Atish Choudhury, MD, PhD: The question is, what are the treatments that are available for patients with metastatic castration-sensitive prostate cancer? Certainly the backbone of all treatment is androgen deprivation therapy with medications that suppress the level of testosterone in the body, because testosterone is the fuel for prostate cancer and gives the signals to grow and spread. So, the studies that have been presented over the last decade have demonstrated that intensification of androgen deprivation with different modalities of treatment seem to correlate with prolongation of survival.

The different options for intensification include docetaxel chemotherapy, different androgen receptor targeted agents, including abiraterone, apalutamide, and enzalutamide, and then doing radiation to the prostate. Now, more recently there’s been data that “triplet” therapy, which is docetaxel in combination with abiraterone as was tested in the PEACE-1 trial, and docetaxel in combination with the AR-targeted agent darolutamide in the ARASENS trial seems to improve outcomes compared to docetaxel alone in MCSPC.

The question now is, of all these treatment options available from ADT alone all the way to this triplet therapy, what’s appropriate for an individual patient? I think that that’s very hard to know. So, certainly in patients who have high-volume disease, and again, there are many different definitions for high volume, one of those definitions was in the TARGET study.There’s a definition that was in the LATITUDE study, and there’s a definition that’s defined purely by number of bone mets as the stop-gap definition.

But whichever definition one chooses to utilize, certainly patients who are chemo-fit and have high-volume disease, we could consider for docetaxel chemotherapy, and there is randomized data that suggests that further intensification with the addition of something like abiraterone or darolutamide does improve outcomes in that particular population. However, in many of our patients who present with MCSPC are not chemo-fit, and so are probably not appropriate docetaxel candidates.And so then the choice becomes whether to use one of those AR pathway targeted agents, and if so, which one.

Then the other question is, in what patients would you recommend doing radiation to the prostate? So, certainly the stampede data that suggests that radiation to the prostate improves overall survival is relevant in patients with low-volume metastatic disease, and in the context of ADT alone.

So, we really don’t know for sure that doing radiation to the prostate in patients who are getting abiraterone, enzalutamide, or apalutamide actually prolong survival or not. But it is something that is commonly done in practice, though there is prospective data from a SWOG study trying to look at this in conjunction with maximal systemic therapy to see is there really an advantage in the context of, again, using maximal systemic therapy.

So, what I would conjecture is that there are very few patients who have contraindications to either AR-targeted therapy who should be treated with ADT alone. It’s pretty clear from all the studies that have presented so far that even in patients with low-volume metastatic disease do benefit from intensification of treatment, and that the quality of life data from these studies also suggests that patients will benefit from earlier treatment with these agents.

I think in general my approach when I see a patient with metastatic castration-sensitive prostate cancer is to assess overall what’s the picture of their disease, is it high-volume disease, is it low-volume disease, is it symptomatic, is it not symptomatic? Is the patient chemo-fit, are they not? Are there contraindications to particular treatments or not? And are they having local symptoms related to prostate cancer in the prostate or at metastatic sites?

So, for patients, again, with high-volume metastatic disease who are chemo-fit, I do think that the data that we have would advocate for us to use triplet therapy with docetaxel with abiraterone, or docetaxel with darolutamide whenever that becomes FDA-approved, with the choice of abiraterone versus darolutamide, based on patient comorbidities, whether there are contraindications to one or the other.

For patients who have low-volume metastatic disease, I do recommend treatment with one of the AR pathway inhibitors, and then I evaluate them for radiation to the prostate. Particularly if they have symptoms, I think that there’s likely to be a benefit, but even without symptoms there certainly may be based on the STAMPEDE study. I also evaluate them to see if they have oligometastatic disease. Do they have one site of involvement, two sites involvement, that would allow radiation to those metastatic sites?

Now, there is no prospective data that suggests that metastases-directed therapy in this setting actually leads to prolongation of survival, but it is a strategy for intensification of treatment that if you radiate the prostate and all sites of metastatic disease and cytoreduce these patients, then it begs the question of can you actually discontinue treatment in a subset of these patients and lead to kind of prolonged treatment-free interval afterwards, which I think is an open question.

Again, I think that there are very few patients with castration-sensitive prostate cancer for whom ADT alone is an appropriate option.

Transcript edited for clarity.