Alicia K. Morgans, MD, MPH: As we wrap this up, I’d love to hear your thoughts on how these intensification strategies may affect biology. Do you think it does? Does the cancer that comes out after these intensifications, particularly after a triple-agent intensification, become more aggressive? Does it change in terms of its phenotype? Does it change in terms of how we need to target it? What are your thoughts, Sandy?

Sandy Srinivas, MD: I don’t think we know the answer for triple therapy yet. But we certainly know from patients who’ve had intense AR [androgen receptor]–targeted therapy that we’re seeing the price we pay for that. There’s the emergence of the neuroendocrine phenotype, which is certainly on the rise. Twenty years ago, even in my clinic, I’d see very few patients coming in with a PSA [prostate-specific antigen] that’s undetectable but a liver full of metastases. That’s becoming more common in our practice. We know the biology is very different for patients with low PSA who have an undifferentiated disease with hard-to-target treat areas, such as liver. The intense AR target the escape mechanism of what comes. We know for at least the AR-targeted therapy that it’s pretty difficult to treat, other than treating them with platinum-based chemotherapy. We treat them like we treat neuroendocrine tumors.

I don’t know what it would be when we do triple therapy. That’s why it’s really important, because these patients all have metastatic disease. We’re not curing them. This strategy might be very different if you’re talking about patients with localized disease where our goal might be to cure a larger fraction. It’s important to be cautious about what this is going to do downstream for our patients. That’s true even today, using all these drugs earlier when patients become castrate resistant. Even though our list of approved drugs exists, we have very few great options. This is a question that I’m looking forward to being answered and knowing what the field will shape out to be.

Alicia K. Morgans, MD, MPH: That’s a great strategy. Certainly, changing the mechanism of action to hopefully target something that hasn’t already evolved resistance is going to be important from my perspective. Scott, what do you think?

Scott T. Tagawa, MD, MS, FACP: I agree. Not that I know the answer, but I don’t think there’s a major difference in biology for someone who got ADT [androgen deprivation therapy]–abiraterone for 3 years and then develops metastatic CRPC [castrate-resistant prostate cancer] vs someone who got frontline mCRPC [metastatic CRPC] therapy and a year and a half of ADT continuation plus the addition of abiraterone at the end. It’s probably similar. There may be some differences in underlying biology in those who present with metastatic disease vs not.

In any case, to respond to Sandy, the key point is what the tumors have become exposed to and resistant to. But I don’t think we should be following these metastatic patients with only PSA, especially now. I don’t know the right answer in terms of the exact imaging frequency. If you look at LATITUDE, it was every 4 months because we’re looking at rPFS [radiographic progression-free survival]. If you look at SWOG-S1216, it was at least 1 year. But there needs to be regular imaging for patients with noncastrate hormone-sensitive castration-sensitive disease who are treated, because there’s a bigger percentage having progression radiographically or clinically without PSA. It’s not the majority, but it’s an important subset.

Alicia K. Morgans, MD, MPH: I agree. In an analysis of the PREVAIL trial, it may have been even up to 20%. This is absolutely something that we as a field need to think about. Hopefully it will be addressed in the next Prostate Cancer Working Group guidelines, which make recommendations for clinical trials. Hopefully they’re considered in our clinical practice a little, along with our NCCN [National Comprehensive Cancer Network] Guidelines, which is where we always have our clinical practice guidelines. Maybe it can be addressed explicitly there in the future.

Transcript Edited for Clarity