Radium-223: Sequence or Overlay in Advanced Prostate Cancer (mCRPC)?

Steven Eric Finkelstein, MD

Dr. Steven Eric Finkelstein

Steven Eric Finkelstein, MD

According to the National Cancer Institute, 238,598 new cases of prostate cancer will have been diagnosed in 2013. More than 90% of men with symptomatic metastatic castration-resistant prostate cancer (mCRPC) have radiologic evidence of metastasis to bone either on technetium SPECT or sodium fluoride PET/CT bone scan.

Unlike with other cancers, it appears that death from mCRPC is often due to bone disease and its subsequent complications. Bone metastasis can cause intense pain, weakness, and bone fractures, greatly impairing patent quality of life, and is associated with disability, increased cost of treatment, and death. In a recent study with mCRPC, the 5-year overall survival (OS) of men with bone metastases was approximately 3%. Treatment options for patients with advanced stage prostate cancer have traditionally been limited. Indeed, the main focus of treatment at this clinical juncture is to improve the quality of life; however, new agents are aiming to improve OS.

On May 15, 2013, the US Food and Drug Administration approved radium-223 dichloride (radium-223; Xofigo; Bayer HealthCare Pharmaceuticals and Algeta ASA) for the treatment of patients with mCRPC with symptomatic bone metastases and no known visceral metastatic disease. This is the sixth novel agent for advanced prostate cancer approved in the past 5 years. Radium-223, the first of its class of alpha-particle emitting radiotherapeutics, mimics calcium and forms complexes with hydroxyapatite at areas of increased bone turnover, such as bone metastases, and kills the prostate cancer cells by causing double-stranded DNA breaks.

As a first-of-its-kind therapy to have significant focused impact on multiple systemic bone metastases, the ability of radium-223 to target lesions with such precision as opposed to beta/gamma-emitting radiotherapeutics or chemotherapy may be revolutionary. The approval of radium-223 was based on ALSYMPCA—a double-blind, randomized, placebo-controlled trial in patients with mCRPC with symptomatic bone metastases and no known visceral metastatic disease.1 In his article, “Radium-223 Dichloride: A Novel Treatment for CRPC and Symptomatic Bone Metastases,” on page 6 of this issue, Nicholas J. Vogelzang, MD, details early clinical experience with radium-223, as well as the results of ALSYMPCA and the practical implications of the use of radium-223 for clinical oncologists. In brief, patients were allocated 2:1 to radium-223, 50 kBq/kg (1.35 microcurie/kg), intravenously, every 4 weeks for 6 cycles plus best standard of care (n = 541) or to matching placebo plus best standard of care (n = 268). With respect to key findings, at the prespecified interim analysis a statistically significant improvement in OS was demonstrated (hazard ratio [HR] 0.70; 95% confidence interval [CI] 0.55-0.88; P = .002). The median OS was 14.0 and 11.2 months in the radium-223 and placebo arms, respectively. The OS benefit in ALSYMPCA was supported by a delay in time to first symptomatic skeletal event favoring the radium-223 arm. Thus, this is considered by many to be an agent given to improve OS rather than just for palliative intent.

This agent may also be quite favorable with respect to side effect profile. Alpha particle range from radium-223 is <100 μm (<10 cell diameters), which limits damage to surrounding normal tissue. The most common (≥10%) adverse events in patients receiving radium-223 were nausea, diarrhea, vomiting, and peripheral edema.2 The most common (≥10%) hematologic laboratory abnormalities were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia.2 Thus, based on ALSYMPCA, the recommended dose and schedule for radium-223 is 50 kBq/kg (1.35 microcuries/kg) administered by slow intravenous injection over 1 minute every 4 weeks for 6 doses.

Yet even as radium-223 is coming into use in clinical practice, numerous key questions remain as to how to best utilize this novel agent. Future clinical trials will need to address the vital issues regarding whether 6 doses are optimal, gather data in specific patient subgroups, and test combinations with other agents such as stereotactic body radiation therapy.

Additionally, there are important questions to be answered, such as the appropriate sequencing of agents for mCRPC in the larger context of magnitude of response/survival benefit and risk/safety profile of various approved agents (hormonal agents, bone-targeted agents, immunotherapy agents) in the CRPC space. There are now 10 agents of potential use for mCRPC: 1) Xofigo (radium-223 dichloride)—an alpha particle-emitting radioactive therapeutic agent; 2) Provenge (sipuleucel-T)—an autologous cellular immunotherapy; 3) Zytiga (abiraterone acetate)—a CYP17 inhibitor used with prednisone; 4) Xtandi (enzalutamide)—an androgen receptor inhibitor; 5) Taxotere (docetaxel)—a microtubule inhibitor; 6) Jevtana (cabazitaxel)—a microtubule inhibitor; 7) Xgeva (denosumab)—a RANK ligand inhibitor; 8) Zometa (zoledronic acid)—a bisphosphonate; 9) Metastron (strontium-89)—a beta particle-emitting radioactive isotope; and 10) Quadramet (samarium-153)—a beta/gamma particle-emitting radioactive isotope. The Table shows selected phase III trials in mCRPC demonstrating an improvement in OS, with the understanding that differences in inclusion and exclusion criteria make it difficult to directly compare clinical trials. The National Comprehensive Cancer Network supports the use of radium-223 as first-line therapy for patients with symptomatic mCRPC with a Category 1 recommendation.

For the future, it may not be an ultimate question of sequence— it may be a question of overlay. In a few years, clinicians may overlay multiple synergistic agents with greatly different mechanisms of action against mCRPC. As is the case in the management of other diseases, the confluence of combinations of agents may need to be the rule and not the exception.

For now, as patients progress with bone-predominant disease on newer agents, single agent radium-223 (with OS benefit supported by delay in time-to-first symptomatic skeletal event) seems a logical choice for community physicians.1

Thus, radium-223 is uniquely positioned to be a first-line option for a large number of patients, as >90% of men with symptomatic mCRPC have bone metastases. In the phase III AFFIRM study evaluating enzalutamide versus placebo in patients with mCRPC previously treated with chemotherapy, 91.5% to 92.2% of patients had bone metastases at enrollment.3 With respect to the phase III COU-AA-301 study evaluating abiraterone acetate plus prednisone versus placebo plus prednisone in patients with mCRPC previously treated with docetaxel, up to 90% of patients had bone metastases at enrollment.4 Lastly, the phase III TAX 327 study evaluating weekly docetaxel plus prednisone, versus every 3 week docetaxel plus prednisone versus mitoxantrone plus prednisone in patients with mCRPC, 90% to 91% of patients had bone metastases at initial enrollment.5 With respect to the lack of PSA changes and response evaluation with radium-223, how to fit this agent into clinical practice seems to be an area of contention between different practitioners.

Signs of disease progression may include rising PSA, radiographic progression, or progression of clinically measurable disease. Use of standard of care radiologic evidence of metastasis to bone on sodium fluoride PET/CT bone scan at baseline and post therapy may help to better define the disease burden and outcome of patients.

Knowing the truth with respect to anatomic sites of prostate cancer disease burden and developing more anatomically targeted treatment strategies makes sense for community physicians. The coupling of advancements in prostate cancer imaging with targeted novel therapy such as radium-223 and/or other directed therapy against bone sites may elicit badly needed gamechanging strides in bone-predominant mCRPC. Taken together, this is an extremely exciting time for patients and doctors battling advanced prostate cancer; future studies will further optimize the confluence of agents in the mCRPC space.

Table. Selected Phase III Trials in mCRPC Demonstrating an Improvement in Overall Survival

Study Control vs experimental arm Patient population Mean change OS (mo) OS (mo) Toxicity
TAX3275 Mitoxantrone/ prednisone vs docetaxel/prednisone Advanced CRPC (n = 1006) 2.9 16.3 vs 19.2 (HR = 0.79; P = .004) AEs greater in docetaxel arm
TROPIC6 Mitoxantrone/ prednisone vs cabazitaxel/prednisone After docetaxel mCRPC (n = 755) 2.4 12.7 vs 15.1 (HR = 0.70; P <.0001) Grade 3 neutropenia (82 vs 58%) Grade 3 diarrhea (6% vs 1%), cabazitaxel vs control arm
COU-AA-3014 Placebo/prednisone vs abiraterone acetate/prednisone After docetaxel mCRPC (n = 1195) 4.6 11.2 vs 15.8 (HR = 0.74; P <.0001) Grade 3-4 fatigue (9% vs 10%), anemia (8% vs 8%), back pain (7% vs 10%), bone pain (6% vs 8%), abiraterone acetate vs placebo groups
AFFIRM3 Placebo vs enzalutamide After docetaxel mCRPC (n = 1199) 4.8 13.6 vs 18.4 (HR = 0.63; P <.001) AEs greater in enzalutamide group (fatigue, diarrhea, hot flashes with seizures were reported in 5 patients, 0.6%)
COU-AA-3027 Placebo/prednisone vs abiraterone acetate/prednisone A symptomatic or minimally symptomatic mCRPC (n = 1088) NA 27.2 vs median not reached (HR = 0.75; 95% CI, 0.61- 0.93; P = .01) However, the prespecified boundary for significance (P ≤.001) was not reached at the observed number of events Grade 3-4 mineralocorticoidrelated AEs and abnormalities on liver-function testing were more common with abiraterone/prednisone
PREVAIL8 Placebo vs enzalutamide Chemotherapynaïve patients with mCRPC (n = 1717) NA Estimated median OS was 32.4 mo (95% CI, 31.5– upper limit not yet reached) in the enzalutamide arm vs 30.2 mo (95% CI, 28–upper limit not yet reached) in the placebo arm Grade 3 or higher cardiac AEs were reported in 2.8% of enzalutamide vs 2.1% of placebo-treated patients
IMPACT9 Control vs sipuleucel-T A symptomatic or minimally symptomatic mCRPC (n = 512) 4.1 21.7 vs 25.8 (HR = 0.775; P = .032) Grade 3 acute infusion reactions were reported in 3.5% and included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported
ALSYMPCA1,2 Placebo + standard care versus radium-223 dichloride + standard care Symptomatic mCRPC with bone metastases; 50% were chemotherapynaïve (n = 921) 3.6 11.3 vs 14.9 (HR = 0.70; P = .00007) Grade 3-4 neutropenia in 2.2% vs 0.7% Grade 3-4 thrombocytopenia in 6.3% vs 2%, radium-223 dichloride vs placebo

AEs, adverse events; CI, confidence interval; HR, hazard ratio; mCRPC, metastatic castration-resistant prostate cancer; mo, months; NA, not applicable; OS, overall survival.


Affiliation:Steven Eric Finkelstein, MD, is national director, 21st Century Oncology Translational Research Consortium; adjunct associate professor, Translational Genomics Research Institute; director, TRC Animal Radiation-Imaging-Immunotherapy Experimental Laboratory (ARIEL); and executive director, Arizona Cancer Research Alliance.

Disclosures:Dr. Finkelstein has served as a consultant or on a paid advisory board for Dendreon Corporation, Medivation, Inc/Astellas Pharma Inc, Bayer HealthCare Pharmaceuticals/Algeta ASA, Spectrum Pharmaceuticals, and Blue Earth; has grants pending from Dendreon Corporation, Medivation, Inc/Astellas Pharma Inc, and Bayer Health- Care Pharmaceuticals/Algeta ASA; has received grants from Dendreon Corporation and Bayer HealthCare Pharmaceuticals/Algeta ASA; and has received lecture fees for speaking at the invitation of Dendreon Corporation and Bayer HealthCare Pharmaceuticals/Algeta ASA.

Address correspondence to: Steven Eric Finkelstein, MD, 21st Century Oncology TRC Headquarters, 7340 E Thomas Road, Scottsdale, Arizona 85259.

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