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Continued Focus on Bone Metastases to Improve Outcomes and Patient Care in Prostate Cancer

Bone metastases are at the center of advanced prostate cancer care, with over 90% of patients with metastatic prostate cancer expected to have bone involvement.1 These metastatic sites can be a cause of substantial pain in our patients, and they have been a key target for therapeutic development. Bone targeted agents have been developed to reduce fragility fractures and skeletal related events, and are now an integral part of the care of patients with metastatic prostate cancer,2,3 Further, radium-223 is a bone-targeted radiopharmaceutical that not only reduces pain burden but was also the first radiopharmaceutical to prolong survival in patients with prostate cancer. Over time prostate cancer studies have investigated the prognostic implications of bone metastases in comparison with other sites and helped us gain insight into the potential future progression or responsiveness of disease.4 Bone metastases have played a large role in the clinical care of patients with prostate cancer, and our approach to them continues to evolve.

One area of continued development around bone metastatic disease involves the increasing utilization of PSMA PET scans in patients with localized prostate cancer. Guidelines suggest that these scans can be used for initial staging in patients with unfavorable intermediate, high, or very high risk localized disease.5 This approach to staging has led to the identification of bone metastases in at least 10% of patients who previously may have been missed by conventional bone and CT scan screening approaches in one landmark stud.6 This new lens on staging has caused stage migration on a large scale, and also raised the issue of high false positive lesions in ribs. It has also given us an opportunity to target oligometastatic sites with SBRT and investigate the use of PSMA targeted radioligand therapies in low volume metastatic states. In clinical practice, and in ongoing clinical trials, we are using this approach to see what was previously invisible to shift the trajectory of disease and investigate how to understand the new status of our patients best.

Further work on therapeutics has also occurred, with the PEACE-3 trial reporting out at ESMO 2024 as new evidence supporting the use of a bone targeted disease control strategy (Gillesson S, ESMO 2024). PEACE-3 is an international randomized phase 3 trial that included patients with metastatic castration-resistant prostate cancer (mCRPC) who were randomized to treatment with enzalutamide with or without radium-223. Patients had to have bone metastatic disease but were asymptomatic or mildly symptomatic from their disease, and they could have had soft tissue involvement but no visceral metastases. Approximately 30% had had prior treatment with docetaxel and approximately 2% had prior exposure to abiraterone acetate in the hormone sensitive setting. Importantly patients were mandated to use bone health agents (bisphosphonates or denosumab) per standard guidelines for mCRPC. In the analysis presented at ESMO, radiographic progression-free survival was prolonged with the combination of radium-223 plus enzalutamide versus enzalutamide alone (HR (95% CI) 0.69 (0.54-0.87)). There was also the suggestion of improved overall survival, which will be followed to ensure that this remains stable over time (HR (95% CI) 0.69 (0.52-0.90). Interestingly there was no difference in skeletal related events or time to pain progression between treatment arms, suggesting that the improvement in disease control was a cancer control effect on the prostate cancer cells themselves rather than simply a reduction in harmful bone related events or improved symptom management alone.

We have a lot to learn when it comes to bone metastases in prostate cancer, and an opportunity to improve the lives of our patients in the process. Whether we use bone health agents when appropriate to reduce complications, improve our ability to target metastases with radiation techniques or combine systemic treatment approaches to include addressing bone metastases, we are shifting the trajectories of cancer control and quality of life in the right direction. Ongoing efforts to improve the lives of our patients will include a focus on bone metastases, and updates in that area will be highlighted here so that we can learn together today, and make a difference in the clinic tomorrow.

Written by: Alicia K. Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA

References:

  1. Bubendorf L, Schöpfer A, Wagner U, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 2000;31(5):578-83. doi: 10.1053/hp.2000.6698
  2. Saylor PJ, Rumble RB, Tagawa S, et al. Bone Health and Bone-Targeted Therapies for Prostate Cancer: ASCO Endorsement of a Cancer Care Ontario Guideline. Journal of Clinical Oncology 2020;38(15):1736-43. doi: 10.1200/jco.19.03148
  3. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369(3):213-23. doi: 10.1056/NEJMoa1213755
  4. Halabi S, Kelly WK, Ma H, et al. Meta-Analysis Evaluating the Impact of Site of Metastasis on Overall Survival in Men With Castration-Resistant Prostate Cancer. J Clin Oncol 2016;34(14):1652-9. doi: 10.1200/jco.2015.65.7270 [published Online First: 20160307]
  5. Edward M. Schaeffer SS, Nabil Adra, Yi An, Daniel Barocas, Rhonda Bitting, Alan Bryce, Brian Chapin, Heather H. Cheng, Anthony Victor D’Amico, Neil Desai, Tanya Dorff, James A. Eastham, Thomas A. Farrington, Xin Gao, Shilpa Gupta, Thomas Guzzo, Joseph E. Ippolito, Micahel R. Kuettel, Joshua Lang, Tamara Lotan, Rana R. McKay, Todd Morgan, George Netto, Julio M. Pow-Sang, Robert Reiter, Mack Roach, Tyler Robin, Stan Rosenfeld, Ahmad Shabsign, Daniel Spratt, Benjamin A. Teply, Jonathan Tward, Richard Valicenti, Jessica K Wong. NCCN Guidelines Version 2.2023 Prostate Cancer. 2023 July 17, 2023. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
  6. Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet 2020;395(10231):1208-16. doi: 10.1016/s0140-6736(20)30314-7 [published Online First: 20200322]