Bone-Targeted Therapies Evolve in Prostate Cancer

Daniel P. Petrylak, MD

Professor, Medical Oncology Director, Prostate Cancer Research Group Yale Cancer Center Leader, Genitourinary Cancers Medical Oncology Team Smilow Cancer Hospital at Yale-New Haven

New Haven, CT

The treatment of bone metastases in prostate cancer has changed over the years, and several options are now either available or under development. Daniel P. Petrylak, MD, director of the Genitourinary Oncology Program at Yale Cancer Center in New Haven, Connecticut, spoke about advances in bone-targeted therapy at the 6th Annual Interdisciplinary Prostate Cancer Congress, which was held in New York City on March 16. “Bisphosphonates used to be the only option,” he said, “but treatment has evolved over the years.”

Bone resorption and bone formation are dysregulated in prostate cancer, and clinical evidence indicates that both processes contribute to bone metastases. The mechanisms for bone metastases are complex, and include tumor stimulation of osteoclasts and osteoblasts, and the response of the bone microenvironment. In addition, factors independent of the tumor may contribute to bone resorption.¹

The bisphosphonate zoledronic acid is approved for the treatment of bone metastases in hormone-refractory prostate cancer and has been shown to reduce time to first skeletal-related event (SRE),² and denosumab, a RANKL inhibitor, has been shown to prevent osteoclast-mediated bone resorption.³ In randomized trials, the incidence of osteonecrosis of the jaw (ONJ) and renal toxicity were about the same for denosumab and bisphosphonates, Petrylak said. “ONJ needs to be monitored for in all bone-targeted therapy.”

Two radionuclides—samarium 153 lexidronam and strontium 89—are FDA-approved for treatment of bone metastases. Clinicians are sometimes reluctant to use these agents in combination with chemotherapy, and as a result, Petrylak said, “we tend to use these too late.” But clinical trials have demonstrated that both agents can be successfully combined with chemotherapy, he said.

The phase III ALSYMPCA) trial analyzed the use of radium-223 chloride in patients with castration-resistant prostate cancer with bone metastases.⁴ Radium-223 is an alpha-emitter that targets bone metastases with high-energy alpha-particles of short range. The study randomized 921 patients to radium-223 plus best standard of care or placebo plus best standard of care. Radium-223 significantly improved overall survival (OS), the primary endpoint, with patients in the experimental arm achieving a median OS of 14.9 months versus 11.3 months for the placebo arm (hazard ratio [HR] = .695; 95% CI, 0.581-0.832; P = .00007).These results represent a 30.5% reduction in the risk of death. The survival benefit was preserved both with and without current use of bisphosphonates and with and without prior use of docetaxel.

Radium-223 significantly prolonged time to first SRE (median, 15.6 months in the treatment arm vs 9.8 months for placebo; HR = 0.658; 95% CI, 0.522-0.830; P = .00037).

The safety and tolerability of radium-223 were favorable, with low myelosuppression. “The safety profile was basically the same as the placebo arm,” Petrylak said. Combination studies with hormonal and chemotherapeutic agents are now under way.

References

1. Guise TA, Mohammad KS, Clines G, et al. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res. 2006;12:6213s-6216s.
2. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94(19):1458-1468.
3. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813-822.
4. Parker C, Nilsson S, Heinrich, D. Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer (CRPC) patients with bone metastases (ALSYMPCA). J Clin Oncol. 2012;30(suppl; abstr LBA4512).