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The Best Use of Antiresorptive Therapy in CRPC Presentation - Matthew Smith

Matthew Smith presented a summary detailing the best use of osteoclast-targeted therapy for patients with bone metastatic castration-resistant prostate cancer (mCRPC) at the Advanced Prostate Cancer Consensus Conference (APCCC) 2019. Emphasizing the importance to distinguish between skeletal-related events and fragility fractures secondary to osteoporosis, Dr. Smith covers the current landscape for FDA approved uses of osteoclast-targeted therapy. He showcases the CALGB 70604 trial where Himelstein and colleagues assessed the effect of longer-interval vs standard dosing of zoledronic acid on skeletal-related events among patients with breast, prostate, multiple myeloma bone metastasis before concluding with his conclusions for fragility fractures and osteoporosis as well as his conclusions for skeletal-related events.


Matthew R. Smith, MD, Ph.D., Professor of Medicine, Harvard Medical School, Assistant in Medicine, Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.

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Matthew Smith: Thank you, Silke and Aurelius for this opportunity. It really will be quite a challenge to synthesize these very disparate views about this topic. My charge is to synthesize the evidence from the three previous speakers and describe best use of osteoclast-targeted therapy in prostate cancer. I'm going to try to do this in a very pragmatic way to inform our voting on these questions tomorrow. The delegates have 123 questions tomorrow. Nine of those are directly or indirectly focused on osteoclast-targeted therapy. And I hope you'll find my comments useful as you decide your votes.

I'd like to begin by pointing out that skeletal-related events and fragility fractures or osteoporosis are distinct clinical entities. Dr. Parker's presentation implied that it's all the same, but it's really not. All men are at risk for fragility fractures and osteoporosis. In contrast, only patients with metastatic prostate cancer, particularly those with progressive disease, experience skeletal-related events. It is important to acknowledge that such patients are also at risk for fragility fractures. And I think therein lies part of the confusion about interpretation of some of the clinical trial data. Fragility fractures occur in the normal skeleton. In contrast, skeletal-related events occur at or around the site of bone metastases. The best way to prevent skeletal-related events is to apply effective anticancer treatment. Some of those same anticancer therapies though commonly used prostate cancer treatments increase the risk of fragility fractures in osteoporosis.

Why is that? Because they have unintended effects on the normal skeleton. Osteoporosis results from an imbalance of normal bone remodeling resulting in net bone loss, and resulting in impaired mechanical integrity of bone over the course of many years. In contrast, skeletal-related events result from tumor mediated bone destruction in very high levels of pathologic osteoclast activation. There is no overlap between FDA approved uses of osteoclast-targeted therapy for osteoporosis, versus skeletal-related events. FDA approved therapies for osteoporosis prevention, or treatment and prevention of fragility fractures include a number of oral bisphosphonates, zoledronic acid in the form of Reclast five milligrams once a year. Or Denosumab 60 milligrams twice a year as Prolia.

The National Osteoporosis Foundation, probably the definitive source of information on prevention of fragility fractures and treatment of osteoporosis, recommends FDA approved medical therapy based on one of the following conditions. A prior vertebral or hip fracture, femoral neck or spine T-score of less than minus 2.5. In other words, a diagnosis of osteoporosis. Or a FRAX 10 year probability of hip fracture greater than 3% or any major osteoporotic fracture of greater than 20%. So why this consideration of clinical risk factors if we already have this reliable measurement of BMD? It's very clear that's because most fractures occur in patients without osteoporosis.

This is data from the National Osteoporosis Risk Assessment or NORA study in postmenopausal women. But the same can be said of men. I present this data because it has this beautiful visual image. In this large study you see in normal distribution of BMD with lower bone mineral density subgroups to the right, and normal or higher BMD subgroups to the left. And there's a stepwise increase in fracture rates shown in the gray bars with lower BMD. So patients with very low BMDs to the right, gray bars are very tall, meaning they have high rates of fracture. But the black bars show the absolute fracture events. And you see that most fractures occur in individuals with a normal BMD. In the NORA study for example, 82% of all fragility fractures occurred in patients with a baseline T-score of greater than minus 2.5.

FDA approved has ... There are two approved FDA therapies for SRE prevention. We have zoledronic acid, four milligrams every three to four weeks marketed as Zometa. As you heard, that's about 10 times the annual exposure compared to the osteoporosis dosing schedule of the same drug. And for denosumab, we have a 120 milligrams Q four weeks as XGEVA® for SRE prevention, 12 times the annual exposure for the same drug used in osteoporosis prevention and treatment.

Why this marked difference? Well, it's very rational. And it's perhaps best shown in this scatter plot. This shows individual patients markers of osteoclast activity shown on the X-axis, and osteoblast activity shown on the Y-axis. These are men with metastatic castration-resistant prostate cancer and bone metastasis. And that tiny little red box on the lower left-hand part of the panel corresponds to normal levels of bone biomarkers in individuals without cancer. So in the case of metastatic prostate cancer, you have wildly abnormal bone remodeling, wildly pathologic levels of osteoclast activation, which requires this greater dose intensity for normalization of bone markers in prevention of SREs.

Think of it this way. Basically, all of osteoporosis occurs within that tiny little red box, and almost all of SREs occurs outside of that box. And in many patients with levels of bone markers that are many-fold the upper limit of normal. Even with these greater intensity of treatment monthly zoledronic acid or monthly denosumab, about 20% of patients with mCRPC in bone metastasis fail to normalize their bone biomarkers. Now, you've seen this study data presented. This is the CALGB study looking at different dosing intervals of zoledronic acid compared standard dosing with monthly zoledronic acid, versus every 12 weeks. So a dose deescalation of zoledronic acid. This was a non-inferiority study. It included patients not with just prostate cancer, but also patients with breast cancer and myeloma. It convincingly showed that less frequent dosing of zoledronic acid achieved less robust inhibition of osteoclastic activity. That's shown on the right-hand panel. And the authors interpreted the cumulative incidents of SREs to mean that the lower dose was just fine.

It should be noted though in considering interpretation of this trial that there are many limitations to the study. First and perhaps most importantly, there can be no assumption of constancy or requirement for valid inference in non-inferiority studies. And as you heard from both of the prior speakers, there have been substantial changes in standards of care, event rate in survival. All of these basically disqualify this study as providing valid inference about the results.

Importantly, the study also included some men, men with hormone-sensitive prostate cancer who had no potential for benefit from zoledronic acid. And that had been established in two prior randomized controlled trials. Another big flaw in this trial is that it included an SRE definition that differed from the original studies of Saad and others. The primary analysis was at 24 months. The primary analysis was the 24 month event rate, but only 43% of patients completed this study at two years. And the median follow-up was only 14 months.

And lastly, the non-inferiority margin included a clinically important difference. So for all these reasons I don't think we can reliably interpret this study as showing that the less frequent schedule was good enough. And then it was also worth noting, even if you accepted that, the study showed that the longer dosing interval did not improve safety or tolerability.

So in summary, fragility fractures are common in men, age, prior fractures and low BMD are the strongest predictors of fracture risk. In men with prostate cancer, fracture risk is further increased by androgen deprivation therapy and androgen pathway inhibitors. Assessment of fracture risk should include evaluation of both clinical risk factors and bone mineral density. If you can only choose one, choose the clinical risk factor assessment, excuse me. Preferably FRAX as that's the best-validated measure. And as you've heard from all the prior speakers, treatment-related fractures are preventable.

In contrast, SREs are a distinct set of clinical problems related to cancer progression in bone. Approved therapies for osteoporosis. And by that I mean the specific drug dosing schedule for osteoporosis are not sufficient to prevent disease-related skeletal morbidity. Zoledronic acid, four milligrams every three to four weeks. Or denosumab 120 milligrams every four weeks significantly decrease SREs in MCRPC in bone metastasis. Zoledronic acid at less frequent schedules might be sufficient for SRE prevention, but the evidence for efficacy is weak, and there's no proven safety benefit. Optimal treatment duration of SRE prevention remains undefined. Thank you.

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