Page 5 - Castration-resistant prostate cancer (CRPC): CUA/CUOG

Guideline: CRPC management

Radium-223 (previously known as alpharadin) is an intra- In the setting of mCRPC, denosumab (120 mg SC every four
venous alpha-emitting agent that mimics calcium, preferen- weeks) compared to zoledronic acid (4 mg IV every four
tially targeting bone metastases. In a randomized, phase weeks) has shown significant improvement in the time to the
3 study, radium-223 given every four weeks for six cycles first SRE (20.7 vs. 17.1 months; p<0.001 for non-inferiority;
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was compared to placebo. Radium-223 demonstrated a p=0.008 for superiority), while OS and PFS were not different. 29
significant improvement in OS and symptomatic SREs. OS No dose modification for renal function is necessary in
was improved by 3.6 months (HR 0.7; p<0.0001) and symp- the case of denosumab; however, the risk of hypocalcemia
tomatic SREs were delayed by 5.8 months (p<0.0001). The is increased and calcium monitoring and supplementation
study included patients with symptomatic bone metastases (with calcium and vitamin D) is recommended for both
who were post-docetaxel or ineligible for docetaxel. The denosumab and zoledronic acid. Denosumab has not been
21
study excluded patients with visceral metastases or lymph studied, however, in patients with severe renal impairment
node metastases greater than 3 cm. PSA measurements while (glomerular filtration rate <30 ml/min).
receiving radium-223 cannot provide evidence of whether Good oral hygiene, baseline dental evaluation for high-
patients are benefitting or not. Given the mechanism of action risk individuals, and avoidance of invasive dental surgery
of the drug, alkaline phosphatase appears to be better marker during therapy are recommended to reduce risk of osteo-
of activity. A phase 3 study in the first-line mCRPC setting necrosis of the jaw (ONJ) for patients treated with bone-
compared radium-223 in combination with abiraterone/pred- targeted therapies (Expert opinion). Zoledronic acid and
nisone vs. abiraterone/prednisone alone and demonstrated no denosumab have been used in combination with all the
advantage and an increased risk of fractures. 22 agents presently in use for the treatment of mCRPC. To date,
Radium-223 should not be combined with abiraterone there have been no additional safety issues of concern that
and a bone-supportive agent (denosumab or zoledronic have been reported.
acid) should always be used when using radium-223 (Level 1, The optimal duration of zoledronic acid and denosumab
Strong recommendation). in men with CRPC and bone metastases is undefined. The
risk of ONJ appears to be related to time on bone-targeted
Supportive agents therapy, therefore, caution should be taken in using these
agents beyond two years (Level 3, Weak recommendation).
Denosumab and zoledronic acid Denosumab and zoledronic acid are not approved
In men with CRPC and bone metastases, denosumab (120 and not indicated for SRE prevention in the treatment of
mg subcutaneous [SC]) or zoledronic acid (4 mg IV) every metastatic castration-sensitive prostate cancer or for bone
four weeks are recommended to prevent disease-related metastases prevention.
SREs, including pathological fractures, spinal cord com-
pression, surgery, or radiation therapy to bone (Level 1, IV. Other supportive care therapies
Strong recommendation).
Bone loss associated with ADT has been shown to increase Systemic corticosteroid therapy
the risk of fracture. 23-27 Moreover, about 90% of patients with Corticosteroid therapy with low-dose prednisone or dexa-
mCRPC will develop bone metastases, which cause local methasone may also offer improvements in PSA values and/
decreases in bone integrity. Patients are at significant risk of or palliative outcomes in up to 30% of patients in both
SREs that include pathological fractures, debilitating bone pain symptomatic and asymptomatic men. Steroids may also
requiring palliative radiation therapy, and spinal cord com- exert an anti-neoplastic effect on prostate cancer (Level 3,
pression. Quality of life is affected by these complications. Weak recommendation). 30
Zoledronic acid is a third-generation nitrogen contain-
ing bisphosphonate. Bisphosphonates other than zoledronic Palliative radiation
acid are not known to be effective to prevent disease-related Bone metastases from prostate cancer are often radiosensitive
SREs. In the placebo-controlled zoledronic acid study, fewer and most men will experience partial or complete pain relief
men receiving zoledronic acid had SREs (38% vs. 49%; from external beam radiation to a specific lesion. Studies have
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28
p=0.02). Zoledronic acid also increased the median time shown that a single fraction of standard palliative radiotherapy
to first SRE (488 vs. 321 days; p=0.01). There was an over- (RT) is as effective as five or more fractions in providing pallia-
all 36% reduction in the rate of SREs in treated patients. 28 tion. However, more patients require retreatment for pain recur-
Treatment with zoledronic acid should not be used in men rence with single fraction radiation. Stereotactic body RT (SBRT)
with baseline creatinine clearance <30 mL/min. is a more precise and may be a more effective form of palliation
Denosumab is a fully humanized monoclonal antibody delivered in five or fewer treatments and may also be considered
against RANK ligand. It has been shown to be effective in particularly for oligometastatic disease where high-dose RT is
preventing bone loss and new vertebral fractures due to ADT. 27 currently being studied for improved oncological outcomes.

CUAJ • October 2019 • Volume 13, Issue 10 311