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Bone-Targeted Therapy in Prostate Cancer

Zoledronic acid

To maintain bone integrity during bone remodeling, homeostasis of osteoblasts increasing bone mass and osteoclasts resorbing bone is required. Bisphosphonates are rapidly absorbed on the bone surface and inhibit osteoclast activity by affecting cytoskeletal dynamics. The Phase III Zoledronic acid 039 trial showed that among men with metastatic castration-resistant prostate cancer (mCRPC), a greater proportion of patients who received placebo had skeletal-related events than those who received zoledronic acid at 4 mg (44.2% versus 33.2%, p =0.021) or those who received zoledronic acid at 8 mg (38.5%, p = 0.222 compared to placebo).4 Furthermore, the median time to the first skeletal-related event was 321 days for patients who received placebo, was not reached for patients who received zoledronic acid at 4 mg (p = 0.011 versus placebo), and was 363 days for those who received zoledronic acid at 8/4 mg (p = 0.491 versus placebo). Pain scores and analgesic requirements increased more in patients who received a placebo than in patients who received zoledronic acid, but there were no differences in survival, disease progression, performance status, or quality-of-life scores among the groups. This clinical trial, published nearly 20 years ago, was crucial in bringing bone health and bone-targeted therapy to the forefront of bone metastasis treatment.

The CALGB 90202 study assessed the efficacy of zoledronic acid in men with castration-sensitive metastatic prostate cancer in an attempt to introduce the bisphosphonate earlier in the disease process.5 Men with castration-sensitive prostate cancer and bone metastases whose ADT was initiated within six months of study entry were randomized 1:1 to receive zoledronic acid (4 mg IV every 4 weeks) or placebo. After their disease progressed to castration-resistant status, all patients received open-label treatment with zoledronic acid. The target accrual for this trial was 680 patients and a planned primary analysis after 470 skeletal-related events, however, the study was discontinued prematurely after accruing 645 patients (299 skeletal-related events). The study found that early zoledronic acid was not associated with increased time to first skeletal-related event: median time to first skeletal-related event was 31.9 months in the zoledronic acid group (95% confidence interval (CI), 24.2 to 40.3) and 29.8 months in the placebo group (95% CI, 25.3 to 37.2; HR 0.97, p=0.385). Furthermore, overall survival was similar between the groups (HR 0.88; 95% CI 0.70 to 1.12). As such, zoledronic acid is only utilized in men with bone mCRPC.

Denosumab

The receptor activator of nuclear factor kB ligand (RANKL) is a cytokine that binds to the RANK expressed by osteoclasts and a key signaling molecule in the maintenance of bone integrity. Denosumab is a human monoclonal antibody directed against RANKL and is licensed in the United States, United Kingdom and Europe for the treatment of men at risk of bone loss or fracture associated with hormonal therapy (age >70 years of age with osteopenia or a history of osteoporotic fracture). In 2011, a Phase III study randomized 1,904 men with CRPC in a 1:1 ratio to receive 120 mg SQ denosumab plus IV placebo or 4 mg IV zoledronic acid plus SQ placebo every 4 weeks.6 The primary endpoint was time to first on-study skeletal-related event.
This trial found that the median time to first skeletal-related event was 20.7 months for patients treated with denosumab compared with 17.1 months for men treated with zoledronic acid (HR 0.82, 95% CI 0.71-0.95). Serious adverse events were comparable between denosumab (63%) zoledronic acid (60%).

A subsequent study by Smith et al. assessed PSA doubling time as a marker for further identifying which men with nonmetastatic CRPC would benefit from denosumab.7 There were 1,432 men randomly assigned 1:1 to monthly subcutaneous denosumab 120 mg versus placebo. This trial found that in the placebo group shorter bone-metastasis free survival was associated with PSA doubling time less than 8 months. When denosumab was assessed, it increased bone-metastasis free survival by a median of 6.0 months at PSA doubling time less than 10 months (HR 0.84, p = 0.042), 7.2 months at PSA doubling time less than 6 months (HR 0.77, p = 0.006), and 7.5 months among men with PSA doubling time less than 4 months (HR 0.71, p = 0.004). Although no overall survival benefit was noted among these subgroups, this study provided further evidence of denosumab’s ability to decrease bone metastasis among men with high-risk nonmetastatic CRPC.

Alpha and Beta Radiopharmaceuticals

Radiopharmaceuticals are systemically administered and deliver radiation preferentially targeting areas of high bone turnover. The beta-emitting radiopharmaceuticals strontium-89, 153Sm-EDTMP, and Re-186 HEDP are all approved for pain palliation secondary to bone metastases. However, these agents are frequently limited by bone marrow suppression toxicity.

Radium-223 is a radiopharmaceutical that mimics calcium and targets new bone growth around bone metastases with alpha particles. The short penetration of these particles results in highly localized tumor-cell killing with minimal damage to the surrounding healthy cells and fewer bone marrow toxic effects.8 The Phase III ALSYMPCA trial lead to FDA approval of radium-223 in the United States for patients with bone mCRPC without visceral metastases.9 In this trial, patients were enrolled that had two or more bone metastases detected on skeletal scintigraphy, were without visceral metastasis who had previously received docetaxel, were docetaxel ineligible, or declined docetaxel. Patients were required to have symptomatic disease, based on the requirement for regular analgesics or prior treatment with external beam radiotherapy for cancer-related bone pain in the preceding 12 weeks. There were 921 patients randomized in a 2:1 ratio to radium-223 (50 kBq per kilogram of body weight intravenously), once every four weeks, plus standard of care versus placebo plus standard of care. At an initial, pre-specified, interim analysis when 314 deaths had occurred, there was a longer median overall survival among patients who received radium-223 (14.0 months) than those receiving placebo (11.2 months) with a resulting 30% decrease in the risk of death (HR 0.70, 95% CI 0.55 to 0.88). Following 528 deaths, median overall survival among patients who received radium-223 was 14.9 months compared to 11.3 months for those receiving placebo (11.3 months). Similarly, the updated analysis confirmed a 30% reduction in the risk of death (HR 0.70, 95% CI 0.58 to 0.83) for patients receiving radium-223. Furthermore, radium-223 delayed time to the first symptomatic skeletal event (median 15.6 months vs 9.8 months; HR 0.66, 95% CI 0.52 to 0.83).

The recently published ERA 223 study randomized 806 patients having chemotherapy-naïve mCRPC with bone metastasis to radium-223 or placebo in addition to abiraterone acetate.10 Symptomatic skeletal event-free survival was the primary outcome. The trial was unblinded prematurely as more fractures and deaths were identified in the radium-223 arm than among patients receiving a placebo. Median skeletal event-free survival was 22.3 months (interquartile range 17.0 to 25.8 months) among patients receiving radium-223 and abiraterone acetate and 26.0 months (interquartile range 21.8 months to 28.3 months) in patients receiving placebo and abiraterone acetate (HR 1.12, 95% CI 0.92-1.37). Fractures were more common among patients receiving radium-223 and abiraterone acetate (29%) than those receiving placebo and abiraterone acetate (11%). Subsequently, the FDA and EMA advised against this combination. At the recent ASCO 2019 annual meeting, Dr. Betrand Tombal presented safety data from the Phase III EORTC-1333-GUCG/PEACE III trial comparing enzalutamide to a combination of radium-223 and enzalutamide in asymptomatic or mildly symptomatic mCRPC patients. After an IMDC mandate for bone protective agents following the results of ERA 223, bone protective agent use increased dramatically from 42.6% to 86.7%. Thus far, the use of bone protective agents in combination with radium 223 plus enzalutamide has diminished the incidence of fractures in this trial.

Additional Therapeutic Agents

There are several new bone targeting therapy drugs that are currently under investigation:11

• Cabozantinib is an oral tyrosine kinase inhibitor that blocks MET, VEGFR-2, as well as other tyrosine kinases such as RET, KIT, AXL and FLT3. MET is overexpressed in bone metastases from prostate cancer, as well as involved in proliferation, differentiation, and migration of osteoclasts and osteoblasts. In a Phase II trial, cabozantinib showed a partial resolution of bone lesions in 56% of patients and complete resolution in 19% of patients.12 However, these results have not been substantiated in Phase III trials.

• Dasatinib is an oral inhibitor of several tyrosine kinases, most notably SRC, which is a key signaling molecule in bone metabolism (a mediator of osteoclast activity involved in the pathogenesis of prostate cancer bone metastasis). In a Phase I/II trial of mCRPC patients, 30% of dasatinib treated patients had resolution of at least one bone lesion and 41% had stable bone scintigraphy.13 In the Phase III READY trial, dasatinib plus docetaxel was compared to docetaxel plus placebo among chemotherapy naïve mCRPC patients.14 Unfortunately, dasatinib plus docetaxel did not improve overall survival. However, the combination trended towards improvement in time to skeletal-related events (HR 0.81, p = 0.08).

• Atrasentan is an oral selective endothelin A (ET-A) antagonist that inhibits the osteoblast-dependent formation of new bone induced by metastatic cancer cells. In a Phase II trial, atrasentan was tested in CRPC patients: although the primary endpoint of rate of pain relief after 12 weeks was not met, atrasentan 10 mg resulted in a significant improvement in Bone Pain Inventory scores.15 Of note, a benefit was demonstrated in pain interference with relations with other people (p = 0.031) and in the worst pain in the last 24 hours (p = 0.03). A Phase III randomized, placebo-controlled trial evaluating atrasentan in non-metastatic CRPC did not meet the primary endpoint of delaying time to disease progression and did not show a significant improvement in time to first skeletal lesion, although atrasentan lengthened PSA doubling time (p = 0.031).16

Conclusions

Given the prevalence of bone metastasis in advanced prostate cancer, bone-targeted therapy is an important treatment for these men. Although to date these agents other than radium-223 have not improved overall survival, the ability to delay time to skeletal-related events is an important endpoint for the quality of life for these patients. Zoledronic acid, denosumab, and radium-223 are currently the gold standard for bone-targeted therapy as additional research is ongoing for improvement in preventing and treating bone metastases among prostate cancer patients.

Published Date: December 2019
Written by: Zachary Klaassen, MD, MSc
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14. Araujo JC, Trudel GC, Saad F, et al. Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol. 2013;14(13):1307-1316.
15. Nelson JB. Endothelin receptor antagonists. World J Urol. 2005;23(1):19-27.
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