Alicia Morgans, MD, MPH: Matthew, you are certainly an expert in bone health and the effects of our treatments and the disease itself on the skeletal health of our patients. I’m wondering if you can walk us through, just briefly, in the castration-resistant setting, what are your thoughts about treatment that maintains or reverses bone loss, improves bone density, and reduces skeletal-related events. How important is that in terms of maintaining quality of life and function for our patients?

Matthew R. Smith, MD, PhD: Think about it in 2 ways. There are the issues, much like Scott has already provided, that we think about treatment-related osteoporosis, or just osteoporosis associated with aging. There, the therapeutic intention is to improve BMD [bone mineral density] and reduce risk of osteoporotic or fragility fractures. That’s relatively easy to do because you can use a drug-dosing schedule that’s already approved for osteoporosis in adults without cancer. In patients with bone metastasis, the severity of the problem is much greater, the levels of osteoclast activation and bone turnover are orders of magnitude higher, and they require specific drug doses and schedules to prevent disease-related skeletal morbidity. The therapeutic intention is different; there we’re using drugs on a monthly or every-3-month schedule and much more potent drugs, and in doses that are higher than used in the case of osteoporosis in the general population.

So, it’s important to think about therapeutic intention and not forget that as an important issue. That has been demonstrated over and over again in early trials as well as in more contemporary trials. For example, in all the studies that looked at nonmetastatic CRPC [castration-resistant prostate cancer], there were 2 key observations. And to this point, one is that very few patients were receiving a bone-protective agent despite all of them being on long-term ADT [androgen deprivation therapy], and the rates of fragility fractures or osteoporotic fractures were relatively high and increased, particularly in patients who received either apalutamide or enzalutamide.

Alicia Morgans, MD, MPH: Thank you for pointing that out and making that distinction, because I think that can be one of the most confusing areas in the treatment of prostate cancer, and so your expertise is very much appreciated. To think about bones a little more, but also to expand that to patients who have soft tissue metastases, especially visceral metastases, Evan, what are your thoughts on the benefits of using a radiopharmaceutical or radioligand agent to address these multicompartment metastases?

Evan Y. Yu, MD: I think there are many ways one can approach this, but I think we recognize the fact that agents like radium-223 are outstanding agents, but for bone metastases only. So, if I have a patient with visceral metastases, I can’t use radium-223. It’s not part of the FDA label in the United States. If they have nodal metastases, then I think there’s some consideration over the rate of growth of those metastases, how large they are, etc, as to whether I’d use radium-223, or when I’d use it. But I would say the 1 advantage to a PSMA [prostate-specific membrane antigen]-targeted therapy is at least in earlier metastatic castration-resistant prostate cancer, it’s highly expressed in probably 85%-plus of those prostate cancer cells.

If you have mixed metastases or metastases that are more soft tissue oriented, I would probably lean more toward use of a PSMA-targeted radioligand therapy. As Scott mentioned just earlier, there is a bit of growing safety data of sequencing one after the next, so it doesn’t preclude the fact to use another radioligand therapy or radiopharmaceutical one after the next. I think in that situation, I would probably lean more toward the PSMA-targeted therapy.

Transcript edited for clarity.