Alicia Morgans: Hi! I'm delighted to have here with me today, Dr. Matthew Smith, who is the Director of GU Medical Oncology at Massachusetts General Hospital, as well as being a Professor of Medicine at Harvard Medical School, and my former mentor, and still mentor in life, in general. Thank you so much for talking with me today.

Matthew Smith: Happy to be here.

Alicia Morgans: Well, thank you. So, Matthew, you are an expert in many things but one of those things is bone health and at APCCC 2019 you really helped us think through osteoclast targeted therapies. It was a really spirited debate pro (Parker) and con (Tombal) about how, how do we use these agents, for how long, and you helped to sort of ... from your perspective, at least, sort through this gray data and say this is how I view the data and this is how we might think about using these drugs. can you give us a summary of that debate and your thoughts?

Matthew Smith: Yes, absolutely. So, I think one of the really nice things that came out of the earlier session (Saad; following discussion with Sartor and Padhani) is that there's a strong consensus that men with prostate cancer are at risk for fractures, particularly so-called osteoporotic or fragility fractures and that risk comes from their age from long-term androgen deprivation therapy use and now, increasing evidence that other treatments that we commonly use to treat prostate cancer further increase fracture risk. Those include the androgen receptor inhibitors, drugs like apalutamide and enzalutamide, like the abiraterone as well.

So that's really important recognition that this is truly an important clinically problem. There's further understanding that we can identify patients at greatest risk using relatively easy to apply clinical tools like the FRAX calculator, for example.

Alicia Morgans: Yes.

Matthew Smith: If you choose, you can further refine fracture risk by measurement of bone mineral density and then to kind of close the loop, there are now, you know, well-established standards of care to prevent fragility fractures in that population.

Alicia Morgans: Yes. So, when you're thinking about fragility fractures and the FRAX calculator, can you just let us know ... do you have to use a DEXA for the FRAX calculator? How do you think through that, just for the clinicians who are not so familiar?

Matthew Smith: Yeah, it's a fine question and one that we'll actually address, the delegates will address in the consensus questions tomorrow. And that really is, you know, do you need to measure bone mineral density to assess fracture risk? I'd turn it around and say you're obligated to consider clinical risk fractures to evaluate fracture risk and the reason for that is very clear, which is that while a low-bone mineral density is a strong predictor of a risk of fracture in an individual, most fractures occur in individuals with a normal bone density. Why is that? Well, because most individuals have normal bone density and that's where most, the majority of fractures in a population occur.

So if you're restricting yourself to intervening only in patients with established osteoporosis by BMD measurement, then you're missing most of the population at risk. And the other thing that, you know, these patients of ours, you know, on these chronic therapies, ADT, anti-androgen, et cetera, that are ... have their risk increase by that ... by those drug therapies, BMD measurement and even the FRAX calculator may underestimate risk-

Alicia Morgans: Yes.

Matthew Smith: ... so this is where I think the consensus has emerged that this is important to identify patients for treatment and for intervention.

Alicia Morgans: So one of the questions, actually, I talked to fellows about this and I remember speaking to you about this, too, is utility of a DEXA scan in a patient who has metastatic disease and the area where that DEXA's going to be measuring.

Matthew Smith: Yeah, and I've seen this go wrong a lot, as well-

Alicia Morgans: Yes!

Matthew Smith: ... in the community where ... so, the challenge of BMD, it's measuring ... basic cross-section of bone mineral density and so if you're measuring bone density of the spine and hip, those are common sites of metastatic disease and so you would artificially inflate measure of bone density. So, I don't recommend measurement of a ... use of a DEXA scan in any patient with bone metastases from prostate cancer-

Alicia Morgans: Yeah.

Matthew Smith: ... it's not necessary. The other, important part is that once you have established metastatic disease to bone, in many of those patients, particularly those with progressive disease, the dominant risk is no longer osteoporosis and fragility fractures, but so-called disease-related skeletal morbidity or, commonly called skeletal-related events or SRE's-

Alicia Morgans: Yes.

Matthew Smith: ... and mechanistically, that's very different. So, with osteoporosis or fragility fractures, you have this situation where normal bone remodeling is altered, there's net bone loss, and the individual's risk for fracture gradually increases over the course of years. With bone metastasis, you have tumor-mediated bone destruction and pathologic osteoclast activation with destruction of bone at specific, anatomic sites-

Alicia Morgans: Yes.

Matthew Smith: ... and in some cases, you know, really nasty complications like pathologic fractures, spinal cord compression, or other painful events that require surgical or radiation intervention.

Alicia Morgans: Absolutely. So when you're faced with someone with metastatic CRPC, and certainly we don't need to do DEXAs in them and, actually, we don't need to really calculate a FRAX, right? That's just for fragility fractures. In those patients, and we know the indication is for monthly zoledronic acid and denosamab, what is your practice? Do you actually do monthly dosing and, if you do, for how long or how do you think through that conundrum?

Matthew Smith: That's the, I'd say, the biggest challenge. So, I'd like to think of it as, really, the switch, right, because if a ... you have a patient who's been on long enough ADT to now be castrate-resistant-

Alicia Morgans: Yes.

Matthew Smith: ... that would imply that there's someone who probably should already be on an osteoclast targeted therapy for prevention of fragility fractures-

Alicia Morgans: Yes.

Matthew Smith: And here's where I prefer to use either annual zoledronic acid or twice-yearly denosamab for osteoporosis prevention and prevention of fragility fractures because when they develop castration-resistant disease, you're going to make a switch in the schedule-

Alicia Morgans: Yes.

Matthew Smith: ... but not the compound, right?

Alicia Morgans: Yes!

Matthew Smith: So zoledronic acid could be monthly, could be a different schedule, come back to that, and that, you know, the approved dose and schedule of zoledronic acid for SRE protection in castration-resistant disease is four milligrams monthly, denosomab 120 milligrams monthly. Whereas, the doses for osteoporosis are about 1/10th to 1/12th that-

Alicia Morgans: Yes.

Matthew Smith: ... and this is where a lot of confusion comes in.

Alicia Morgans: Yeah.

Matthew Smith: Because, I think, clinicians in the community and some academic physicians say, well, if it's the same drug, it must be doing the same thing, so either would be fine-

Alicia Morgans: Yes.

Matthew Smith: ... but, I don't believe that to be true.

Alicia Morgans: No, and, you know, certainly there's a risk to these drugs, as well and we, especially in the fragility fracture space, we want to use the appropriate dose which is going to be four to five milligrams once a year for the zoledronic acid and then monthly 60 ... not monthly, 60 twice-yearly-

Matthew Smith: Exactly.

Alicia Morgans:  ... and, and the denosomab manufacturers made it a little bit easy for us. They, you actually named the-

Matthew Smith: Yes.

Alicia Morgans: ... the brand names differently.

Matthew Smith: I was avoiding using the brand name-

Alicia Morgans: Yes!

Matthew Smith: ... but there's a reason for it in this case.

Alicia Morgans:  Yeah.

Matthew Smith: And I ... and it can go wrong both ways. I'd say one of the more egregious ways it could go wrong would be using an SRE dose and schedule in a patient-

Alicia Morgans: In fragility.

Matthew Smith: ... without bone metastasis, which would be gross over treatment-

Alicia Morgans: Yes.

Matthew Smith: ... for osteoporosis. I've seen that occur. And then you're definitely exposing patients to potential drug-related toxicity that would be unnecessary.

The other way you could go wrong would be, I think, to wait too long-

Alicia Morgans: Yes.

Matthew Smith: ... to switch to the SRE prevention dose and schedule.

The way I think about it is, first, the priority is it's patient selection. So the patients who I'm making that switch to ... so, SRE prevention dose and schedule are really patients who've developed progressive disease and have a substantial burden of metastatic disease to bone. So that, maybe ... so if they're responding nicely to first-line treatment, say, with abi or enza, I may wait until they progress and are starting chemotherapy, as an example, before I make that switch.

Matthew Smith: And then, the secondary question is, you know, what's the right schedule?

Alicia Morgans: Yes.

Matthew Smith: There, too, we're in a fairly thin area of evidence-

Alicia Morgans: Yes.

Matthew Smith: There have been studies that have tried to address the schedule issue. One commonly cited CLGB study published a couple years ago looked at four-week versus 12-week schedule of zoledronic acid-

Alicia Morgans: Yes.

Matthew Smith: ... looking at the primary endpoint of incidents of skeletal-related events at two years. That was a non-inferiority study and that presents a lot of challenges. The study clearly showed two things, I would say. That with the less frequent schedule, you had less potent inhibition of osteoclast activity, which would predict that you might have a higher rate of events-

Alicia Morgans: Yes.

Matthew Smith: And they also showed no difference in safety, so, despite less-frequent dosing, there appeared to be no safety benefit. For the primary end-point, they concluded that the two schedules were non-inferior, but here we have a problem. There's a high bar for non-inferiority trials and there are many limitations in this trial that, I think, make that conclusion relatively weak.

Those include the fact that there can be no constancy. That the field has changed a lot. There are new drugs. Patients have fewer events and live longer. They included patients who had no potential for benefit, including the inclusion of patients with hormone-sensitive metastatic prostate cancer, a population that we've already shown bisphosphonates are not effective for, not necessary for SRE prevention.

Alicia Morgans: Mm-hmm.

Matthew Smith: And so, the other part is, even the primary endpoint was bit different than in prior studies and further, their primary analysis at 24-months ... was at 24-months but only about 40% of the patients reached the two-year mark on the study and the median follow up was only about 14-months.

So, the evidence, the conclusion that there, the two schedules are non-inferior are ... inferior I would say is relatively weak. It might be true, but I don't think we can rely on that data too heavily.

Alicia Morgans: Yeah. Well, it's interesting. So there is a study coming ... it's still in process as I understand, but here in Switzerland, that Silke talked about at one of the recent ASCO events, and, at this point, the only thing that was available was safety data and there was a higher rate of hypocalcemia in patients who were receiving more frequent treatments, but we hope to understand, maybe, whether the dosing schedule, in a prospective manner and in a mCRPC population will actually be ... will actually be necessary to have this monthly versus to have it less often.

Matthew Smith: And the ... if I could speculate, I'd say that the right answer is probably, you know, that it's not going to be one answer for every patient but that's what we'll be left with, right-

Alicia Morgans: Yeah.

Matthew Smith: ... in the sense that there are patients who monthly treatment may be far too much and there are other patients where monthly treatment is inadequate because their bone disease is off to the races.

Alicia Morgans: Yes. And so, the other thing that people sometimes talk about is when you're on an effective, like you said, an AR directed therapy, for example. When you're on that therapy, that therapy's effective, you have a lower rate of SRE's. You're on an effective treatment. At least, from a, you know, study population level, not from a necessarily patient, individual patient level. And one of the concerns that I have with that statement, although it may be true, I can't necessarily predict, in advance, when this patient is going to fail therapy because by the time I see that PSA rising and by the time I see progression on imaging, it's actually, probably, a little too late. That that patient's had this window of risk.

So, what are your thoughts on that conundrum? Perhaps you, you haven't heard that, but that's certainly what I've heard.

Matthew Smith: No, I think, I think you're absolutely right. So, I do believe that the best way to prevent SRE's is to control the underlying malignancy.

Alicia Morgans: Yes!

Matthew Smith: And I think there's consistent evidence supporting that case. But to your point, well, how do you know when an individual patient will progress and this is, actually, where the schedule question we're asking would certainly be convened. I would much prefer that the ... that the flawed trial I just referred to, would have much stronger evidence and I'd be more comfortable making that switch to a less frequent schedule where there'd be less reluctance to do so earlier, maybe starting first-line treatment with the mCRPC, for example.

Alicia Morgans: Well, maybe we should do another study like that in the [inaudible] and choose the right population and choose the right schedule and choose the right follow-up period and we could, we could answer the question but, we'll have to continue that discussion.

Matthew Smith: Agreed, yeah.

Alicia Morgans: So, do you have any, any further advice for clinicians who are trying to really care for the bone health of their patients? Recognizing how important it is?

Matthew Smith: Yes, so certainly, some of the new information of the past year, part of came out of this ERA 223 trials-

Alicia Morgans: Yes.

Matthew Smith: ... so the genesis of that trial were basic observations. Abiraterone acetate improves progression free in overall survival at mCRPC. Radium-223 improved survival and delays symptomatic skeletal events. So, it seemed to make perfect sense to combine the two drugs. That was done and, with the unexpected observation that the addition of radium-223 had no improvement in event-free survival. But worse, it increased the risks for fractures substantially, including fractures at sites of bone that were uninvolved by cancer.

In subset ... in exploratory analysis, the receipt of an osteoclast targeted therapy at baseline appeared to mitigate much of that risk and then ongoing work in the PEACE-III study of enzalutamide plus or minus radium seems to support that assertion. So, my take away from all that is when you're treating a patient with radium-223, I think it's very important that you've already initiated osteoclast targeted therapy in a manner appropriate for SRE prevention.

Alicia Morgans: Absolutely. I think we've learned a lot from that trial and it reminded all of us of the importance of bone health. Even as your former fellow, sometimes I find myself not always putting that as one of the high priority issues. Of course, I always do, but, you know, it is not something that is always top of mind with all of the things that we're thinking about for our patients.

Matthew Smith: Yeah, we have a lot ... we have a lot of other decisions to make and the priority's always going to be cancer control.

Alicia Morgans: But this is a huge part of ... not necessarily just cancer control, but caring for the patient. Because a fracture is going to increase his mortality, perhaps, and certainly limit mobility and also potentially limit that person's ability to be independent and certainly to function or, even if golf was the thing that he loved most, he's going to have trouble golfing if he's got a hip fracture.

Matthew Smith: Agreed.

Alicia Morgans: So, I sincerely appreciate your time and your guidance on this and I wish you a wonderful rest of your meeting.

Matthew Smith: Glad to do it. Thank you.