Metastasis to bone is the hallmark of prostate cancer and a major source of disease-related morbidity and mortality. In addition to prostate cancer cells, other major players in the vicious interactive cycle of prostate cancer bone metastasis are osteoblasts, osteoclasts, and mineralized bone matrix—together producing a heterogeneous mixture of osteoblastic and osteolytic lesions, the net effects of which, if uncontrolled, include bone pain, pathologic fractures, cord compression, and disease progression leading to death. Therefore, the targeting of bone in this disease has been a clinical and research focus for several decades, including evaluation of numerous interventions targeting different key pathways.

Several agents have received FDA approval based on pain palliation or reduction of skeletal-related events. The first bone-targeted agent to be approved was strontium chloride Sr-89, with other subsequently approved agents including zoledronic acid, samarium Sm-153 lexidronam pentasodium (Quadramet), and denosumab (Xgeva). However, none of these agents demonstrated a significant effect on objective disease progression or survival. Furthermore, most were tested in an era with limited effective therapy for management of metastatic castration-resistant prostate cancer.

Radium-223 Trial

In a recently reported phase III trial, radium-223 (Xofigo), an alpha emitter that selectively binds to areas of increased bone turnover in bone metastases, was associated with significantly prolonged overall survival (14.9 months) as compared with placebo (11.3 months) in patients with metastatic castration-resistant prostate cancer with or without prior docetaxel therapy.

It is important to highlight that patients included in the study were not excluded based on prior docetaxel therapy and were required to have symptomatic bone metastasis with regular use of analgesics or treatment with external-beam radiation therapy for cancer-related bone pain within 12 weeks from registration. However, patients were excluded if they had a history of or current visceral disease irrespective of site or significant malignant adenopathy (> 3 cm in the short-axis diameter).

Although the study allowed concomitant best “standard of care,” technically that did not involve any agent with a demonstrated impact on survival. The observed survival benefit was consistent across several important patient and disease-related characteristics, including prior docetaxel therapy.

Remaining Questions

With its positive impact on survival, radium-223 becomes another important therapeutic agent in the expanding armamentarium of agents that can improve survival in patients with metastatic castration-resistant prostate cancer. However, several questions remain to be answered to help guide optimal use of this and similar agents in everyday practice.

For example, although radium-223 significantly prolonged the time to the first symptomatic skeletal event (median, 15.6 vs 9.8 months) compared to placebo, it is not clear what impact it had on pain reduction or elimination. The study required either symptomatic disease with regular use of analgesics or recent treatment with external-beam radiation therapy for cancer-related bone pain, so it is unclear if the observed effects can be extrapolated to patients with asymptomatic bone metastasis. The trial was conducted in an era predating availability of abiraterone (Zytiga) and enzalutamide (Xtandi); therefore, it is not clear if the effects of the agent will be applicable in the setting of a rapidly evolving treatment landscape or whether it may be more optimally used in combination or sequential therapy strategies.

Bone-Targeted Therapy

Although bone is the major clinically evident site of disease, data from autopsy series and clinical trials clearly highlight the systemic nature of prostate cancer metastasis beyond bone. In addition to lymph nodes, for example, data from the S9916 and TAX-327 studies indicate that at least one-fifth of patients had visceral disease—and this number may increase as patients live longer and get exposed to more agents. Therefore, within the context of the totality of metastatic castration-resistant prostate cancer disease biology, bone only–targeted therapy as single agent is not adequate—which is why it will be important to see the outcomes of the planned combination trials with radium-223.

Another important point worth highlighting is the fact that the results of this trial provide the long-awaited first proof of principle that effective bone-targeted therapy can impact survival—adding another validated target in addition to androgen receptors and microtubules.

Going forward, it will be important to further evaluate the role of this agent in earlier settings—eg, in patients with metastatic castration-­resistant prostate cancer and asymptomatic bone metastasis, particularly in combination therapy, and in patients with hormone-sensitive prostate cancer and bone metastasis, in combination with androgen deprivation.

Conclusions

The past decade has seen unprecedented progress in the management of patients with metastatic castration-resistant prostate cancer. Although these patients now have many options, the disease continues to be terminal. Considering the totality of the disease biology and the modest impact on survival with currently approved single agents, it is critical that multitargeted, biologically and mechanistically rational combination therapy strategies be pursued. Ideally, this will be done in carefully defined disease populations in order to enhance antitumor effect, maximize benefit /risk ratio, and ultimately produce a more profound impact on survival. ■

Dr. Hussain is Cis Maisel Professor of Oncology, Professor of Medicine and Urology, Associate Director for Clinical Research, Co-Leader, Prostate Cancer Program, University of Michigan Comprehensive Cancer Center.

Disclosure: Dr. Hussain will be one of the lead investigators for an upcoming randomized phase II trial sponsored by Bayer.