking them to surgical orchiectomies or doing medical orchiectomies, specifically with GnRH analogues or antagonists, blocking the connectivity, if you would allow me to use  that expression, between brain and testicles so testosterone goes down to a castrated level.

That has been historically the standard of care for many years, however, over the last decade or so multiple randomised clinical trials, level 1 evidence, have demonstrated that the addition of systemic therapy to that androgen deprivation approach is of paramount importance for our patients. When you think of that, part of my discussion related to the importance of defining volume of disease and volume, simplistically, is the amount of disease that you have throughout your scans and also the location of where those lesions are. Although there may be multiple ways of defining volume, we really think pragmatically of two types of patients – those with low volume disease and those with high volume disease. For those patients with low volume disease the standard of care is to suppress male hormone and to add one of the novel androgen receptor inhibitors, either apalutamide or enzalutamide or darolutamide, recently FDA approved in the United States actually over the last seven days or so.

Adrenal biosynthesis inhibitor, specifically abiraterone acetate, is also standard of care for this selected group of patients. Now, when you think of the addition of docetaxel-based chemotherapy, although one could argue that low volume patients can also embark on docetaxel, most of us in clinical practice are reserving docetaxel for those patients with high volume disease.

So regardless of volume, high or low volume, the same treatments remain the best option for our patients. What changes is that if you have low volume disease and you happen to have your primary tumour in place there is a role for primary radiotherapy to that prostate gland. So basically you do androgen deprivation therapy, you pick the best systemic therapy that you have – either an ARI or an adrenal biosynthesis inhibitor or, for that matter, chemotherapy – and you complete radiation therapy to the primary tumour. That is the best data that we have to improve outcome for those patients.

Now, contrary, for those patients with high volume disease the standard of care is to, yet again, suppress testosterone production with ADT and to add treatment intensification with abiraterone or an ARI, or chemotherapy for that matter. But if you have a patient who has their primary tumour in place there doesn’t appear to be a role for primary radiation therapy to those patients.

Equally important is the recognition that within those patients with low volume disease we have a subset of patients also known as having oligometastatic disease which is very little disease. And although the true definition of oligometastatic disease is not well defined, we still debate as to the number and the location – if it’s bone only or lymph node only or the combination of both with a restricted number of lesions 3-5. Having said that, we have recognised that a very selective group of patients should be able to actually do quite well if you treatment intensify them with ADT plus one of those agents that I described earlier and also to consider radiation therapy to those sites of oligometastatic disease. There is emerging data to suggest that even when you complete that, get the patients off their systemic therapy, once they recover testosterone production then some patients can be rendered free of disease for years. So that is a big aspect of what we’ve been trying to do.

We also mentioned something about the importance of PSMA imaging. Certainly the utility of the use of traditional CT scans and technetium-99 bone scans have become obsolete for us in prostate cancer. Now the technology that we use is far more sophisticated and we really are talking about PSMA driven technology using PET scan where you use 18 F or Gallium-11. The bottom line is that when you do that sophisticated technology and use it for our patients then you’re more likely to find disease and the bigger question in the field right now is if you were to find PSMA avid disease in a patient who did have a negative bone scan on a traditional CT scan without objective disease, if that new imaging technology would change how you think of that patient, meaning patients who are non-metastatic in conventional imaging and now become metastatic in the PET imaging. For us right now there are still some concerns as to false positives and whether or not if every metabolic update that you see is consistent with metastatic disease, if you need to biopsy or not. There are areas in the space where we continue to struggle but for the most part most of us who are seeing high SUV activity in sites of metastatic disease are thinking of those patients as metastatic in nature and proceeding with the treatments that I just described.

Equally important is the recognition that PSMA can also be used as a therapeutic option for our patients. Certainly we have right now in the United States the approval of 177 Lu PSMA, which is Lutetium-177, based upon the VISION trial which is a trial that was done in late patients in the castration refractory setting post-chemo, post-oral therapy with PSMA avid disease proven by PET PSMA. The field is moving forward and trying to move that technology earlier in the castration sensitive space. So we talk a little bit about that sequence of events.

Lastly, one of the biggest concerns or controversies right now in the field relates to how we pick treatments. Two important trials were discussed – one called PEACE-1 that looks at triple therapy, and by that I mean suppression of testosterone, six cycles of docetaxel followed by an adrenal biosynthesis inhibitor, or the ARASENS data that talks about triple therapy but instead of doing it in a sequential manner we do suppression of testosterone with ADT, six cycles of docetaxel while you have the patient on an androgen receptor inhibitor known as darolutamide. Those two trials, certainly ARASENS demonstrated a survival benefit for patients getting ADT, chemo and the androgen receptor inhibitor compared to ADT and chemotherapy. That raises the question of whether or not that triple approach for high volume patients is better than ADT plus one of the novel hormonal agents and that data we don’t have. So right now the complexity in the field is that for us, when we see high volume patients, now we’re debating the merits of doing triple therapy. If you do so, the question is triple up front or triple in a sequence, meaning ADT chemo followed by. Those are areas where we actually still need to understand maybe a bit more biomarker-driven data, perhaps more molecular driven ways to define our patient population rather than just by simple volume. So those are some of the aspects that we review in our presentation.

How can a treatment algorithm help in the systemic management of advanced prostate cancer?

Unequivocally one of the concerns that we have is if we look at actually [inaudible] analysis in the United States at the very least a significant portion of our patients with metastatic disease are not receiving treatment intensification which, to me, is hard to understand why not since we’ve been talking about these agents for the last 5-7 years or so with very compelling data.

So what has changed is that now we can talk to patients and actually illustrate to them the importance of intensification. There’s a drastic improvement in survival, there is a significant delay in time to progression, specifically defined by radiographic findings or symptomatic disease or from death from any cause. Certainly we have the ability to control active disease with controlling symptoms and by default making scans, at least for those patients with measurable disease you can actually do some solid responses, not only serologically but radiographically as well.

So if you start with the best approach up front what that creates, to some extent, is the limits and/or challenges the sequence of events when people become castration resistant. I can tell you right now that if you do ADT chemo plus an oral novel hormonal agent, as you move into the castration resistant space, probably most people will actually put a patient on a Lutetium PSMA approach now that it’s approved. On the contrary, if you initiate therapy with ADT and an oral agent then certainly chemotherapy in the sequential setting becomes important, Lutetium may be also relevant, at least for those who have seen chemotherapy, but it challenges the sequence of management when you become castration resistant.

Equally important is the recognition, as I said earlier as well, of the importance of genomics. So we have to actually look at germline mutations, we have to look at somatic mutations for our patients with advanced disease as we may be able to identify a subset of patients who may be candidates for PARP inhibitors as well, especially those who have DNA repair deficiencies or homologous recombination repair deficiencies. There is also the opportunity for a selected group, a smaller group, but still the option for some selected patients in a tumour agnostic manner to receive immune checkpoint blockade with agents such as nivolumab and/or pembrolizumab, two checkpoint inhibitors that are able to block the PD-1 pathway. That is specifically for patients with microsatellite unstable tumours or patients with tumour mutational burden over 10% or so.

So definitely genomics have become part of what we do and critically important not only to counsel patients but also to define therapeutic alternatives as people move through the natural sequence of events.