Purpose: Prostate stereotactic body radiation therapy (SBRT) is an effective approach for localized prostate cancer. The most common location for local recurrence after prostate radiation therapy is at the site of a magnetic resonance imaging-visible tumor at diagnosis. Therefore, we investigated the toxicity associated with focal boost SBRT. Methods and Materials: Patients with intermediate or high-risk prostate cancer were recruited in a single-institution, prospective phase 2 trial, DELINEATE cohort E. SBRT to a dose of 36.25 Gy, with a simultaneous integrated boost to the tumor (s) up to 45 Gy in 5 fractions, was delivered to 49 men. The primary endpoint assessed late grade 2+ and late grade 3+ Radiation Therapy Oncology Group (RTOG) bowel toxicity at 1 year. Secondary endpoints included acute and late toxicity measured with clinician- and patient-reported outcomes and freedom from biochemical or clinical failure. Results: Median follow-up was 48.8 months. Most (63%) were classified as having National Comprehensive Cancer Network intermediate-risk disease, the remainder high risk. The median (IQR) boost volume was 1.9 (IQR, 1.4-2.81) cm3, and all patients received at least short-course hormone therapy. The highest rate of acute RTOG gastrointestinal (GI) and genitourinary (GU) of grade 2+ was seen at weeks 3 and 4, respectively, settling to baseline levels by week 12. Cumulative 1-year incidence of RTOG grade >= 2 GI late toxicity was 6.1% (90% CI, 2.4%-15.1%). There was no reported late grade 3 or worse bowel toxicity using RTOG or the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) scales. There was no late grade 3+ GU CTCAE toxicity, but 4.1% recorded RTOG grade 3 GU toxicity by 1 year. Cumulative 1-year incidence of RTOG grade >= 2 GU toxicity was 10.2%. Conclusions: Delivery of a focal boost with SBRT is feasible, with point estimates of toxicity rates below the prespecified safety levels for this pilot study. The incidence of GU toxicity has predominance over GI toxicity, and further analysis is ongoing to help identify the determinants of urinary toxicity after prostate SBRT. (c) 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

OBJECTIVES:Treatment options for metastatic hormone-sensitive prostate cancer (mHSPC) have expanded, with evidence supporting prostate radiotherapy in low-volume disease. However, evidence for consolidative radiotherapy to residual sites in patients rendered oligometastatic after systemic therapy is lacking. Advanced imaging with WB-MRI and PSMA PET/CT enables more accurate assessment of tumour burden and response. METHODS:This feasibility study assessed response to initial systemic treatment with an ARPI or docetaxel in 29 patients with polymetastatic (>5 metastases) HSPC. PSA and WB-MRI response using MET-RADS-P criteria were recorded. RESULTS:20/29 (69.0.%) of patients were down-risked to oligometastatic disease (≤5 sites) after a median of 5.5 (IQR 5-5.8) months, identified on WB-MRI. Median PSA was 0.2 ng/ml (IQR 0.1-0.7) in down-risked patients versus 1.5 ng/ml (IQR 1.1-84) in those not down-risked. Residual intraprostatic disease was seen in 55% (11/20) of down-risked patients. CONCLUSIONS:Most patients were down-risked on WB-MRI, supporting the existence of an induced oligometastatic state and providing rationale for the STAR TRAP randomised trial (ISRCTN16448082), which will assess the role of consolidative radiotherapy in this setting. ADVANCES IN KNOWLEDGE:WB-MRI correlates with PSA response and shows potential as an imaging biomarker in mHSPC in this small feasibility study.

5001 Background: The STAMPEDE trials showed that adding abiraterone acetate + prednisolone (AAP) ± enzalutamide (ENZ) to standard of care androgen deprivation therapy (SOC) improves metastasis-free survival (MFS) in high-risk non-metastatic (M0) prostate cancer (PCa) patients (pts). However, variable responses & adverse events underscore the need for prognostic & predictive biomarkers. We evaluated performance of a validated MMAI algorithm (ArteraAI Prostate Test v1.2) to identify pts who benefit most from the addition of AAP ± ENZ (ARPI). Methods: High-risk M0 STAMPEDE pts treated with SOC+ARPI (N=555) or SOC (N=781) with sufficient quality H&E biopsy images & clinical data (T stage, age, PSA) were included. MMAI score association with PCa specific mortality (PCSM, primary outcome measure) & distant metastasis (DM) was analyzed using Fine-Gray regression & cumulative incidence curves, with other cause mortality treated as competing risks. MFS was assessed using Cox regression & Kaplan-Meier curves. An optimal cut-point was identified via grid search to maximize ARPI benefit separation across biomarker positive (pos, MMAI in top quartile) & negative (neg) subgroups. Hazard ratios [95% CI] & p values are reported. Results: PCSM median follow-up was 6.0 years (N=1336). Continuous MMAI scores were statistically significantly associated with poorer PCSM (1.65 [1.43-1.90], p<0.001), MFS (1.42 [1.29-1.56], p<0.001) & DM (1.54 [1.36-1.74], p<0.001). Using clinically-established prognostic cut-offs, 89% of pts were MMAI high-risk. The optimal ARPI MMAI cut-point identified 334 biomarker-pos pts who had significantly higher PCSM than biomarker-neg pts. A statistically significant biomarker-treatment interaction for PCSM (p-int=0.04) revealed that biomarker-pos pts treated with ARPI had improved PCSM (0.42 [0.24-0.74], p=0.003), while biomarker-neg pts did not derive a treatment benefit (0.85 [0.56-1.29], p=0.45). Estimated 5-year PCSM was 9% for biomarker-pos pts receiving ARPI vs. 17% with SOC, compared to 4% & 7% for biomarker-neg pts, respectively, with similar results observed in M0N0 pts (Table 1). Conclusions: For the first time, we demonstrate that a validated MMAI algorithm can identify high-risk non-metastatic PCa pts most likely to benefit from the addition of ARPI. Notably we identify a positive biomarker-treatment interaction in the highest MMAI score quartile, which in cases of clinical equipoise could inform clinical decision-making. We highlight MMAI’s potential to optimize treatment decisions & spare biomarker-neg pts from unnecessary therapy & toxicities. Clinical trial information: NCT00268476 . Estimated 5-yr absolute risk reduction from ARPI vs SOC-treated patients by biomarker groups in M0 (M0N0) pts. Biomarker-neg Biomarker-pos PCSM 3% (1%) 8% (9%) MFS 2% (-1%) 17% (16%) DM 5% (3%) 12% (15%)

BACKGROUND AND OBJECTIVE:Innovations have improved outcomes in advanced prostate cancer (PC). Nonetheless, we continue to lack high-level evidence on a variety of topics that greatly impact daily practice. The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) surveyed experts on key questions in clinical management in order to supplement evidence-based guidelines. Here we present voting results for questions from APCCC 2024. METHODS:Before the conference, a panel of 120 international PC experts used a modified Delphi process to develop 183 multiple-choice consensus questions on eight different topics. Before the conference, these questions were administered via a web-based survey to the voting panel members ("panellists"). KEY FINDINGS AND LIMITATIONS:Consensus was a priori defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. The voting results show varying degrees of consensus, as discussed in this article and detailed in the Supplementary material. These findings do not include a formal literature review or meta-analysis. CONCLUSIONS AND CLINICAL IMPLICATIONS:The voting results can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers in prioritising areas for future research. Diagnostic and treatment decisions should always be individualised on the basis of patient and cancer characteristics, and should incorporate current and emerging clinical evidence, guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2024 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials.

The event-based model of disease progression (EBM) infers a temporal ordering of biomarker abnormalities, defining different disease stages, from cross-sectional data. A key modelling choice of the EBM is that biomarker abnormalities, termed events, are serially ordered. However, this choice enforces a strict equality between the number of input biomarkers and the number of modelled disease stages, limiting the EBM's ability to infer simple staging systems and identify latent disease processes driving multiple biomarker changes. To overcome this, we introduce the parsimonious event-based model of disease progression (P-EBM). The P-EBM generalises the EBM to allow multiple new biomarker abnormalities, termed "simultaneous events", at each model stage. We evaluate the P-EBM performance in simulated data and demonstrate its ability to reconstruct event orderings with arbitrary arrangements under realistic experimental conditions. In sporadic AD data from the Alzheimer's Disease Neuroimaging Initiative, the P-EBM estimated a sequence with 7 model stages from a dataset of 12 biomarkers that more closely fitted the data than the EBM. The inferred sets of simultaneous events, such as decreased cerebrospinal fluid total tau and p-tau181, correspond closely to known underlying disease processes. P-EBM patient stages were strongly associated with clinical diagnosis at baseline and future conversion and could be accurately estimated from a smaller number of biomarkers than the EBM. The P-EBM enables the data-driven discovery of simple disease staging systems which could highlight new latent disease processes and suggest practical strategies for patient staging.

PURPOSE:Stereotactic body radiation therapy (SBRT) is increasingly used for oligometastatic prostate cancer, although most published series include mixed histologies and only a few patients achieve long-term disease-free survival. This retrospective study presents one of the largest prostate-only cohorts, aiming to identify who benefits most from SBRT. METHODS AND MATERIALS:From 2011 to 2023, 234 patients with ≤3 hormone-sensitive metachronous prostate cancer oligometastases were treated with SBRT at the Royal Marsden Hospital, London, and Sutton, UK. Concurrent androgen deprivation therapy (ADT) was allowed by clinician discretion. Treatment and outcome data were collected to assess the association between covariates and radiological progression-free survival (rPFS), ADT-free survival, and prostate cancer-specific survival (PCSS). RESULTS:In total, 308 lesions were treated in 234 patients. After a median follow-up of 56.5 months, median rPFS was 22 months and ADT-free survival was 42 months. The 5-year rPFS, ADT-free survival, and PCSS were 22.9%, 42.3%, and 96.4%, respectively. Concurrent ADT was used in 140 patients (59.8%). Prostate-specific antigen doubling time ≤ 3 months was a significant predictor for shorter rPFS [hazard ratio (95% CI) 1.52 (1.07-2.16), P = .001], and concurrent ADT use improved rPFS [0.52 (0.37-0.73), P < .001]. Nodal disease at primary presentation [2.08 (1.10-3.92), P = .023] and greater than 1 oligometastases [1.88 (1.25-2.82), P = .002] were inversely associated with ADT-free survival. Concurrent ADT use [0.40 (0.27-0.58), P < .001] improved ADT-free survival. Concurrent ADT use with SBRT did not improve eugonadal rPFS and eugonadal ADT-free survival. Patients diagnosed with oligometastases using baseline prostate-specific membrane antigen positron emission tomography/computed tomography had longer median ADT-free survival than those diagnosed with "other" imaging methods (52 vs 32 months, P = .041). For PCSS, more than 1 oligometastasis [6.08 (1.20-30.78), P = .029] and nodal disease at primary presentation [6.48 (1.16-36.15), P = .033] were associated with worse survival [5.95 (1.02-34.9), P = .048]. CONCLUSIONS:We present one of the largest SBRT case series specific to hormone-sensitive metachronous oligometastatic prostate cancer. After 5 years, 22.9% remained radiologically recurrence free and 42.3% remained ADT-free.

BACKGROUND:Metformin is a widely used anti-diabetic drug. Several studies have suggested that metformin has anticancer activity in some malignancies, including prostate cancer. Metformin might also mitigate the adverse metabolic effects of androgen-deprivation therapy (ADT). We hypothesised that metformin might improve survival in patients with metastatic hormone-sensitive prostate cancer and reduce metabolic complications associated with ADT. METHODS:The STAMPEDE multi-arm, multi-stage, randomised phase 3 trial recruited patients with high-risk locally advanced or metastatic adenocarcinoma of the prostate staged by conventional imaging with isotope bone and CT scanning. This publication reports findings for the most recent STAMPEDE research question, testing the addition of metformin to standard of care for non-diabetic (glycated haemoglobin [HbA1c] <48 mmol/mol [equivalent to <6·5%]) patients with metastatic disease with adequate renal function (glomerular filtration rate ≥45 ml/min/1·73 m2) and WHO performance status 0-2. This trial recruited from 112 hospitals in the UK and Switzerland to the STAMPEDE protocol. Patients were randomly allocated (1:1) to standard of care or standard of care plus metformin 850 mg twice daily. Random assignment was by telephone using minimisation with a random element of 20% (developed and maintained by the MRC Clinical Trials Unit at UCL), stratified for randomising hospital, age (<70 years vs ≥70 years), WHO performance status (0 vs 1 or 2), type of ADT, regular long-term use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs; yes vs no), pelvic nodal status (positive vs negative), planned radiotherapy (yes vs no), and planned docetaxel or androgen receptor pathway inhibitor (ARPI) use (docetaxel vs abiraterone, enzalutamide, or apalutamide vs none). Standard of care comprised ADT with or without radiotherapy and with or without docetaxel or ARPI. The primary outcome measure was overall survival, defined as the time to death from any cause, assessed in the intention-to-treat population. Safety was assessed in patients who started treatment. The trial is registered with ClinicalTrials.gov, NCT00268476 and ISRCTN, ISRCTN78818544. FINDINGS:Between Sep 5, 2016, and Mar 31, 2023, 1874 patients with metastatic disease were randomly allocated to standard of care (n=938) or standard of care plus metformin (n=936). The median patient age was 69 years (IQR 63-73) and the median PSA was 84 ng/mL (24-352). 1758 (94%) of 1874 patients were newly diagnosed with metastatic disease and 116 (6%) were diagnosed with metachronous relapsing disease. 1543 (82%) of 1874 patients received ADT plus docetaxel and 52 (3%) received abiraterone, enzalutamide, or apalutamide. The median time to most recent case report form follow-up was 60 months (IQR 49-72). 473 deaths were reported in the standard of care group; median survival was 61·8 months (IQR 29·7 to not reached). There were 453 deaths in the metformin group; median survival was 67·4 months (32·5 to not reached; HR 0·91, 95% CI 0·80-1·03; p=0·15). Grade 3 or worse adverse events were reported in 487 (52%) of 938 patients in the standard of care group and 523 (57%) of 921 patients in the standard of care plus metformin group. 61 (7%) patients in the standard of care group and 84 (9%) patients in the standard of care plus metformin group reported at least one grade 3 or worse gastrointestinal adverse event; all other body systems showed no difference in grade 3 adverse events. There were six drug-related deaths in the standard of care group and one in the standard of care plus metformin group. INTERPRETATION:We did not find significant evidence of an overall survival benefit of adding metformin to standard of care in the overall population of patients with metastatic hormone-sensitive prostate cancer. The side-effect profile of metformin was as expected and consisted mainly of diarrhoea. Adverse metabolic side-effects of ADT were significantly reduced in the metformin group compared with the standard of care group. FUNDING:Cancer Research UK, Prostate Cancer UK, and UK Research and Innovation Medical Research Council.

The assessment of imaging biomarkers is critical for advancing precision medicine and improving disease characterization. Despite the availability of methods to derive disease heterogeneity metrics in imaging studies, a robust framework for evaluating measurement uncertainty remains underdeveloped. To address this gap, we propose a novel Bayesian framework to assess the precision of disease heterogeneity measures in biomarker studies. Our approach extends traditional methods for evaluating biomarker precision by providing greater flexibility in statistical assumptions and enabling the analysis of biomarkers beyond univariate or multivariate normally-distributed variables. Using Hamiltonian Monte Carlo sampling, the framework supports both, for example, normally-distributed and Dirichlet-Multinomial distributed variables, enabling the derivation of posterior distributions for biomarker parameters under diverse model assumptions. Designed to be broadly applicable across various imaging modalities and biomarker types, the framework builds a foundation for generalizing reproducible and objective biomarker evaluation. To demonstrate utility, we apply the framework to whole-body diffusion-weighted MRI (WBDWI) to assess heterogeneous therapeutic responses in metastatic bone disease. Specifically, we analyze data from two patient studies investigating treatments for metastatic castrate-resistant prostate cancer (mCRPC). Our results reveal an approximately 70 tumors across both studies, objectively characterizing differential responses to systemic therapies and validating the clinical relevance of the proposed methodology. This Bayesian framework provides a powerful tool for advancing biomarker research across diverse imaging-based studies while offering valuable insights into specific clinical applications, such as mCRPC treatment response.

Purpose Optimal management of oligoprogressive prostate cancer while on androgen receptor pathway inhibitors (ARPIs) is not known. The TRAP trial tests the role of stereotactic body radiation therapy (SBRT) in this setting. The objective of this phase 2 prospective, nonrandomized, single-arm trial was to determine if local control of oligoprogressive disease with SBRT can delay further progression by >4 months, postponing time to next therapy. Methods and Materials Men with castration-resistant prostate cancer with ≤2 oligoprogressive sites developing on treatment with an ARPI, after initial response to therapy, were recruited. All patients were treated to a dose of 30 Gy in 5 fractions (alternate days) or 36 Gy in 6 fractions weekly (prostate only). Results Eighty-six men were recruited between October 2018 and February 2023. SBRT was delivered to 81 men. Mean age was 74 years. Most patients (67%) had 1 oligoprogressive disease lesion. Sites irradiated were bone (59%), lung (1%), lymph node (32%), and prostate (7%). Median follow-up was 22.9 months at the time of analysis. Fifty-five (68%) patients had progressed, 33 (41%) of patients progressed within 6 months of radiation therapy. Median progression-free survival (PFS) was 6.4 months (95% CI, 5.9-11.4). An estimated 39% (95% CI, 29-49) of patients have a prolonged PFS of > 12 months.Thirty-three (41%) of patients had started new treatment or died. Median time to either next treatment or death was 27.0 months (95% CI, 14.9-29.6). Median overall survival was 27.2 months (95% CI, 24.7-36.6). Four deaths occurred within 6 months of SBRT; none were related to radiation therapy treatment. Conclusions The TRAP trial has demonstrated a median PFS of 6.4 months after SBRT for oligoprogression of prostate cancer, meeting the primary endpoint. Further analysis of biomarker panel including circulating DNA and whole-body magnetic resonance imaging will promote better patient selection.

Prostate cancer is the most common cancer in two thirds of the world, with an expected doubling in both incidence and mortality in the next two decades. No strong environmental associations exist for the development of prostate cancer; therefore, lifestyle measures are unlikely to mitigate this increasing burden. The last three decades have seen rapid developments in the diagnostic and therapeutic landscape of prostate cancer, including multiparametric magnetic resonance imaging, positron emission tomography, robotic surgery, image-guided hypofractionated and stereotactic radiotherapy, novel anti-androgens and radioligand therapies. Prostate cancer is unique in that not everyone with a diagnosis needs treatment, and active surveillance is the preferred option for some. This review discusses the contemporary management of all stages of prostate cancer in the light of these modern developments, enabling holistic individualization of treatment, and describes the promise of future research to further improve outcomes.

BACKGROUND AND OBJECTIVE:The treatment landscape for advanced prostate cancer has evolved significantly over the past decade. The introduction of docetaxel, androgen receptor pathway inhibitors (ARPIs), poly(ADP-ribose) polymerase inhibitors, and targeted radionuclides has redefined the treatment paradigm, with a focus now on early treatment intensification through combination therapies. This narrative collaborative review summarises the current evidence of combination therapies in locally advanced and metastatic hormone-sensitive prostate cancer (mHSPC). METHODS:We conducted a literature search up to November 2024. Search terms included "metastatic hormone-sensitive prostate cancer", "metastatic castration-sensitive prostate cancer", "locally advanced prostate cancer", "combination", "intensification", and "de-escalation". Articles were selected by the authors based on their scientific merit, clinical impact, and relevance to provide a summary of the evidence surrounding combination therapy in locally advanced prostate cancer and mHSPC. KEY FINDINGS AND LIMITATIONS:A doublet approach with an androgen deprivation therapy (ADT) backbone and an ARPI is now considered the standard treatment for mHSPC, with a triplet regimen incorporating docetaxel considered in select subgroups. Similar efforts to improve survival in the high-risk localised and locally advanced disease setting have led to several trials evaluating the benefit of combination therapy in addition to standard-of-care surgery or radiotherapy with ADT. Continued improvements in survival have turned the focus to optimising patient selection for treatment intensification and, in some cases, de-escalation, with the goal of reducing unnecessary overtreatment and minimising harm from long-term treatment toxicity. This is particularly important with the integration of prostate-specific membrane antigen positron emission tomography, which has led to the earlier detection of metastatic disease. CONCLUSIONS AND CLINICAL IMPLICATIONS:In select subgroups, early treatment intensification with combination therapy leads to improved survival, though it can be associated with long-term toxicity.

Purpose To demonstrate the safety and feasibility of 2-fraction stereotactic body radiation therapy (SBRT) for prostate cancer. Methods and Materials This single-center, noncomparative, phase 2/R-IDEAL 2b trial randomized 46 patients with intermediate/lower high-risk prostate cancer with visible gross tumor volume on multiparametric magnetic resonance imaging to receive 36.25 Gy in 5 fractions over 10 days or 24 Gy in 2 fractions with a gross tumor volume boost up to 27 Gy over 8 days. All treatment was delivered on a magnetic resonance linac with daily adaptive replanning. The primary endpoint was acute grade ≥2 (G2+) genitourinary (GU) toxicity (Common Terminology Criteria for Adverse Events version 5.0). Secondary endpoints include gastrointestinal (GI) toxicity and patient-reported outcomes. Results G2+ GU acute toxicity was observed in 6 of 22 patients (27.3%; 95% CI, 0.11-0.50) in the 2-fraction group and 7 of 24 patients (29.2%; 95% CI, 0.13-0.50) in the 5-fraction group. There were no grade 3 GU toxicities. G2+ urinary frequency rose from 4.5% (1 of 22) at week 2 to 13.6% (3 of 22) at week 4 in 2-fraction SBRT. G2+ urinary frequency peaked earlier in 5-fraction SBRT at 16.7% (4 of 24) in week 2, falling to 12.5% (3 of 24) at week 4. At 12 weeks, median Expanded Prostate Cancer Index Composite-26 urinary incontinence score was 85.5 (IQR, 75-100) for 2-fraction SBRT and 100 (IQR, 93.8-100) for 5-fraction SBRT. Urinary irritative-obstructive scores were higher at 12 weeks in the 2-fraction group (93.8; IQR, 87.5-100) than in the 5-fraction group (87.5; IQR, 81.3-93.8). Peak International Prostate Symptoms Score was lower in the 2-fraction group (8; IQR, 4-11) than in the 5-fraction group (13.5; IQR, 10-17). G2+ GI acute toxicity occurred in 3 of 24 (6.8%) after 5-fraction SBRT, but none after 2-fraction SBRT. Conclusions Acceptable acute GU toxicity was seen after 2-fraction SBRT. Acute GI toxicity was low. Randomized trials are warranted to explore late toxicity and biochemical control.

Objectives To investigate whether baseline 18F-sodium fluoride (NaF) and 18F-choline PET activity is associated with metastatic castration-resistant prostate cancer (mCRPC) global and individual bone metastases’ DWI MR imaging response to radium-223 treatment. Methods Thirty-six bone-only mCRPC patients were prospectively recruited from three centers. Whole-body (WB)-MRI with DWI and 18F-NaF and 18F-choline PET/CT were performed at therapy baseline and 8-week intervals. In each patient, bone disease median global (g)ADC change between baseline and follow-up was calculated. Additionally, up to five bone target lesions per patient were delineated and individual median ADC change recorded. An ADC increase > 30% defined response per-patient and per-lesion. For the same targets, baseline 18F-NaF and 18F-choline PET SUVmax were recorded. Mean SUVmax across patient targets was correlated with gADC change and lesion SUVmax with per-lesion ADC change. Results A total of 133 lesions in 36 patients (14 responders) were analyzed. 18F-NaF PET per-patient mean SUVmax was significantly higher in responders (median = 56.0 versus 38.7 in non-responders; p = 0.008), with positive correlation between SUVmax and gADC increase (rho = 0.42; p = 0.015). A 48.7 SUVmax threshold identified responders with 77% sensitivity and 75% specificity. Baseline 18F-NaF PET per-lesion SUVmax was higher in responding metastases (median = 51.6 versus 31.8 in non-responding metastases; p = 0.001), with positive correlation between baseline lesion SUVmax and ADC increase (rho = 0.39; p < 0.001). A 36.8 SUVmax threshold yielded 72% sensitivity and 63% specificity. No significant association was found between baseline 18F-choline PET SUVmax and ADC response on a per-patient ( p = 0.164) or per-lesion basis ( p = 0.921). Conclusion 18F-NaF PET baseline SUVmax of target mCRPC bone disease showed significant association with response to radium-223 defined by ADC change. Clinical relevance statement 18F-sodium fluoride PET/CT baseline maximum SUV of castration-resistant prostate cancer bone metastases could be used as a predictive biomarker for response to radium-223 therapy. Key Points • 18F-sodium fluoride PET baseline SUVmax of castration-resistant prostate cancer bone metastases showed significant association with response to radium-223. • Baseline 18F-sodium fluoride PET can improve patient selection for radium-223 therapy. • Change in whole-body DWI parameters can be used for response correlation with baseline 18F-sodium fluoride PET SUVmax in castration-resistant prostate cancer bone metastases.