Bone Metastases a Major Concern in Prostate Cancer

The leading agents for palliative care and the prevention of skeletal-related events for patients with bone metastases are zoledronic acid (Zometa) and denosumab (Xgeva, Prolia). Additionally, some studies have suggested that corticosteroids can relieve pain associated with bone metastases.

Other options provide therapeutic relief for patients, and some are associated with an extension in overall survival (OS). External radiation therapy can be used when metastases are limited to a few locations. Another option, radiopharmaceuticals, can provide both systemic and localized care. The only FDA-approved agent in this class for men with prostate cancer is radium-223 (Xofigo). This agent helps relieve bone pain by treating bone metastases while also preventing prostate cancer from further spreading to the bones. Radium-223 has been shown to improve OS for men with bone-metastatic castration-resistant prostate cancer (CRPC).

Prognostic and Predictive Uses of CTCs in mCRPC

Circulating tumor cells (CTCs) have been recognized as a potential source of prostate cancer seeding to distant metastatic sites (typically bone) for over a century, and with ongoing improvements in isolation and characterization methodology, CTCs are now being more rigorously investigated as potential predictive biomarkers in men with mCRPC.

In 2008, a multicenter prospective study showed that CTCs were an accurate independent predictor of OS for men with mCRPC.¹In this study, 276 patients with progressive mCRPC who were initiating a new line of chemotherapy were evaluated for the presence of CTCs by blood draw before treatment, and at monthly intervals thereafter.

Interestingly, the CTC counts were also significantly better (P= .0218) than prostate specific antigen (PSA) decrement algorithms (ie, 30% PSA reduction) at predicting OS. Patients whose baseline CTC counts when from unfavorable to favorable saw improved OS versus those with favorable baseline CTCs who turned unfavorable. The results confirmed the prognostic value of baseline CTCs, and also showed for the first time that post-treatment CTCs could predict survival in mCRPC.

The SWOG S0421 trial, a phase III study examining the use of docetaxel three times per week (with or without atrasentan) in men with mCRPC and bone involvement further explored the use of CTCs.²The findings suggested that an early (cycle 1) rise in CTCs while on docetaxel might portend a poor outcome, and could influence management strategies, so as to potentially forego additional docetaxel in favor of another treatment option in such a patient.²

In the phase III ALSYMPCA trial, which led to the FDA approval of radium-223, 921 men with mCRPC with two or more bone metastases, no visceral metastases, and who were unsuitable for, or had received prior docetaxel were randomized to radium-223 or pla-cebo for 6 intravenous injections.^3,4The results of the study showed a survival benefit of 3.6 months in the final analysis for patients on radium-223 versus placebo (median 14.9 vs 11.3 months; HR, 0.70;P<.001).⁴

Since CTCs are widely associated with the development of bone metastases, a study assessed the viability of using these markers to predict response to radium-223.5 In the study, blood samples were collected from 46 patients with mCRPC treated with radium-223 at baseline, at cycle 3, and at progression, and were centrally analyzed using the CellSearch methodology. Response was defined in the study as >50% decrease in CTCs at cycle 3 relative to baseline or &le;5 CTCs, progression was defined as >50% increase in CTCs or >5 CTCs, and stabilization was defined as neither response nor progression.¹¹

Results of this study showed that a CTC response was observed in 29% of patients (n = 8), disease stabilization in 42% of patients (n = 12), and progression in 29% of patients (n = 8). Notably, those with 5 or fewer CTCs at cycle 3 had a greater likelihood of remaining on treatment, with 88% (14/16) remaining on treatment after cycle 3, versus 50% (6/12) with >5 CTCs at cycle 3 (P=.04).⁵

CTCs at baseline also tended to identify patients likely to continue past cycle 3, with 87% (13/15) of those with &le;5 CTCs at baseline remaining on treatment after cycle 3 versus 54% (7/13) of those with >5 CTCs (P= .09). Although requiring further validation, the authors suggest the response to radium-223 and its use beyond cycle 3 can be predicted using CTCs as a biomarker.

Further advances in the characterization of CTCs, which move beyond their simple enumeration also have the potential to advance the use of this diagnostic

strategy in prostate and other cancers.¹²New technologies that aim to characterize genetic changes in CTCs (such as mutations that may confer resistance to selected therapies) will likely provide further information about drug resistance and enable clinicians to distinguish among available treatment choices in the increasingly complex setting of mCRPC.⁶

References

1. de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14(19):6302-6309.
2. Goldkorn A, Ely B, Quinn DI, et al. Circulating tumor cell counts are prognostic of overall survival in SWOG S0421: a phase III trial of docetaxel with or without atrasentan for metastatic castrationresistant prostate cancer. J Clin Oncol. 2014;32(11):1136-1142.
3. Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014;15(7):738-746.
4. Parker C, Nilsson S, Heinrich D, et al.; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.
5. Suárez C, Castellano D, Angel J, et al. Determining viability of circulating tumor cells (CTCs) as a predictive biomarker for response in patients (pts) with metastatic castrate resistant prostate cancer (mCRPC) treated with radium 223 (Ra). J Clin Oncol. 33, 2015 (suppl; abstr e16051).
6. Miller S. New circulating tumor cell technology could advance personalized medicine in prostate cancer. Nanomedicine (Lond). 2013;8(5):683-684.