Review of Radium-223 and Metastatic Castration-Sensitive Prostate Cancer

Abstract

Background:

Radium-223 is approved for treatment of bone metastases in metastatic castration-resistant prostate cancer (mCRPC). After the ALSYMPCA trial showed overall survival benefit with the addition of radium-223 to standard of care in mCRPC in 2013, there have been numerous publications and trials using radium-223 in mCRPC. Recently, there has been interest in using radium-223 earlier in the metastatic prostate cancer timeline, in metastatic castrate-sensitive prostate cancer (mCSPC); however, currently, radium-223 in mCSPC treatment is investigational.

Aim:

A literature search was conducted to review the use of radium-223 in mCSPC treatment from 1980 to 2019. A review of both radium-223 articles and abstracts was performed. Search terms included metastatic prostate cancer and radium-223, mCSPC, hormone-sensitive metastatic prostate cancer, radium-223, and oligometastatic disease. The results were limited to studies involving multiple patients with mCSPC.

Conclusion:

There are a limited number of studies of radium-223 in mCSPC treatment and the authors report on these studies (two published studies and four ongoing trials). Trials are currently underway to assess if radium-223 could be used in mCSPC as a treatment for bone metastases and micrometastases. Future data from these trials will be informative as to the benefit of radium-223 in mCSPC treatment and may change treatment paradigms for mCSPC. This review will focus on trials assessing the role of radium-223 in mCSPC.

Background

Over the past 5 years, there has been progress in development of novel drugs for metastatic prostate cancer and there are several new drugs that can be used in the frontline setting.^1
–3 Most of the breakthroughs have been in systemic treatments still targeting the hormone-sensitive nature of prostate cancer (metastatic castrate-sensitive prostate cancer [mCSPC]). Metastatic prostate cancer patients are divided into two groups: mCSPC and metastatic castration-resistant prostate cancer (mCRPC). mCSPC is also termed metastatic, hormone-sensitive prostate cancer (mHSPC).

This review article uses the term mCSPC for clarity to distinguish studies in the setting of mCRPC versus mCSPC using both acronyms to differentiate the responsiveness to castration therapy. Overall, mCSPC patients are earlier in the timeline of their metastatic prostate cancer disease. mCSPC patients may have oligometastatic disease when newly diagnosed with prostate cancer or they may have metastatic disease diagnosed after treatment of the prostate primary. The common thread in mCSPC patients is that they are still sensitive to hormone treatment (i.e., androgen deprivation treatment [ADT]), the backbone of treatment for metastatic prostate cancer.

According to the NCCN (National Comprehensive Cancer Network), there are many systemic nonradiation treatment options for mCSPC in combination with ADT, including abiraterone, docetaxel, enzalutamide, and apalutamide.⁴ All of these treatment options have level 1 evidence. Recently, there has been one radiation option, external beam radiation therapy (EBRT), for the prostate primary in the setting of low-volume metastatic disease, according to the STAMPEDE (Systemic Therapy for Advancing or Metastatic Prostate Cancer) randomized study.⁵ To date, radium-223 has not been used in large studies on mCSPC and is the subject of this review article.

Radium-223 and mCSPC Timeline

Radium has had an interesting history in prostate cancer and radiation oncology since the early 1900s. As early as 1913, radium was used to treat an enlarged prostate and shown to cause atrophy of the prostate hyperplasia.⁶ Since then, radium has been used for a variety of other malignancies usually with direct application using needles or catheters.⁷ To quote the early article by Gordon–Watson, “radium is like a wild horse which must first be tamed, before it can be harnessed…. Whether it will take a place as a leader, or wheeler, or as a spare, remains to be seen.”⁷

Radium-223 received Food and Drug Administration (FDA) approval in 2013 for mCRPC.³ Radium-223 targets lesions with bone turnover, thus making it very useful for treating metastatic bone lesions in prostate, and due to its inherent alpha decay properties, there is less normal tissue affected by radium-223 versus its older counterparts, samarium and strontium.⁸

A pivotal trial, the ALSYMPCA trial, documented the benefit of radium-223 in metastatic prostate cancer, that is, in mCRPC.^1,9 In this phase III randomized trial, patients were given radium-223 only after most standard of care options for mCRPC had been exhausted and, in a majority of cases, included prior chemotherapy and/or palliative radiation EBRT.^1,10 Radium-223 is FDA approved in mCRPC treatment and is used in clinical practice based on the ALSYMPCA data. Overall survival benefit was reported in the ALSYMPCA trial with addition of radium-223.¹ Its alpha decay properties also make it attractive for use in the clinic as it requires minimal shielding and can be given through IV in an outpatient setting; treatment is a 1-min IV push and monitoring is usually complete in less than 1 h.¹ A full treatment schedule comprises one injection once a month for 6 months.

Radium-223 is well tolerated and has now been used in many mCRPC trials. Most of the literature on radium-223 focuses on treating symptomatic mCRPC usually after many lines of metastatic treatment that may include second-generation androgen pathway inhibitors and docetaxel chemotherapy.¹¹ Recently, trials using radium-223 when patients are not symptomatic have been reported, with promising results.¹² Phase III trials have just started to assess early use of radium-223 in a patient's treatment paradigm, although only after a patient is deemed castration resistant, that is, mCRPC and not mCSPC.¹²

Heidenreich et al. recently completed a phase IIIb study on asymptomatic mCRPC patients. These patients had to have bone-predominant metastatic disease and no visceral metastases; lymph nodes <6 cm were allowed in this study.¹² Asymptomatic mCRPC patients had better prostate-specific antigen (PSA) response and better overall survival.¹² This trial suggests that radium-223 should be considered earlier in the metastatic prostate cancer timeline and may have more benefit than reported in the original ALSYMPCA trial.¹ This seems logical given that radium-223 can induce double-stranded DNA breaks and thus cancer cell death similar to EBRT.² This is already an early signal that radium-223 may provide more use than just bone metastasis palliation.

Another intriguing idea is that radium-223 may reverse mCRPC to mCSPC based on a case report by Ricci et al.¹³ Ricci et al. reported on one patient who converted from mCRPC to mCSPC after administration of radium-223.¹³ In the case report by Ricci et al., the patient in question had a complete response (CR) to radium-223. Fifteen months later, the patient progressed, but was now hormone sensitive, that is, mCSPC, and was treated accordingly. The change back to mCSPC potentially alters prognosis to a more favorable condition.¹³ This suggests that the castration status of prostate cancer is on a continuum and that novel treatment combinations involving radiation may affect the hormone-sensitive status of metastatic prostate cancer patients.

Other articles have suggested that EBRT can help partially revert mCRPC and increase patient sensitivity to hormone-sensitive agents; an exploratory analysis of 15 patients by Lohaus et al. demonstrated PSA response in 11 patients.¹⁴ Radium-223 has limited toxicity and this is another factor leading to the interest in using radium-223 earlier in the timeline of treating metastatic prostate cancer patients.^15,16

There are no data to suggest that radium-223 may work better in mCRPC versus mCSPC treatment because the mechanism is similar to EBRT; radium-223 can cause double-strand breaks in DNA. The early use of radium-223 has probably not been pursued until recently because there are many systemic nonradiation options for patients with mCSPC. To date, there have been no randomized trials incorporating radium-223 in mCSPC treatment. The authors' review article discusses potential future application of radium-223 in the mCSPC setting. It is a brief, but comprehensive, review of studies using radium-223 in the mCSPC setting.

This review will highlight studies recently completed and studies currently underway that are focused on using radium-223 in mCSPC treatment. Six studies are highlighted in this review article. The studies are safety and feasibility studies using a combination of treatments for mCSPC.^16,17 There are four ongoing studies using radium-223 in mCSPC treatment with some combination of EBRT, stereotactic body radiation therapy (SBRT), and ADT. The hypothesis in the current studies is that radium-223 will help treat micrometastases, while the SBRT and EBRT treat the gross macrometastatic disease in limited volume metastatic (i.e., oligometastatic) prostate cancer patients.

Materials and Methods

A literature search was conducted to review the use of radium-223 in mCSPC treatment from ∼1980 to 2019. PubMed, Web of Science, and Scopus were queried. A comprehensive search of radium-223 articles and abstracts was performed. Search terms included metastatic prostate cancer and radium-223, mCSPC, hormone-sensitive metastatic prostate cancer, radium-223, and oligometastatic disease.

Results

To date, only six articles and abstracts used radium-223 in mCSPC treatment. This section details the two published studies and four ongoing trials documenting early use of radium-223 in mCSPC patients. The use of combination therapy with radium-223 is variable and so each trial has its own caveats also detailed in the subsections below.

Combination treatment with radium-223 and ADT alone for mCSPC patients

A small study by Osvaldo et al.¹⁵ analyzed the compassionate use of radium-223 in mCSPC patients¹⁵ (Study No. 1, Table 1). In this study, seven patients were treated with six cycles of radium-223 and ADT.¹⁵ Side-effects were as expected, with moderate changes in neutrophils and hemoglobin. Although ADT alone is known to have benefits in mCSPC treatment, there was some improvement in pain with the addition of radium-223.¹⁵ All patients underwent ¹⁸F-NaF positron emission tomography and computed tomography (PET/CT) scans for imaging assessment. Four patients had a significant standardized uptake value (SUV) change in ¹⁸F-NaF PET/CT after just three cycles of radium-223, suggesting that ¹⁸F-NaF PET/CT helps predict treatment responses.¹⁵ This early feasibility study suggests that radium-223 can be safely given to mCSPC patients and already hinted that ¹⁸F-NaF PET/CT may help predict the response to radium-223, similar to reports of ¹⁸F-NaF PET/CT predicting radium-223 response in mCRPC patients.¹⁵ This is only a hypothesis-generating observation since the confounding factor is the concomitant use of ADT.^18,19 This is one early study reporting on the use of radium-223 in mCSPC patients.

Table 1.

List of Current and Ongoing Radium-223 Trials in Metastatic Castrate-Sensitive Prostate Cancer

Study No.	Radium-223 trials in mCSPC	Patient No.	ADT	Chemotherapy	Local treatment for prostate primary (Y/N); (type: EBRT or RP)	SBRT/SABR	Completed/ongoing	Tumor response
1	Osvaldo et al. (2017)¹⁵	7	Yes	No	No	No	Completed	PR: 4 patients (57%)
2	Wenter et al. (2017)¹⁶	10	Yes	No	Yes; RP	No	Completed	PR: 3 patients (30%)
3	ADRRAD³	30	Yes	Y—prestudy docetaxel allowed	Yes; EBRT 74Gy (37fx) to prostate, 60Gy (37fx) to pelvic lymph nodes	No	Ongoing	PR: 7 patients
4	Radium Ra-223 Dichloride, Hormone Therapy, and SBRT in Treating Patients with Metastatic Prostate Cancer¹¹ NCT#03361735	24	Yes	No	Yes: EBRT or RP—prestudy	Yes; Bone: 27Gy (3fx)	Ongoing	N/A
5	Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to Bone (RROPE) NCT#03304418	20	No	No	Yes; EBRT	Yes; Bone: 16Gy (1fx) Bone: 24Gy (3fx) Bone 30Gy (5fx) Prostate: 32.4Gy (6fx)	Ongoing	N/A
6	Radium-223 and SABR vs. SABR for Oligometastatic Prostate Cancers (RAVENS) NCT#04037358	64	No	No	Yes; EBRT or RP	Yes; Bone: 1–5fx	Ongoing	N/A

Fx, number of radiation fractions; Gy, gray.

ADT, androgen deprivation therapy; CR, complete response; EBRT, external beam radiation therapy; mCSPC, metastatic castrate-sensitive prostate cancer; N/A, not applicable; PR, partial response; SBRT, stereotactic body radiation therapy; SABR, stereotactic ablative body radiotherapy.

Combination treatment with radium-223, ADT, and radical prostatectomy for mCSPC patients

Wenter et al.¹⁶ assessed the feasibility of using radium-223 in mCSPC treatment in another small case series of 10 patients. Of the 10 patients, 7 were able to complete the six standard cycles of radium-223¹⁶ (Study No. 2, Table 1). ADT was given concurrently with the radium-223, but not docetaxel or abiraterone. This is another case series documenting radium-223 use in mHSPC. The patients in this study typically had widespread metastatic bone disease.¹⁵ Even with this high metastatic burden, seven patients had some response. Of those seven patients, three patients had CR and four patients had SD. Three patients had significant treatment response to radium-223 and ADT, as assessed by bone scan imaging.¹⁶ These are intriguing data because they suggest that in some patients, radium-223 may provide a robust response analogous to addition of docetaxel or abiraterone with lesser side-effects and impact on quality of life, although the confounder is that some patients respond favorably to ADT alone.^20
–22 They also suggest that there are subsets of bone metastases that respond better to radium-223. Imaging biomarker studies in future may help delineate which patients respond best to radium-223, and the authors have listed below potential imaging biomarkers that could be utilized in ongoing trials.

Ongoing Trials of Combination Treatment with Radium-223 and/or SBRT, EBRT, RP, and ADT for mCSPC

Combination treatment with radium-223, ADT, and prostate EBRT in mHSPC patients

The previous trial by Wenter et al.¹⁶ assessed the use of radium-223 in patients who received radical prostatectomy as their definitive treatment of the prostate. Recent trials (HORRAD and STAMPEDE) have suggested that EBRT for the prostate primary tumor can also have benefit in subsets of patients with mCSPC.^5,23 The subset benefit is for mCSPC patients with low-volume metastatic disease (i.e., oligometastatic disease based on STAMPEDE and CHAARTED [Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer] criteria).^24,25 EBRT for the prostate is currently part of the NCCN guidelines for mCSPC patients with low-volume metastatic disease. The evidence is not considered level 1 as it was a subset analysis of the STAMPEDE phase III trial. The low-volume metastatic disease subset of the STAMPEDE trial was preplanned and showed overall survival benefit of adding prostate EBRT in mCSPC treatment.

The first ongoing trial using radium-223 and concurrent prostate EBRT in mCSPC treatment is the ADDRAD trial (Study No. 3, Table 1). This is an ongoing trial analyzing the use of radium-223 in patients who receive definitive prostate radiation EBRT instead of radical prostatectomy for their prostate primary.³ In this trial, radium-223 is given concurrently with whole pelvis radiation (74Gy to the prostate and 60Gy to the pelvic lymph nodes). Thirty patients are planned for accrual, 20 patients have been accrued thus far. The results of 10 patients on the ADRRAD trial were just presented in abstract form in 2018.³ So far, the trial shows limited grade 3 adverse events: 4.2%. Seven of the 10 patients had partial response on whole-body magnetic resonance imaging. This trial suggests that radium-223 can be used safely in the mCSPC setting. Moreover, this trial allowed the use of docetaxel before starting radium-223, so it will be useful to assess the biochemical control and progression-free survival of patients who received docetaxel, prostate EBRT, and radium-223 versus historical controls of docetaxel alone, as per the CHAARTED trial.^20,21

Ongoing oligometastatic mCSPC trials: radium-223 to treat micrometastatic disease in mCSPC patients

The previous trials used radium-223 for stage IV mCSPC patients with numerous bone metastases. Recently, radiation oncology has been used in aggressive treatment of a subset of these patients with limited bone metastases (i.e., oligometastatic disease) through localized radiation treatment (i.e., SBRT).²⁶ Hellman and Weischelbaum first discussed the notion of oligometastases and that there may be some patients who may present with stage IV, but only limited stage IV.²⁷ If one could control the oligometastatic lesions, then theoretically one could clear the disease by localized treatments such as radiation. With the advent of SBRT, ablative local control of oligometastatic lesions became more a reality over palliative treatment.²⁶ Recent trials have been published on the use of SBRT in oligometastatic disease. Two studies were prostate specific (POPSTAR and STOMP) and both trials suggested that not all men need continuous, lifelong systemic treatment.^26,28 None of these randomized trials incorporated radiopharmaceuticals such as radium-223, which may help delay further need for systemic treatment, in a subset of metastatic prostate cancer patients. There are three ongoing studies on NCI clinical trials.gov addressing this question in oligometastatic patients. All three hypothesize that administering radium-223 earlier could help treat micrometastatic lesions not depicted on current imaging.

NCT#03361735: ADT, SBRT, and radium-223 in mCSPC

At City of Hope, the authors first proposed using radium-223 in oligometastatic mCSPC treatment in 2015 after the results of the ALSYMPCA trial were published.¹¹ At this point, there were already a number of centers conducting trials on SBRT alone for oligometastatic disease (STOMP and POPSTAR).^26,28 City of Hope had also already conducted a trial of oligometastatic mCSPC treatment initiated in 2005, NCI#00544830,⁵ and reported that treating all oligometastatic diseases and then stopping ADT were feasible for a prolonged period of time.²⁹ In this previous trial, the authors had combined 9 months of ADT with radiation to the prostate as well as palliative radiation to all oligometastatic sites (≤5 bone metastases).²⁹

The authors' current City of Hope phase II oligometastatic prostate cancer study combines SBRT with radium-223 and short-course ADT in mCSPC treatment (NCT#03361735)^11,30 (Study No. 4, Table 1). The study is entitled: Radium Ra-223 Dichloride, Hormone Therapy, and SBRT in Treating Patients with Metastatic Prostate Cancer. The primary endpoints are time to treatment failure as per PSA guidelines and the objective response rate. There are data to suggest that ADT sensitizes prostate cancer cells to radiation and so the authors have kept the use of ADT in their treatment paradigm.^31,32 In the authors' institutional experience, four patients have completed six cycles of radium-223 (similar to the ALSYMPCA trial) in their trial and a fifth patient completed the treatment protocol off trial.¹¹ The feasibility results of these five patients will be reported in a future publication as the authors continue to accrue information to the study.¹¹

NCT#03304418: SBRT and radium-223 in mCSPC

A second phase IIa trial of radium-223 in combination with SBRT for bone metastases and prostate radiation is being conducted at the University of Utah (NCT#03304418) (Study No. 5, Table 1). The study is entitled: Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to Bone (RROPE). No systemic treatment is allowed during this trial. Endpoints include time to ADT use as well as quality of life metrics and overall survival. Results are pending. It will be interesting to compare this study with STOMP that applied SBRT or surgery only to oligometastatic sites.²⁶

NCT#04037358: SBRT +/− radium-223 in mCSPC

A third randomized phase II trial of radium-223 and stereotactic ablative body radiotherapy (SABR)/SBRT versus SABR/SBRT alone has recently started accrual at Johns Hopkins (NCT#04037358) (Study No. 6, Table 1). The study is entitled: Radium-223 and SABR versus SABR for Oligometastatic Prostate Cancers (RAVENS). In this trial, patients will be randomized to the addition of radium-223 in combination with SABR/SBRT to assess if addition of radium-223 delays progression compared with SBRT alone. No ADT will be administered during this trial. Endpoints include progression-free survival. These three trials will help determine if SBRT and radium-223 are safe and if the combination of external and internal radiation is potentially better than SBRT alone (Table 1).

Assessment of response to radium-223 in mCSPC patients

This literature review was conducted to report on trials of radium-223 in early metastatic prostate cancer, mCSPC. There are very limited data given the extensive number of treatment paradigms existing for mCSPC. Due to the fact that there are already a number of level 1 systemic drugs that are used in mCSPC treatment, one needs to find the best population for early radium-223 use versus these other agents. Biomarkers and more selective imaging studies would help in this situation and could be proposed as amendments to the ongoing trials listed above. Currently, NCCN recommends bone scan and CT scan as the standard imaging modalities for metastatic prostate cancer patients.

One imaging agent proposed as a predictor of radium-223 response is ¹⁸F-NaF PET/CT.³³ The mechanism of ¹⁸F-NaF is similar to ^99mTc bone scans, in that both target the hydroxyapatite on bone surfaces.³⁴ In the case of ¹⁸F-NaF, this interaction generates fluoroapatite.³⁴ The uptake of ¹⁸F-NaF is a marker of bone remodeling.³⁴ In an early study by Cook et al., five patients with mCRPC were imaged by ¹⁸F-NaF PET/CT pre- and post-radium-223.¹⁸ Three patients who had a PSA decline also had decrease in SUV of the ¹⁸F-NaF PET/CT after one cycle (only one cycle of the six cycles was administered in this early pilot study).¹⁸ The extent of uptake on ¹⁸F-NaF PET/CT may even predict risk of skeletal-related events (SREs) in patients treated with radium-223 as per the study by Etchebehere et al.¹⁹ Of 42 patients with mCRPC, patients with high average SUV of disease had an odds ratio of 1.3 for an SRE.¹⁹

¹⁸F-NaF PET/CT has been shown to be a predictive biomarker for radium-223 by Murray et al. Murray et al. demonstrated that ¹⁸F-NaF PET/CT before and after the first cycle (first of six planned cycles) of radium-223 could predict the response to treatment by the SUV (baseline uptake) of ¹⁸F-NaF PET/CT.³³ They were able to show that the level of SUV of ¹⁸F-NaF PET/CT correlated with the uptake of radium-223. The same imaging modality, ¹⁸F-NaF PET/CT, has also been shown recently as a predictor of SBRT response in metastatic prostate cancer patients.³⁵ Hardcastle et al. demonstrated SUV max decrease in ¹⁸F-NaF PET/CT scans after SBRT for prostate bone metastases in 29/33 lesions.³⁵ Three lesions with progression showed an increase of SUV max after SBRT on the ¹⁸F-NaF PET/CT, and one patient with increase of SUV max had a fracture.³⁵ Langsteger et al. believe that ¹⁸F-NaF PET/CT should replace bone scans due to better spatial resolution and better image quality.³⁶ Ongoing trials could incorporate ¹⁸F-NaF PET/CT so that the response to any radiation can be assessed, that is, radium-223, EBRT, or SBRT. Newer imaging scans such as prostate-specific membrane antigen (PSMA)-based PET/CT may also help assess the response to radium-223.

Discussion

This concise review article highlights the use of radium-223 in mCSPC treatment. From their literature search, the authors identified two completed studies and four ongoing trials. These six studies have been reviewed in this article. The early data from the two published studies suggest that radium-223 is safe in the early mCSPC setting. The four ongoing trials will help determine both safety and preliminary efficacy of radium-223 in combination with EBRT, SBRT, and ADT. Each trial has a different patient population and a combined review of all data will help guide treatment decisions on the use of radium-223 in mCSPC treatment.

The results of these trials in the upcoming years may suggest a novel role for radium-223 in mCSPC treatment. Ultimately, phase III data will be needed to provide level I evidence on the timeline of administering radium-223 sequentially, or with standard chemotherapy or hormonal agents (docetaxel and abiraterone), to mCSPC patients.^21,22 Radium-223 could be one of a new class of radiopharmaceuticals that can treat micrometastatic disease in stage IV prostate cancer patients. If radium-223 is found to be beneficial in delaying bone progression, other α-emitters conjugated to disease-specific molecules (i.e., PSMA) may also prove to be of therapeutic use in mCSPC treatment especially for patients with more visceral disease over bone disease.

Combination therapy of radiopharmaceuticals may be the future. With the widespread use of SBRT to treat gross macrometastatic disease, radiopharmaceutical agents may show more benefit in treating micrometastatic disease. Recent studies that incorporate biomarkers, both imaging studies and immune correlatives, will help delineate who benefits most from radium-223 use. Multiple iterations of combination therapy (radium-223, EBRT, SBRT, systemic treatment, and surgery) could then be devised for mHSPC/mCSPC patients. The future may well see radium-223 as a “leader” and not just a “spare.”⁷

Footnotes

Acknowledgment

The author(s) wish to thank Andrea Lynch, City of Hope Library Services, for her assistance with the literature search.

Disclosure Statement

Bayer is sponsoring the investigator (Dandapani) who initiated the trial of radium-223 in combination with SBRT and ADT.

Funding Information

No funding was received for this paper.

References

Parker

, Nilsson

, Heinrich

, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med, 2013; 369:213.

Morris

, Corey

, Guise

, et al. Radium-223 mechanism of action: Implications for use in treatment combinations. Nat Rev Urol, 2019; 16:745.

Turner

, Jain

, Mitchell

, et al. First results from the ADRRAD trial—Combination androgen deprivation therapy (ADT), whole pelvis radiotherapy (WPRT) and radium 223 in recently diagnosed metastatic hormone sensitive prostate cancer (MHSPCa). Clin Oncol, 2018; 30:196.

Weiner

, Nettey

, Morgans

. Management of metastatic hormone-sensitive prostate cancer (mHSPC): An evolving treatment paradigm. Curr Treat Options Oncol, 2019; 20:69.

Parker

, James

, Brawley

, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): A randomised controlled phase 3 trial. Lancet, 2018; 392:2353.

Young

. The use of radium and the punch operation in desperate cases of enlarged prostate. Ann Surg, 1917; 65:633–641.

Gordon-Watson

. How far can radium replace radical surgery for cancer of the rectum. Ann Surg, 1931; 93:467–475.

Kerr

. Ra-223 targets skeletal metastases and spares normal tissue. Lancet Oncol, 2002; 3:453.

Berkowitz

, Janik

, Stewart

, et al. Safety, efficacy, and pharmacokinetics/pharmacodynamics of daclizumab (anti-CD25) in patients with adult T-cell leukemia/lymphoma. Clin Immunol, 2014; 155:176.

10.

Sartor

, Coleman

, Nilsson

, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: Results from a phase 3, double-blind, randomised trial. Lancet Oncol, 2014; 15:738.

11.

Dandapani

, Dorff

, Kortylewski

, et al. Radium 223 dichloride in combination with androgen deprivation therapy and stereotactic body radiation therapy for patients with stage IV oligometastatic castration sensitive prostate cancer: Clinical trial in progress. Int J Radiat Oncol Biol Phys, 2019; 104:1193.

12.

Heidenreich

, Gillessen

, Heinrich

, et al. Radium-223 in asymptomatic patients with castration-resistant prostate cancer and bone metastases treated in an international early access program. BMC Cancer, 2019; 19:12.

13.

Ricci

, Frantellizzi

, Bulzonetti

, et al. Reversibility of castration resistance status after Radium-223 dichloride treatment: Clinical evidence and review of the literature. Int J Radiat Biol, 2019; 95:554.

14.

Lohaus

, Zöphel

, Löck

, et al. Can local ablative radiotherapy revert castration-resistant prostate cancer to an earlier stage of disease?. Eur Urol, 2019; 75:548.

15.

Osvaldo

, Salvador

, Zael

, et al. Radium-223 IN metastatic hormone-sensitive high-grade prostate cancer: Initial experience. Am J Nucl Med Mol Imaging, 2017; 7:236.

16.

Wenter

, Herlemann

, Fendler

, et al. Radium-223 for primary bone metastases in patients with hormone-sensitive prostate cancer after radical prostatectomy. Oncotarget, 2017; 8:44131.

17.

Medina

, Garcia

, Santana

, et al. Usefulness of radium-223 in metastatic hormone-sensitive prostate cancer: A single centre experience. Eur J Nucl Med Mol Imaging, 2019; 46(SUPPL 1):S626.

18.

Cook

, Parker

, Chua

, et al. 18F-fluoride PET: Changes in uptake as a method to assess response in bone metastases from castrate-resistant prostate cancer patients treated with 223Ra-chloride (Alpharadin). EJNMMI Res, 2011; 1:4.

19.

Etchebehere

, Araujo

, Fox

, et al. Prognostic factors in patients treated with 223Ra: The role of skeletal tumor burden on baseline 18F-fluoride PET/CT in predicting overall survival. J Nucl Med, 2015; 56:1177.

20.

Sweeney

, Chen

, Carducci

, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med, 2015; 373:737.

21.

James

, Sydes

, Clarke

, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet, 2016; 387:1163.

22.

James

, de Bono

, Spears

, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med, 2017; 377:338.

23.

Boevé

LMS

, Hulshof

MCCM

, Vis

, et al. Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial: Data from the HORRAD trial. Eur Urol, 2019; 75:410.

24.

Sundahl

, Tree

, Parker

. The emerging role of local therapy in metastatic prostate cancer. Curr Oncol Rep, 2020; 22:2.

25.

Burdett

, Boevé

, Ingleby

, et al. Prostate radiotherapy for metastatic hormone-sensitive prostate cancer: A STOPCAP systematic review and meta-analysis. Eur Urol, 2019; 76:115.

26.

Ost

, Reynders

, Decaestecker

, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: A prospective, randomized, multicenter phase II trial. J Clin Oncol, 2018; 36:446.

27.

Hellman

, Weichselbaum

. Oligometastases. J Clin Oncol, 1995; 13:8.

28.

Siva

, Bressel

, Murphy

, et al. Stereotactic abative body radiotherapy (SABR) for oligometastatic prostate cancer: A prospective clinical trial. Eur Urol, 2018; 74:455.

29.

Twardowski

, Ye

, Pal

, et al. Androgen deprivation and radiation with helical tomotherapy to metastases in patients with oligometastatic hormone—Sensitive prostate cancer. Ann Oncol, 2012; 23:309.

30.

Alwaheeb

, Henderson

, Weins

, et al. Alpha-actinin-4 defficient mice develop focal and segmental glomerulosclerosis with features of collapsing glomerulopathy. Modern Pathol, 2007; 20:271A.

31.

Tarish

, Schultz

, Tanoglidi

, et al. Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair. Sci Transl Med, 2015; 7:312re311.

32.

Zietman

, Prince

, Nakfoor

, et al. Neoadjuvant androgen suppression with radiation in the management of locally advanced adenocarcinoma of the prostate: Experimental and clinical results. Urology, 1997; 49(3A Suppl):74.

33.

Murray

, Chittenden

, Denis-Bacelar

, et al. The potential of ²²³Ra and ¹⁸F-fluoride imaging to predict bone lesion response to treatment with ²²³Ra-dichloride in castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging, 2017; 44:1832.

34.

Kulshrestha

, Vinjamuri

, England

, et al. The role of 18F-sodium fluoride PET/CT bone scans in the diagnosis of metastatic bone disease from breast and prostate cancer. J Nucl Med Technol, 2016; 44:217.

35.

Hardcastle

, Hofman

, Lee

, et al. NaF PET/CT for response assessment of prostate cancer bone metastases treated with single fraction stereotactic ablative body radiotherapy. Radiat Oncol, 2019; 14:164.

36.

Langsteger

, Rezaee

, Pirich

, et al. F-NaF-PET/CT and. Semin Nucl Med, 2016; 46:491.