Prostate cancer’s unique affinity for metastasis to the bone creates a unique need to prevent skeletal-related events (SREs) in order to maximize mobility and quality of life. Drs. Graff and Beer provide a timely review of two groups of therapeutic agents widely utilized in men with advanced prostate cancer: bone-supportive agents (denosumab and zoledronic acid), which reduce or delay SREs but do not contribute to survival, and the newer life-extending systemic therapies for metastatic castration-resistant prostate cancer (mCRPC), which have also recently been shown to reduce or delay SREs (abiraterone, enzalutamide, and radium-223). The availability of the latter group of agents, as well as the side-effect profile and cost of bone-supportive agents, raises questions regarding the role of bone-supportive agents in the era of more effective therapies for prostate cancer. Rather than preventing receptor activator of nuclear factor kappa-B ligand (RANKL)–mediated osteoclast activation (denosumab), or creating a physical barrier to bone turnover (bisphosphonates), eradication of tumor cells that are hijacking the normal bone remodeling machinery could potentially be the most efficient way to prevent bone destruction. Furthermore, benefits of bone-supportive therapies must be weighed against cost and toxicity, which Drs. Graff and Beer have outlined. However, since SREs occurred in significant percentages of patients in all of the studies of life-extending systemic therapies, combining both classes of agents may continue to be necessary. Investigation into groups of patients for whom bone-supportive therapy is most or least beneficial is warranted.
The exploratory enzalutamide subgroup analysis determined that SREs were not delayed for men concurrently receiving bisphosphonate therapy. This raises the question of whether combination therapy is necessary for all patients. On the other hand, in the Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, there appeared to be additive benefit for patients treated with radium-223 who were also receiving bisphosphonates. The difference could be related to the higher-risk population enrolled in ALSYMPCA—men who had pain from bony metastatic disease. These emerging data make it imperative that we invest some effort in updating our treatment paradigm for men with prostate cancer and bone metastases, and move from a one-size-fits-all approach to something more rational and individualized.
Which prostate cancer patients are at greatest risk for SREs?
One strong predictor of risk for SREs is prior diagnosis of an SRE. For instance, in men with prostate cancer who experienced spinal cord compression, published series indicate a 27% to 45% risk of experiencing a second episode of spinal cord compression within 2 years.[3,4] In fact, the Cancer and Leukemia Group B (CALGB) 90202 trial, which found no delay in SREs with zoledronic acid compared with placebo in 645 men with androgen-sensitive prostate cancer and at least one bone metastasis, found a nearly significant benefit in the small subgroup of men with prior SRE (n = 82). For these men, there was a delay in SREs, with a median time to event of 31.9 months for zoledronic acid compared with 17.6 months for placebo (hazard ratio, 0.56; 95% confidence interval [CI], 0.31–1.02). The hypothesis generated from this experience is that a trial design in an enriched population might have revealed an advantage to early application. Clinical variables such as prior SRE, overall disease burden, and location of bone metastases should be evaluated as enrichment strategies for future trials of bone-supportive interventions.
In addition to clinical variables, there are urine and serum biomarkers that could be helpful. Urine N-telopeptide levels, for instance, are highly predictive of SRE risk, with levels > 100 nmol/mmol Cr predicting a 3.25× greater incidence of SREs (95% CI, 2.26–4.68) in prostate cancer patients. Normalization of urine N-telopeptide levels has been associated with improved survival. A more commonly available biomarker is serum alkaline phosphatase (SAP), which can reflect activity of bone metastases, although the bone-specific alkaline phosphatase fraction is more specific. SAP was used as a stratifying factor in the ALSYMPCA trial, and radium-223 delayed SREs regardless of SAP, although overall survival was not prolonged in the subgroup with SAP < 220 IU/L. With further exploration of clinical and laboratory variables as they relate to SREs in mCRPC patients receiving life-extending therapies and/or bone-supportive therapies, it may be possible to develop algorithms that could be used to stratify men into groups of highest or lowest benefit from bone-supportive therapies.
How much bone-supportive therapy is needed?
Since the most feared complications of bisphosphonates (renal toxicity, atypical femur fractures) and of both bisphosphonates and RANKL inhibition (osteonecrosis of the jaw) are dose-dependent, identifying the optimal duration of therapy for these agents is important. While men at highest risk might benefit from indefinite treatment, for most men it seems likely that there could be an induction period, with more frequent dosing of bone-supportive agents, followed by a less frequent maintenance schedule or even a holiday. Identifying a marker capable of determining that SRE risk has been reduced by the current therapy would be helpful for defining the optimal course of induction, as well as for facilitating monitoring during maintenance, to ensure that bone turnover has not increased to a range of increased SRE risk. Potential markers for this use include radiographic imaging (such as 18F-sodium fluoride positron emission tomography [PET] bone scans) or blood- or urine-based markers, such as N-telopeptide.
In conclusion, enhanced control of osseous metastases with both systemic life-extending therapies and bone-support medications has meaningful clinical impact for prostate cancer patients. Our next challenge will be to better define their optimal use in combination or sequence, and tailor their application to the subgroups most likely to benefit.
Financial Disclosure: Dr. Dorff has received honoraria from Astellas and has served as a consultant for Medivation and Dendreon. Dr. Pal has consulted for Astellas.
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