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CRPC: Preventing Complications With Bone-Targeted Agents

Insights From: Evan Yu, MD, University of Washington; Ulka Vaishampayan, MD, Barbara Ann Karmanos Cancer Institute ; Neeraj Agarwal, MD, Huntsman Cancer Institute
Published: Thursday, Dec 06, 2018



Transcript: 

Evan Yu, MD: Bone health is very important for patients with prostate cancer, for both those with nonmetastatic disease and metastatic disease. There are clearly data for use of agents like denosumab in patients who have nonmetastatic disease and in preventing osteoporotic fractures in the setting of metastatic castration resistant prostate cancer. There are data with zoledronic acid to prevent skeletal-related events. There are data with denosumab showing superiority over zoledronic acid in prevention of skeletal-related events. Those events include pathologic fractures, the need for surgery in bone, radiation of bone, or spinal cord compression. Some studies include hypercalcemia as well.

The practical question is when to introduce these agents. You certainly wouldn’t be wrong to do a DEXA [dual-energy x-ray absorptiometry] scan in anybody with nonmetastatic disease, and if they have osteopenia or osteoporosis, start them on 60 mg of denosumab every 6 months to prevent osteoporotic fractures. That is a common practice that I do.

For those with metastatic disease, I don’t do it for hormone-sensitive disease because there are 2 randomized trials using zoledronic acid for hormone-sensitive disease showing no survival benefit and no skeletal benefit. There was a CALGB [Cancer and Leukemia Group B] study and the STAMPEDE trial, which had the zoledronic acid arm. That being said, for castration-resistant prostate cancer, I do utilize both zoledronic acid or denosumab—probably more denosumab, given its superiority—to prevent skeletal-related events. The key thing is that we now have so many effective agents that lead to decreased skeletal morbidity. For instance, abiraterone, enzalutamide, and radium-223 all prevented skeletal-related events in their clinical trials. I don’t always feel the urgency to start everyone on one right off the bat. When I tend to introduce these agents, it’s for patients who might be progressing after first-line therapy. But they’re clearly important to prevent these events.

Neeraj Agarwal, MD: Once bone metastasis has been identified in the presence of castrate resistant disease, it is very important to use bone-targeting agents in a timely fashion. The 2 agents we use very commonly include bisphosphonates, such as zoledronic acid, or RANK [nuclear factor-κB] ligand inhibitors, such as denosumab. Both of these agents in separate randomized trials have been shown to delay skeletal-related events such as fractures. As we discussed, these are the most common cause of suffering and death in our patients.

Ulka Vaishampayan, MD: Bisphosphonate therapies have been shown to be efficacious in metastatic prostate cancer with bone metastases. The evaluation of zoledronic acid, specifically within the bisphosphonates, was done in the metastatic CRPC setting where it showed a delay in skeletal-related events as compared to placebo.

Zoledronic acid is an intravenous medication that’s given once a month. Starting it early on to prevent bone loss is a reasonable consideration, even when you’re starting androgen deprivation therapy. Clearly, fracture risk is going up as these patients have longer life expectancy now with all these treatments. They are leading an active lifestyle, so you do need to factor that in when you’re considering the patient’s risk factor. Preventing fracture is a tremendous way to prevent patient mortality. Especially for elderly men, about the age of 70, hip fracture is a big reason for mortality. All of these factors are critically important to start evaluating bone density, even when patients are just getting started on androgen deprivation therapy. Clearly, we should continue that assessment and consideration of bone-targeted therapy, definitely in the castrate resistant setting but even sometimes earlier in the hormone-sensitive setting.

For bisphosphonate therapy, zoledronic acid is the one that’s most commonly used in metastatic prostate cancer. It’s given once a month through intravenous injection for patients with osteoporosis or to prevent bone loss. It can be used at a much lower frequency, once every 6 months or  once a year, etcetera. The possible complications that need to be considered include hypocalcemia. Typically, we check the calcium level before delivering the medication. If it’s not normal, there should definitely be a discussion with the patients about starting them on calcium and vitamin D supplements.

Frequently, studies show that a number of patients are vitamin D deficient and have low calcium levels. That is a critically important thing. The other thing is that dental evaluation is important prior to starting this because any dental extractions, etcetera—there is osteonecrosis of the jaw, which is a reported adverse event—can be fairly disabling. It’s important to prevent it rather than try to treat it after it occurs. The other thing specific to zoledronic acid is that creatinine or kidney function does need to be monitored, and the dose has to be changed or adjusted depending on the creatine clearance of the patient.

Transcript Edited for Clarity
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Transcript: 

Evan Yu, MD: Bone health is very important for patients with prostate cancer, for both those with nonmetastatic disease and metastatic disease. There are clearly data for use of agents like denosumab in patients who have nonmetastatic disease and in preventing osteoporotic fractures in the setting of metastatic castration resistant prostate cancer. There are data with zoledronic acid to prevent skeletal-related events. There are data with denosumab showing superiority over zoledronic acid in prevention of skeletal-related events. Those events include pathologic fractures, the need for surgery in bone, radiation of bone, or spinal cord compression. Some studies include hypercalcemia as well.

The practical question is when to introduce these agents. You certainly wouldn’t be wrong to do a DEXA [dual-energy x-ray absorptiometry] scan in anybody with nonmetastatic disease, and if they have osteopenia or osteoporosis, start them on 60 mg of denosumab every 6 months to prevent osteoporotic fractures. That is a common practice that I do.

For those with metastatic disease, I don’t do it for hormone-sensitive disease because there are 2 randomized trials using zoledronic acid for hormone-sensitive disease showing no survival benefit and no skeletal benefit. There was a CALGB [Cancer and Leukemia Group B] study and the STAMPEDE trial, which had the zoledronic acid arm. That being said, for castration-resistant prostate cancer, I do utilize both zoledronic acid or denosumab—probably more denosumab, given its superiority—to prevent skeletal-related events. The key thing is that we now have so many effective agents that lead to decreased skeletal morbidity. For instance, abiraterone, enzalutamide, and radium-223 all prevented skeletal-related events in their clinical trials. I don’t always feel the urgency to start everyone on one right off the bat. When I tend to introduce these agents, it’s for patients who might be progressing after first-line therapy. But they’re clearly important to prevent these events.

Neeraj Agarwal, MD: Once bone metastasis has been identified in the presence of castrate resistant disease, it is very important to use bone-targeting agents in a timely fashion. The 2 agents we use very commonly include bisphosphonates, such as zoledronic acid, or RANK [nuclear factor-κB] ligand inhibitors, such as denosumab. Both of these agents in separate randomized trials have been shown to delay skeletal-related events such as fractures. As we discussed, these are the most common cause of suffering and death in our patients.

Ulka Vaishampayan, MD: Bisphosphonate therapies have been shown to be efficacious in metastatic prostate cancer with bone metastases. The evaluation of zoledronic acid, specifically within the bisphosphonates, was done in the metastatic CRPC setting where it showed a delay in skeletal-related events as compared to placebo.

Zoledronic acid is an intravenous medication that’s given once a month. Starting it early on to prevent bone loss is a reasonable consideration, even when you’re starting androgen deprivation therapy. Clearly, fracture risk is going up as these patients have longer life expectancy now with all these treatments. They are leading an active lifestyle, so you do need to factor that in when you’re considering the patient’s risk factor. Preventing fracture is a tremendous way to prevent patient mortality. Especially for elderly men, about the age of 70, hip fracture is a big reason for mortality. All of these factors are critically important to start evaluating bone density, even when patients are just getting started on androgen deprivation therapy. Clearly, we should continue that assessment and consideration of bone-targeted therapy, definitely in the castrate resistant setting but even sometimes earlier in the hormone-sensitive setting.

For bisphosphonate therapy, zoledronic acid is the one that’s most commonly used in metastatic prostate cancer. It’s given once a month through intravenous injection for patients with osteoporosis or to prevent bone loss. It can be used at a much lower frequency, once every 6 months or  once a year, etcetera. The possible complications that need to be considered include hypocalcemia. Typically, we check the calcium level before delivering the medication. If it’s not normal, there should definitely be a discussion with the patients about starting them on calcium and vitamin D supplements.

Frequently, studies show that a number of patients are vitamin D deficient and have low calcium levels. That is a critically important thing. The other thing is that dental evaluation is important prior to starting this because any dental extractions, etcetera—there is osteonecrosis of the jaw, which is a reported adverse event—can be fairly disabling. It’s important to prevent it rather than try to treat it after it occurs. The other thing specific to zoledronic acid is that creatinine or kidney function does need to be monitored, and the dose has to be changed or adjusted depending on the creatine clearance of the patient.

Transcript Edited for Clarity
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