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mCRPC with Bone Metastasis

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

Alicia Morgans | January 30, 2025

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.

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Dr. Alicia Morgans, MD

Alicia Morgans, MD, MPH, is a Genitourinary Medical Oncologist and the Director of the Survivorship Program at Dana-Farber Cancer Institute. A clinician and investigator, she has expertise in clinical trials and patient-reported outcome measures, as well as incorporating patient preferences and beliefs into clinical decision making. Her research has investigated complications of systemic therapy for prostate cancer survivors, including the study of skeletal, cardiovascular, diabetic, and cognitive complications. Her work has been funded by grants from the Prostate Cancer Foundation and the Department of Defense. She is a member of the advanced and localized prostate cancer treatment guidelines committee of the American Urologic Association, and is a member of the cardio-oncology committee of the American Heart Association. Since 2016, she has been President of the Medical Advisory Board for ZERO, a non-profit organization dedicated to supporting education and research funding for prostate cancer research.

Videos
Clinical Conversations by Experts
PEACE 3 Trial Results Show Promise for Radium-223 and Enzalutamide in Asymptomatic mCRPC - Fred Saad
2024 NCCN Guidelines: Managing Bone Health in Prostate Cancer Patients - Rashid Sayyid & Zachary Klaassen
Alpha vs Beta Emitters in Prostate Cancer Radiopharmaceuticals: Energy, Range, and Cytotoxicity - Alan Bryce
Safety and Disease Related Outcomes of mCRPC Patients Who Were Treated with Radium-223 Then 177Lu-PSMA (RALU) - Neal Shore
The Association Between the Time Interval Between Sequential Treatment With Radium-223 Therapy and 177Lu-PSMA in the RALU Study - Kambiz Rahbar
Sequencing Radiopharmaceuticals: Efficacy and Safety Data of Radium-223 Followed by Lutetium-177-PSMA in the RALU Study - Oliver Sartor
Optimal Treatment Sequencing with Radiopharmaceuticals After Radium-223 in Men with Newly Progressed Prostate Cancer – A Cased Based Review - Phillip Koo, Neal Shore, & Alicia Morgans
Optimizing Multi-Disciplinary Care Teams for Radiopharmaceutical Administration - Neal Shore
The Correlation Between Alkaline Phosphatase Decline and Overall Survival in Men with Metastatic Castration-Resistant Prostate Cancer in the REASSURE Study - Nicholas James
223Ra Use Before 177Lu-PSMA for Patients with Bone-predominant mCRPC, The RAdium LUtetium (RALU) Study, Journal Club - Zachary Klaassen
Multidisciplinary Care Teams to Optimize Care of Patients with Bone Metastatic CRPC - Tanya Dorff
Optimizing the Use of Radium-223 Through Multidisciplinary Collaboration - Phillip Koo
Treatment Sequencing with Radium-223 in Symptomatic Disease - Fred Saad
A Real-World Analysis of Pain Efficacy of Radium-223 Treatment Among Patients With Metastatic Castration-Resistant Prostate Cancer and Symptomatic Bone Metastases – the REASSURE Trial – Celestia Higano
Real-World Safety and Effectiveness of Radium-223 in Japanese Patients with Castration-Resistant Prostate Cancer (CRPC) and Bone Metastasis - Beyond the Abstract
The NCCN Guidelines on the Use of Radium-223 in Prostate Cancer - Tanya Dorff
Optimal Patient Selection for Treatment with Radium-223 in mCRPC Towards Improved Overall Survival and Improved Quality of Life - Brenda Martone
Ensuring Patients Have Access to Radium-223 as a Therapeutic Option: The DORA Trial - Michael Morris
The Effect of Mandated Bone Protective Agents on Fracture Risk With Longer Follow-Up (EORTC 1333 / PEACE III Trial) – Fred Saad
Radium-223 plus Enzalutamide vs Enzalutamide Alone in Metastatic Castration-Resistant Prostate Cancer - Benjamin Maughan
The Combination of Pembrolizumab and Radium-223 in Metastatic Castration-Resistant Prostate Cancer (mCRPC) - Atish Choudhury
Sequential Radium-223 Treatment of mCRPC That Progressed After First-Line Novel Antihormonal Therapy, A Real-World Clinical Outcomes Study - Oliver Sartor
Bone Health and Osteoclast Targeted Therapies in Advanced Prostate Cancer - Matthew Smith
Bone Targeted Theranostics with 18F-NaF/ 223Ra Cl2 in Prostate Cancer - Hossein Jadvar
Real-World Clinical Outcomes with Radium-223 in Metastatic Castration-resistant Prostate Cancer - Neal Shore
Radium 223 Dichloride Use in Patients with Castrate Resistant Prostate Cancer - Hossein Jadvar
The Risk of Dose De-intensifying Treatment, Bone Health in Prostate Cancer - Fred Saad
Radium-223 and Bone Health Agents: Lessons Learned Presentation - Oliver Sartor
Antiresorptive Therapy to Reduce SRE Risk For The Majority of Men with CRPC and Bone Metastases Presentation - Bertrand Tombal
Radium-223 in Clinical Practice - Phillip J. Koo
Decreased Fracture Rate When Adding Bone Protecting Agents to Radium-223: PEACE III- Bertrand F. Tombal
Real World Treatment Experience with Radium-223 - Dan George
Bone Health in Prostate Cancer - A Conversation with Neal Shore and Oliver Sartor
Physician-Scientist Review Articles
State of the Evidence Review Articles
Written by Rashid Sayyid MD, MSc and Zachary Klaassen, MD, MSc
October 30, 2024

Introduction

Radium-223 dichloride (radium-223) is a targeted alpha emitter that selectively binds to areas of increased bone turnover in bone metastases and emits high-energy alpha particles of short-range (<100 μm). Radium-223 acts as a bone-seeking calcium mimetic and binds into newly formed bone stroma, especially within the microenvironment of osteoblastic or sclerotic metastases. Double-stranded DNA breaks result secondary to the high-energy alpha-particle radiation.
Written by Rashid K. Sayyid, MD, MSc, University of Southern California, Los Angeles, CA and Zachary Klaassen, MD, MSc, Wellstar MCG Health, Augusta, GA
August 23, 2024

Introduction

The treatment landscape of metastatic castrate-resistant prostate cancer (mCRPC) has long been dominated by androgen receptor pathway inhibitors (ARPIs) and chemotherapeutic agents. There are currently, however, two radioligands that are United States Food and Drug Administration (FDA)-approved for the treatment of mCRPC patients:

Written by Zachary Klaassen, MD, MSc
February 27, 2020

Patients with advanced prostate cancer are at significant risk of skeletal-related events (SREs) due to a complex interplay between bone health and prostate cancer due to cancer biology and the predilection of prostate cancer to spread to bone, the toxicity of prostate cancer treatments, and shared epidemiology of the two conditions.

 

Written by Zachary Klaassen, MD, MSc
December 10, 2019
Prostate cancer metastases to the bone is a late manifestation of the prostate cancer disease spectrum, often painful for the patient and potentially dangerous in the setting of skeletal-related events. Among prostate cancer patients, the cumulative incidence of bone metastasis at one and five years after diagnosis is 8% and 17%, respectively1.
Written by Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
December 3, 2019
Radiopharmaceuticals are pharmaceutical agents containing radioisotopes and emitting radiation that may be used for diagnostic or treatment purposes. The ALSYMPCA trial was the first to demonstrate that radiopharmaceuticals could improve overall survival, in addition to skeletal-related events, in patients with metastatic castrate-resistant prostate cancer. On the basis of this observation, there is an ongoing effort to identify molecular targets for linkage to radiopharmaceuticals.
Written by Zachary Klaassen, MD, MSc
April 16, 2019
Prostate cancer exhibits a wide spectrum of disease behaviour. Despite the majority of cases presenting with relatively indolent biologic behaviour, prostate cancer remains the second leading cause of cancer-related death in the United States, behind only lung cancer.
Physician-Scientist Commentaries
Peer-reviewed Abstract Supplemental Commentaries
Written by Ronan Flippot, MD, MSc
The VISION trial was the first phase 3 study to demonstrate an overall survival benefit for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy lutetium-177 Lu-PSMA-617 (Lu-PSMA) over the standard of care in patients with castration-resistant prostate cancer previously treated with chemotherapy and second-generation novel hormonal agents (NHA). Following these results, Lu-PSMA has been approved in most European countries in this population.
Written by Dianne Bosch, MD & Maarten J. van der Doelen, MD, PhD
Metastatic castration-resistant prostate cancer (mCRPC) patients with symptomatic skeletal metastases can be treated with radium-223 therapy. This alpha emitter that selectively targets bone metastases was proven to be of clinical benefit in the phase 3 ALSYMPCA trial.
Written by John S. Wang, Terence Wong, Kevin A. Wu, Trey C. Mullikin, Andrew Armstrong
We present the case of a patient with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) who underwent treatment with lutetium Lu-177 vipivotide tetraxetan (also known as 177Lu-PSMA-617) due to progressive disease despite multiple lines of therapy, including chemotherapy, hormonal therapy, and radiation, encompassing palliative mediastinal and central nervous system radiation.
Conference Coverage
Conference Highlights Written by Physician-Scientist
Presented by Ana Kiess, MD, PhD
The 2024 ASTRO annual meeting included a late-breaking abstract session, featuring a presentation by Dr. Ana Kiess discussing outcomes of the RAVENS phase 2 randomized trial assessing outcomes of radium-223 + stereotactic ablative radiotherapy versus stereotactic ablative radiotherapy alone for oligometastatic prostate cancer. Previously, the STOMP1 and ORIOLE2 randomized clinical trials showed progression-free survival benefits of metastasis-directed therapy alone without ADT for oligometastatic hormone-sensitive prostate cancer:
Presented by Deborah Mukherji, MBBS, FRCP
 The 2024 ESMO annual meeting included a session on prostate cancer, featuring a discussant presentation by Dr. Deborah Mukherji discussing two abstracts including “RAPSON: Open-label, multicenter randomized trial of Radium-223 -> docetaxel versus docetaxel -> Radium-223 sequence in mCRPC with prospective biomarker evaluation” by Dr. Vincenza Conteduca and “Adding metformin to ADT for patients with mHSPC: Overall survival results from the multi-arm, multi-stage randomized platform trial STAMPEDE” by Dr. Silke Gillessen.
Presented by Vincenza Conteduca, MD
The 2024 ESMO annual meeting included a session on prostate cancer, featuring a presentation by Dr. Vincenza Conteduca discussing results from RAPSON, an open-label multicenter randomized trial of Radium-223 -> docetaxel versus docetaxel -> Radium-223 sequence in mCRPC with prospective biomarker evaluation. Defining the most effective treatment sequence between the α emitter Radium-223 and docetaxel is pivotal for optimizing bone-dominant mCRPC outcomes.
Presented by Silke Gillessen Sommer, MD
(UroToday.com) The 2024 European Society for Medical Oncology (ESMO) Annual Congress held in Barcelona, Spain between September 13th and 16th, 2024 was host to a presidential symposium of practice-changing trials. Professor Silke Gillessen presented the initial results of EORTC-GUCG 1333/PEACE-3
Presented by Kambiz Rahbar, MD
The 2024 ESMO annual meeting included a session on prostate cancer, featuring a presentation by Dr. Kambiz Rahbar discussing the final safety and efficacy analysis of RaLu assessing 177Lu-PSMA therapy in patients with prior radium‑223. Radium-223 is an established alpha particle emitting radionuclide therapy with an acceptable safety profile.
Presented by Meryam Losee, BS
At the SNMMI 2024 Annual Meeting, Dr. Meryam Losee presented the results of a study evaluating the effect of bone marrow disease on hematologic toxicity and PSA response to 177Lu-PSMA-617 therapy. 
Presented by Ashwin Sachdeva, MBBS, PhD, FRCS
The 2024 American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago, IL between May 31st and June 4th, 2024 was host to a session addressing techniques to minimize the effects of androgen deprivation therapy (ADT) while explore alternatives in prostate cancer management. Dr. Ashwin Sachdeva discussed the appropriate use and timing of bone resorptive agents in patients with advanced prostate cancer.
Presented by Amit D. Raval, PhD
The 2024 GU ASCO annual meeting featured a prostate cancer session and a presentation by Dr. Amit Raval discussing real-world utilization patterns of radium-223 in metastatic prostate cancer in the United States. Radium-223 is approved for use in men with symptomatic castration-resistant prostate cancer (CRPC) with bone metastases, demonstrating benefits in terms of overall survival and quality of life with a reliable safety profile.1
Presented by Hanbo Zhang, MD, FRCPC
The 2024 GU ASCO annual meeting featured a prostate cancer session and a presentation by Dr. Hanbo Zhang discussing a real-world analysis of survival and fracture risk with radium-223 therapy in metastatic castrate-resistant prostate cancer (mCRPC). Radium-223 is a life-prolonging radionuclide therapy for men with bone-predominant mCRPC based on the phase 3 ALSYMPCA trial.
Presented by Joe O'Sullivan, MD FRCPI, FFRRSCI, FRCR
The 2022 ESMO annual meeting featured a prostate cancer session, including a presentation by Dr. Joe O'Sullivan discussing alkaline phosphatase decline and pain response as markers for overall survival in patients with mCRPC treated with radium-223 in the REASSURE study.
Presented by Elena Castro, MD
In the on-demand poster session of the ESMO Annual Congress, Dr. Elena Castro presented results from the PRORADIUM cohort (NCT02925702) examining the effect of germline mutations on outcomes for patients treated with radium-223.
Presented by Celestia S. Higano, MD, FACP
In the on-demand poster session of the ESMO Annual Congress, Dr. Higano presented a real-world analysis of pain efficacy of radium-223 treatment among patients with metastatic castration-resistant prostate cancer (mCRPC) and symptomatic bone metastases.
Presented by Stephen A. Boorjian, MD
The AUA annual meeting’s evolving landscape of advanced prostate cancer treatment session included a talk by Dr. Stephen Boorjian discussing bone health and radionuclide therapy. Dr. Boorjian notes that there are several clinically relevant aspects of bone health in CRPC including (i) the issue of bone loss, given that the median age of patients with CRPC is similar to the age of at-risk patients for physiologic/age-related decrease in bone mineral density
Presented by Silke Gillessen, MD
Beginning with the introduction of docetaxel for metastatic castration resistant prostate cancer (mCRPC) in 2004, there has been a dramatic and rapid proliferation of systemic therapy options in advanced prostate cancer including a number of novel hormonal therapies (including abiraterone acetate and enzalutamide),
Presented by Michael J. Morris, MD
At the 2021 ASCO Dr. Michael Morris and colleagues reviewed the trial design for a phase III study to determine the clinical benefit of docetaxel versus docetaxel and Radium-223 in patients with mCRPC, the DORA trial.
Presented by Adam Kessel, medical student at the University of Utah
In this poster, the authors presented efficacy and safety results from a phase 2 single-center randomized study of enzalutamide monotherapy versus combination enzalutamide and radium-223 in progressive metatstatic castration-resistant prostate cancer (mCRPC)
Presented by Lawrence Mbuagbaw, MD, MPH, Ph.D.
At the 2021 ASCO GU, Dr. Lawrence Mbuagbaw and colleagues presented results of their real-world study evaluating clinical outcomes of patients when Radium-223 was used early (second-line) or late (third or later lines) among men with mCRPC.
Presented by Alexander Meisel, MD
The neutrophil-to-lymphocyte ratio (NLR) could be established as an important prognostic marker for the outcome of metastatic castration-resistant prostate cancer (mCRPC) patients treated with chemotherapy, steroids, and novel androgen receptor directed therapies.
Presented by Catherine H. Marshall, MD, MPH
 Immune modulation may be enhanced by radiation therapy through a variety of mechanisms, including via enhanced display of tumor-associated antigens. Furthermore, radiopharmaceutical agents have been shown to upregulate tumor antigens in prostate cancer models,1
Presented by Silke Gillessen, MD
San Francisco, CA (UroToday.com) Silke Gillessen, MD presented a study comparing two different dosing frequencies of Denusomab in patients with castration-resistant PC, and evaluating the rate of hypocalcemia in the two treatment options.
Presented by Matthew R. Smith, MD, Ph.D.
Munich, Germany (UroToday.com) Radium-223 is an alpha emitter which selectively treats bone metastases with alpha radiation.1 In a recent GU ASCO oral presentation, a radium-223 pharmacodynamic study demonstrated
Presented by Matthew R. Smith, MD, Ph.D.
Munich, Germany (UroToday.com) As has been the trend in management of advanced solid malignancies, there has been increasing interest 
Publications
Articles and Abstracts

Prostate-specific membrane antigen (PSMA)-PET was introduced into clinical practice in 2012 and has since transformed the staging of prostate cancer. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria were proposed to standardise PSMA-PET reporting.

We present the case of a patient with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) who underwent treatment with lutetium Lu-177 vipivotide tetraxetan (also known as 177Lu-PSMA-617) due to progressive disease despite multiple lines of therapy, including chemotherapy, hormonal therapy, and radiation, encompassing palliative mediastinal and central nervous system radiation.
Metastatic castration-resistant prostate cancer (mCRPC) patients with symptomatic skeletal metastases can be treated with radium-223 therapy. This alpha emitter that selectively targets bone metastases was proven to be of clinical benefit in the phase 3 ALSYMPCA trial.1
The VISION trial was the first phase 3 study to demonstrate an overall survival benefit for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy lutetium-177 Lu-PSMA-617 (Lu-PSMA) over the standard of care in patients with castration-resistant prostate cancer previously treated with chemotherapy and second-generation novel hormonal agents (NHA). Following these results, Lu-PSMA has been approved in most European countries in this population.
IMPORTANCE: Targeted alpha therapy attempts to deliver systemic radiation selectively to cancer cells while minimizing systemic toxic effects and may lead to additional treatment options for many cancer types.
San Francisco, CA (UroToday.com) -- A team of researchers led by Duke Cancer Institute scientists Steven Patierno, Ph.D.; Daniel George, MD; Jennifer Freedman, Ph.D.; Jiaoti Huang, MD, Ph.D. and Amanda Hargrove, Ph.D. have been awarded a Movember Foundation-Prostate Cancer Foundation Challenge Award. The project includes a number of key co-investigators including Terry Hyslop, PhD (Biostatistics), Michael Kelley MD and Megan McNamara MD (key clinical oncology collaborators at the Durham Veterans Administration Hospital), James Abbruzzese, MD (DCI Associate Director for Clinical Research) and Hailiang Hu, PhD (senior scientist in Pathology). Muthana Al Abo, Ph.D., MD, joins the teams as a PCF Young Investigator. The $1 million award will support a two-year project investigating targeting RNA splicing for therapeutic application in race-related aggressive and lethal prostate cancer in African American and Caucasian patients, including Veterans.
San Francisco, CA (UroToday.com) MD Anderson researchers develop a model for spying on prostate cancer and bone dynamics

Scientists at The University of Texas MD Anderson Cancer Center have engineered a system allowing microscopic monitoring and imaging of cancer that has spread to the bone in mice so they can better understand and develop treatment for bone metastasis in humans.
Radium-223 dichloride (Ra-223) is the first bone-targeting agent showing improvement in overall survival in patients with castration-resistant prostate cancer (CRPC) and bone metastases. We aimed to assess feasibility of Ra-223 treatment in patients with metastatic hormone-sensitive prostate cancer (mHSPC).
This article [1] is a comprehensive analysis of 10 prostate cancer patients who received Ra-223-treatments. These patients were imaged with multiple quantitative PET methods according to our own algorithm [2], including fluoro-18-choline-PET and sodium fluoride-18 PET. These patients were additionally treated with multidisciplinary methods, including other radiation therapies. We recently reported an overall survival of 8.4 years in 46 patients of high-risk T3-4NXM1 primarily metastatic prostate cancer [2].

The landscape of metastatic prostate cancer has changed recently with the availability of six new molecules showing an overall survival benefit. The development of compounds able to decrease the rate of complications from bone metastasis has also led to improvements in overall morbidity associated with this disease.

In the previously reported ALSYMPCA trial in patients with castration-resistant prostate cancer and symptomatic bone metastases, overall survival was significantly longer in patients treated with radium-223 dichloride (radium-223) than in patients treated with placebo.

OBJECTIVE - Prostate cancer (PC) is the most common cancer in Western countries. Recent advances in the treatment of metastatic castration resistant prostate cancer (mCRPC) have caused significant pressure on health care budgets.

BACKGROUND - Radium-223 dichloride (radium-223), a first-in-class alpha-emitting radiopharmaceutical, is recommended in both pre- and post-docetaxel settings in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases based on overall survival benefit demonstrated in the phase 3 ALSYMPCA study.

BACKGROUND - Radium-223 is a bone-targeting radiopharmaceutical that extends survival in mCRPC. Postapproval data are limited, and the value of biochemical and radiologic monitoring during radium therapy is unknown.

Improving options for patients with metastatic castration-resistant prostate cancer (mCRPC) provide latitude in designing treatment plans that meet patients' medical needs and personal goals.

Even when symptoms, such as pain, impose significant impacts on their daily lives, many men with advanced prostate cancer do not report the symptoms to their doctors, according to an international survey of both patients and their caregivers to explore this issue. Symptoms may go unrecognized as being associated with cancer, or men deliberately choose not to speak about them with their doctors. As a result, they may not receive interventions that could ease the discomfort.

BACKGROUND - Radium-223 prolongs overall survival in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases, regardless of prior docetaxel. Whether or not chemotherapy can be safely administered following radium-223 treatment is of clinical importance.