Risk of bone fractures in patients with prostate cancer treated with maximal androgen blockade therapy: a systematic literature review and meta-analysis.

e17111 Background: Androgen deprivation therapy (ADT) increases the risk of fractures. The addition of an androgen receptor pathway inhibitor (ARPI) to ADT (MAB) has shown to improve outcomes compared to ADT monotherapy in patients (pts) with metastatic castration-resistant PC (mCRPC), non-mCRPC (nmCRPC), metastatic hormone-sensitive PC (mHSPC), high-risk localized disease and high-risk biochemical relapse. There is no definitive evidence whether MAB increases the risk of fractures compared to ADT alone. Methods: We conducted a systematic review of all clinical trials assessing treatment with an ARPI plus ADT for pts with PC having placebo plus ADT as control arm, using the PubMed/Medline and Cochrane library databases. We also performed a meta-analysis to compare the risk of fractures of each ARPI versus placebo. Further we assessed the number of pts receiving bone protecting agents (BPA) in the studies selected. The comparison between ARPI and placebo in terms of risk of fractures was performed using odds ratio (OR) as meta-analytic outcome. Results: We identified 15 studies comprising 15183 pts (8638 treated with an ARPI and 6545 with placebo), of which 3 studies evaluated abiraterone, 3 apalutamide, 3 darolutamide and 6 enzalutamide. Each ARPI resulted in a statistically significant increase in the risk of fractures compared to placebo (see table), but without statistical differences among the different ARPIs since there is an overlap between the confidence intervals (CI) of the pooled outcome measure of different ARPIs compared to placebo. Only 7/15 studies reported the number (n°) of pts treated with a BPA of which 4 were in mCRPC, 2 in nmCRPC and one in the mHSPC setting. The highest percentage was found in studies including mCRPC pts, of which 35-50% received a BPA. In the studies in the nmCRPC setting, 10-11% of pts received a BPA while in the only mHSPC study reporting data on the use of BPA only two pts (0.4%) in the ARPI group received BPA and no patient in the placebo group. Conclusions: In our meta-analysis MAB resulted in a statistically significant increase in fracture risk compared to ADT regardless of the ARPI used. Data on the use of BPA should be properly reported in future clinical trials. Since long term MAB represents the standard of care in various settings of PC, the use of a BPA should be generally recommended. Dosing and frequency of BPA needs to be adapted according to the specific PC setting. [Table: see text]

The purpose of this study was to investigate an association between lung hyperinflation and the risk of bone fracture in patients with chronic obstructive pulmonary disease (COPD).Methods. The study involved 125 smokers with COPD. The patients treated with systemic steroids were excluded from the study. Lung function and bone mineral density were measured in all the patients. The risk of osteoporotic bone fractures was calculated by FRAX tool.Results. Lung hyperinflation increased according to the COPD stage. The highest total lung capacity (TLC) was observed in patients with 4 stage COPD (131.43 ± 38.99%pred.) followed by 126.68 ± 21.58%pred. in 3 stage COPD and 115.39 ± 23.68%pred. in 2 stage COPD (p < 0.05). The highest risk of hip fracture (> 3) was calculated for 24.24% of patients with residual lung volume (RV) < 200%pred. and for 45.71% of patients with RV > 200%pred. Conclusions. The risk of hip fracture was significantly associated with the severity of hyperinflation in COPD patients. The highest risk of fractures was found in patients with 4 stage COPD.

Risk of Clinical Fractures After Gonadotropin-Releasing Hormone Agonist Therapy for Prostate Cancer

Incidence, Management, and Prevention of Gynecomastia and Breast Pain in Patients with Prostate Cancer Undergoing Antiandrogen Therapy: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BackgroundFracture risks and associated factors are poorly understood in middle-aged and older Asian populations with inflammatory bowel disease (IBD). Therefore, we investigated fracture risk and the effects of comorbidities and lifestyle habits on the risk of developing fractures in middle-aged and older Korean patients with IBD.MethodsWe conducted a nationwide population-based cohort study using data from the National Health Insurance Corporation Database. Patients with IBD who underwent the National Screening Program and were over 40 years of age were included in the study. We compared patients with age- and sex-matched controls. The incidence of fractures, including vertebral, hip, and other sites, was determined using claims data.ResultsThe risk of total fractures and vertebral fractures was significantly higher in the IBD group (adjusted hazard ratio [HR], 1.31, 95% confidence interval [CI], 1.16–1.48; adjusted HR, 1.59, 95% CI, 1.33–1.92, respectively). Obesity, diabetes, hypertension, and lack of exercise were associated with increased fracture risk in patients with ulcerative colitis (UC). In contrast, the risk increases in patients with Crohn’s disease regardless of comorbidities and lifestyle preferences.ConclusionThe risk of bone fracture, especially vertebral fracture, is high in middle-aged and older Korean patients with IBD. Obesity, diabetes, hypertension, and lack of exercise are all risk factors associated with bone fractures in patients with UC. These findings are helpful for clinicians to educate patients with IBD on bone health and raise awareness of bone fractures in patients with UC who have specific risk factors.

Androgen Receptor Pathway Inhibitor Monotherapy in Prostate Cancer: Safety, Oncologic Outcomes, and Quality of Life-A Systematic Review and Meta-analysis.

Introduction: Primary hyperparathyroidism, a prevalent endocrine disorder, is known to cause osteoporosis. This study aims to examine the association between primary hyperparathyroidism and the risk of bone fracture. Materials and Methods: A systematic review and meta-analysis approach was employed in this article. The databases ProQuest, PubMed, Web of Science, Cochrane, and the search engine Google Scholar were searched up to June 20, 2023. Data analysis was conducted applying STATA 14 software. Results: Primary hyperparathyroidism increased the risk of any fractures overall (OR: 1.45, 95% CI: 1.26–1.67) in patients aged 50-59 years (OR: 1.37, 95% CI: 1.18–1.60) and in those aged 60-69 years (OR: 1.60, 95% CI: 1.25–2.05). Moreover, primary hyperparathyroidism led to an increased risk of vertebral fracture (OR: 1.90, 95% CI: 1.12–3.22), foot fracture (OR: 1.55, 95% CI: 1.09–2.20), femur fracture (OR: 1.51, 95% CI: 1.16–1.96), and osteoporotic fracture (OR: 1.42, 95% CI: 1.24–1.64). However, no statistically significant association was reported between primary hyperparathyroidism and the risk of hip fracture (OR: 1.11, 95% CI: 0.90–1.38), hand fracture (OR: 1.55, 95% CI: 0.88–2.75), forearm fracture (OR: 1.51, 95% CI: 0.52–4.39), femoral neck fracture (OR: 1.12, 95% CI: 0.56–2.25), and cervical fracture (OR: 1.40, 95% CI: 0.63–3.13). Conclusion: The risk of any fractures in patients with primary hyperparathyroidism was 45% higher than in healthy individuals and increased with advancing age. Furthermore, primary hyperparathyroidism elevated the risk of vertebral fracture by 90%, foot fracture by 55%, femur fracture by 51%, and osteoporotic fracture by 42%. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO (ID: CRD42024563393) and Research Registry (UIN: reviewregistry1851) websites.

In real-world practice in Japan, standard treatment for metastatic hormone-naïve prostate cancer (mHNPC) is androgen deprivation therapy (ADT), administered as monotherapy, combined androgen blockade (CAB), ADT plus androgen receptor pathway inhibitors (ARPIs), or ADT plus docetaxel. In a previous interim analysis of the large-scale, longitudinal, multicentre, J-ROCK registry study of real-world clinical and patient-reported outcomes, ADT plus ARPI or ADT plus docetaxel was used more frequently than ADT/CAB in patients (aged ≥ 20 years) with newly diagnosed LATITUDE-criteria high-risk mHNPC. This post hoc analysis of the J-ROCK study evaluated prostate-specific antigen (PSA) response, progression-free survival (PFS), time to castration-resistant prostate cancer (CRPC), overall survival (OS) and safety in patients with high-risk mHNPC who received ADT/CAB (cohort 1) or ADT plus ARPI (cohort 2B) in subgroups were defined according to the following known prognostic factors at baseline: age, Gleason Grade Group (GGG), alkaline phosphatase (ALP), hemoglobin (Hb) and lactate dehydrogenase (LDH). This analysis included 947 evaluable patients (371 in cohort 1 and 576 in cohort 2B). PSA response rates remained similar among age and GGG subgroups in both cohorts, but were reduced in cohort 2B patients with elevated ALP, low Hb, and elevated LDH. Time to CRPC and OS were longer in cohort 2B than in cohort 1, regardless of prognostic factors. Among patients with poor prognosis (older, high GGG, low Hb, elevated LDH), OS decline occurred earlier in cohort 1 versus cohort 2B. A trend towards a plateau in the time to CRPC curve was observed in both cohorts, even in patients with poor prognosis. Safety data were not affected by prognostic factors or treatment. These findings suggest that novel ADT plus ARPI regimens for LATITUDE-criteria high-risk mHNPC may improve real-world outcomes compared with ADT monotherapy or CAB, particularly among patients with poor prognosis.

Prostate cancer (PC) treatment, particularly androgen deprivation therapy (ADT), remains pivotal, albeit linked to increased fracture risk due to osteoporosis. The advent of novel hormonal agents (NHAs) has spurred inquiries into their influence on bone health. This study aimed to evaluate the impact of NHAs on bone health in patients receiving combination therapy. We conducted a retrospective analysis using Taiwan’s National Health Insurance Research Database, encompassing men aged 45 and above diagnosed with PC without bone metastasis and undergoing ADT between 2000 and 2018. The study involved 25,949 patients, categorized into those receiving standard ADT (n = 25,166) and those on NHA combination therapy (n = 783). Our analysis delved into fracture risk, comorbidities, and osteoporosis treatments. Patients on NHA combination therapy faced significantly higher risks of any osteoporotic fracture and major osteoporotic fracture than those on ADT alone (HR = 1.29, 95% CI 1.04–1.61; HR = 1.37, 95% CI 1.06–1.75, respectively). Notably, age emerged as a critical factor, with the highest risk observed in those aged 90 or above. The 5-year overall survival rates were lower for patients who experienced any osteoporotic fracture, major osteoporotic fracture, and hospitalization due to osteoporotic fracture compared to those who did not experience these fractures (51.5% vs. 56.5%, 47.1% vs. 56.7%, and 48.2% vs. 56.3%, respectively, p < 0.001). Furthermore, patients not using any bone-modifying agents had the highest risk for all fracture types. In conclusion, NHA combination therapy in PC patients potentially escalates the risk of osteoporotic fractures, especially in older individuals. Our findings underscore the pivotal role of osteoporosis treatments in preventing fractures, emphasizing the importance of evaluating fracture risk in patients undergoing NHA combination therapy.

11164 Background: Androgen deprivation therapy is associated with an increased risk of fracture. ARPIs are widely used to manage advanced prostate cancer (PCa). However, there is limited long-term data on fracture risk following ARPIs and how the risk might vary with different health conditions. This study aims to fill these gaps. Methods: This study used the SEER-Medicare linked files to identify men diagnosed with PCa between 1/1/1999 and 12/31/2019 and who received abiraterone with prednisone (AAP) or enzalutamide (ENZA) between 1/1/2013 and 12/31/2020. The primary endpoint is the time to first fracture after the index date (first date of AAP or ENZA). The history of fracture was based on claims one year before the index date. Fine and Gray’s sub-distribution hazard model was used to estimate the effect of various risk factors. We used the cumulative incidence function to quantify fracture risk. Results: This study comprised 10,463 patients (6,037 with AAP and 4,426 with ENZA). Most patients were over 75 with a comorbidity score of 1 or higher. Among 1,445 patients who had a fracture the year before the index date, the risk of fracture after ARPI reached 50% (95% CI 47% - 53%) within 3 years, compared to 26% (95% CI 25%-27%) among those without a fracture. After adjusting for bone health agent use, comorbidities, and sociodemographic factors, a history of fracture was associated with 2.8 fold risk of fracture after AAP (RR=2.80, 95% CI 2.47 – 3.18) and 2.85 fold risk after ENZA (RR=2.85, 95% CI 2.45-3.30). Use of bone health agents within 3 months before the index date was associated with a 20-25% lower fracture risk. Conclusions: This large population-based study shows that the risk of fracture following ARPIs is substantial, especially among those who suffered a fracture before ARPIs. It is crucial to consider the history of fracture when making treatment choices and monitoring strategies. Better management of bone health is crucial for men treated with ARPIs.

ABSTRACTObjectiveThis study evaluated treatment patterns and factors associated with androgen deprivation therapy (ADT) intensification with androgen receptor pathway inhibitors (ARPI) and/or docetaxel among older men with mHSPC in the United States.MethodsThe study utilized a retrospective cohort of 6850 older men (age ≥ 67 years) diagnosed with mHSPC between July 2016 and December 2019 from the Surveillance, Epidemiology, and End Results Medicare‐linked database. Men must maintain continuous enrollment in Medicare fee‐for‐service Parts A/B/D for ≥ 12 months before mHSPC diagnosis and ≥ 6 months after diagnosis. Initial treatment was classified as ADT alone, ADT + ARPI, or ADT + docetaxel. Factors associated with initial treatment were examined using multivariable multinomial logistic regression.ResultsThe study cohort (mean age = 76.6 years, SD = 7.0) was mostly non‐Hispanic white (77.7%), followed by non‐Hispanic Black (8.4%) and Hispanic (6.5%). 30.4% received no systemic drug therapy within 6 months of mHSPC diagnosis, 47.1% received ADT alone, 14.8% received ADT + ARPI, and 5.9% received ADT + docetaxel. Among men treated with ADT, there was an increase in ADT + ARPI treatment from 19.0% to 30.0% and a concomitant decline in ADT monotherapy from 72.1% to 62.6% between 2017 and 2019, while ADT + docetaxel treatment marginally decreased from 8.8% to 7.3%. In multinomial logistic regression, men with de novo mHSPC were more likely to receive ADT + docetaxel (aOR = 2.73, 95% CI = [2.07, 3.60]) or ADT + ARPI (aOR = 1.56, 95% CI = [1.32, 1.84]); whereas men with higher frailty index were less likely to receive ADT + docetaxel (aOR = 0.93, 95% CI = [0.91, 0.95]) or ADT + ARPI (aOR = 0.97, 95% CI = [0.96, 0.98]). Specifically, ADT + ARPI was less likely to be utilized among the lower socio‐economic status groups.ConclusionsThree in 10 older men with mHSPC received no systemic treatment. Although there was a gradual uptake of ARPIs, monotherapy with ADT was still highly prevalent, suggesting the integration of intensified treatment is still suboptimal. Targeted interventions are necessary to enhance guideline adherence among older and frail men with mHSPC.

The current guidelines for treating metastatic castration-sensitive prostate cancer (mCSPC) recommend treatment intensification of androgen deprivation therapy (ADT) with the addition of an androgen receptor pathway inhibitor (ARPI), with or without docetaxel. However, the adoption of these treatment options has been slow, leading to therapeutic inertia. This real-world study was conducted to investigate the occurrence of adverse events (AEs) among treated patients diagnosed with mCSPC in the United States. This retrospective claim review estimated the occurrence of AEs among patients with mCSPC from January 2014 to June 2021 in the PharMetrics® Plus data set. The study focused on 10 common AEs (fatigue/asthenia, gastrointestinal [GI] AEs, skin/nail/hair AEs, immunodeficiency/thrombocytopenia, hot flash, sexual function AEs, anemia, hypertension, pain, and edema) known to occur in ≥10% of patients and ≥2% more prevalent than those treated with ADT alone as selected from the US Food and Drug Administration prescribing information and published results from clinical trials. Proportions of patients experiencing these AEs at Day 90, 180, and then every 180 days until month 30 during the follow-up period were estimated using cumulative hazard plots. Results were adjusted using inverse probability of treatment weighting (IPTW) across four treatment groups: ADT alone, ADT + nonsteroidal anti-androgen (NSAA) (bicalutamide, nilutamide, or flutamide), ADT + docetaxel, and ADT + ARPIs (abiraterone, apalutamide, or enzalutamide). ADT-alone cohort was the reference group for all comparisons. A total of 4145 patients were included (ADT alone: 2318, ADT + NSAA: 632, ADT + docetaxel: 471, ADT + ARPIs: 724). At baseline, median (interquartile range [IQR]) age was 64.3 (60.1-73.1) years; most common sites of metastasis were bone only (n = 1886, 45.5%) and node only (n = 1237, 29.8%); most used medications were pain medications (n = 2182, 52.6%) and corticosteroids (n = 1213, 29.3%). Median (IQR) duration of follow-up 10.2 (6.1-16.6) months in ADT alone, 6.7 (4.1-11.5) months in ADT + NSAA, 5.1 (4.3-5.9) months in ADT + docetaxel, and 11.0 (6.6-17.0) months in ADT + ARPI cohort. The reported AEs increased over time for all assessed AEs, across all treatment groups. Compared with ADT alone, no statistically significant difference in the proportion of patients with AEs was seen in the ADT + ARPI or ADT + NSAA cohorts at months 3 and 12; a significantly higher proportion of patients in the ADT + docetaxel cohort experienced 6 of the 10 assessed AEs at month 3 (fatigue/asthenia, GI AEs, skin/nail/hair AEs, immunodeficiency/thrombocytopenia, hot flash, anemia). During the follow-up period, on IPTW analysis, compared with ADT alone, a significantly higher proportion of patients experienced AEs with seven AEs in the ADT + docetaxel group (fatigue/asthenia, GI AEs, skin/nail/hair AEs, immunodeficiency/thrombocytopenia, hot flash, anemia, edema; p < 0.001 for all seven), three AEs in the ADT + ARPI group (hot flash, p = 0.05; anemia, p = 0.01; edema, p = 0.019), and one AE in the ADT + NSAA group (anemia, p = 0.029). The proportion of patients with sexual function AE did not significantly differ between the treatment groups and ADT alone. Results of this large, real-world study demonstrated that all treatment groups experienced an increase in the rates of AEs over time, including ADT alone. Most AE rates with ADT + ARPIs were comparable with ADT + NSAA and not significantly different from ADT alone. ADT + docetaxel cohort was associated with significantly higher rates for all AEs over time except hypertension, sexual dysfunction, and pain. This study provides real-world evidence on AEs, beyond controlled clinical trials, and may assist healthcare providers to make better-informed decisions about disease management among patients with mCSPC.

Limited real-world data exist on the effectiveness of treatment intensification (TI) with androgen receptor pathway inhibitors (ARPI) in de novo metastatic castration-sensitive prostate cancer (mCSPC). This study compared outcomes of TI or first-generation nonsteroidal antiandrogens (NSAAs) to androgen-deprivation therapy (ADT) alone in US patients with de novo mCSPC. Veterans Affairs patients with de novo mCSPC (February 2018-June 2020) confirmed via chart review were grouped into ADT alone, ADT + NSAAs, or ADT + ARPI cohorts using predefined recruitment quotas. Outcomes included inverse probability of treatment weighting (IPTW)-adjusted overall survival (OS), progression to metastatic castration-resistant prostate cancer (mCRPC), and prostate-specific antigen (PSA) response. A total of 384 patients were identified (ADT alone: 163, ADT + NSAA: 101, ADT + ARPI: 120). Median follow-up was 37.2, 38.1, and 34.8 months for ADT alone, ADT + NSAA, and ADT + ARPI, respectively. Compared with ADT alone, ADT + ARPI showed significantly better OS (HR [95% CI]: 0.61 [0.43 to 0.87], p = 0.007), lower risk of progression to mCRPC (0.46 [0.33 to 0.66], p < 0.001), and higher PSA response rate (PSA decline of ≥50% and ≥90% from baseline, and to <0.2 ng/mL and <0.1 ng/mL any time during first-line treatment; all p < 0.05). Outcomes with ADT + NSAA did not differ from ADT alone. ADT + ARPI was the most common second-line mCSPC and first-line mCRPC treatment. First-line ADT + ARPI was associated with significantly improved outcomes vs ADT alone in de novo mCSPC. These real-world results align with the benefits demonstrated in trials, supporting integration of TI with ARPIs into clinical practice to improve survival outcomes in patients with de novo mCSPC.

65 Background: Intensified androgen deprivation therapy (ADT) with an androgen receptor pathway inhibitor (ARPI) and/or docetaxel has led to improved outcomes for metastatic hormone-sensitive prostate cancer (mHSPC) in multiple clinical trials. Achievement of an undetectable PSA nadir has been associated with improved clinical outcomes, but real-world data across treatment regimens are limited. Methods: We evaluated PSA response and outcomes for patients with mHSPC treated with ADT monotherapy (mono), ADT + ARPI, and ADT + docetaxel in the International Registry for Men with Advanced Prostate Cancer (IRONMAN). All patients with mHSPC enrolled in IRONMAN between 2017 and August 2023 in the United States, Canada, Spain, and England were included. Patients treated with triplet therapy were excluded due to small numbers. Undetectable PSA nadir, defined as PSA &lt;0.2 ng/mL, was evaluated at 6 and 12 months after treatment start. In this real-world study, relapse was defined as meeting one of the following criteria: PSA progression (≥25% PSA increase from nadir and absolute increase &gt;2 ng/mL), treatment change preceded by new metastasis location, or change to a neuroendocrine prostate cancer regimen. Rates of relapse were calculated using Kaplan Meier estimates, with confidence intervals based on standard errors calculated using the Greenwood formula. Results: Among 1,377 eligible patients, treatment was most commonly ADT + ARPI (n=775) followed by ADT mono (n=375) and ADT + docetaxel (n=227). In the overall population, PSA nadir &lt;0.2 ng/mL was achieved in 40% (n=554) at 6 months and 51% (n=702) at 12 months. Rates of PSA nadir &lt;0.2 ng/mL at 6 months were: 51% for ADT + ARPI, 27% for ADT mono, and 26% for ADT + docetaxel. At 12 months, rates of PSA nadir &lt;0.2 ng/mL increased to: 63% for ADT + ARPI, 38% for ADT mono, and 32% for ADT + docetaxel. During a median follow-up of 18 months, 291 patients (21%) experienced disease relapse; 19% experienced PSA progression. The percentage of patients in each treatment group with disease relapse at months 12, 24, and 36 of treatment are shown (Table); treatment groups are divided by whether patients had achieved PSA nadir &lt;0.2 ng/mL in 6 months. Conclusions: In this non-randomized, real-world registry, patients with mHSPC who achieved a PSA nadir &lt;0.2 ng/mL had a lower relapse rate than patients who did not, regardless of treatment. Percentage (95% CI), [number at risk] of patients with relapse at timepoint. Treatment Month 6 Month 12 Month 24 Month 36 ADT Monotherapyn=375 PSA &lt;0.2 ng/mL 0%(0, 0)[60] 1.7%(0, 5.0)[31] 11%(0, 24)[15] PSA ≥0.2 ng/mL 18%(11, 24)[80] 41%(30, 51)[38] 45%(33, 55)[19] ADT + ARPIn=775 PSA &lt;0.2 ng/mL 2.2%(0.6, 3.8)[288] 9.7%(5.9, 13)[166] 18%(12, 24)[76] PSA ≥0.2 ng/mL 21%(16, 26)[178] 42%(35, 49)[81] 50%(42, 58)[37] ADT + Docetaxeln=227 PSA &lt;0.2 ng/mL 8.2%(0.2, 16)[44] 22%(8.9, 33)[29] 36%(18, 50)[14] PSA ≥0.2 ng/mL 34%(25, 43)[69] 62%(50, 72)[21] 73%(59, 82)[12]

TPS5129 Background: Management of patients (pts) with mCSPC remains a challenge due to its incurable nature and heterogeneous response to androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPI). Recent analyses of phase III ADT + ARPI trials show that mCSPC with suboptimal PSA response (≥0.2ng/ml at 6-12 months) have poor prognosis, short time to castration-resistance (CRPC) and 30-36 month median overall survival (OS). While docetaxel could also be utilized in mCSPC, there is equipoise about its use in ARPI-treated pts because of 1) an absence of randomized data for docetaxel in this setting, 2) toxicity of docetaxel with impact on quality of life for pts, and 3) selection of docetaxel treatment by disease volume rather than disease biology. CCTG-PR26 (TRIPLE-SWITCH) is a joint CCTG-SWOG trial run through the NCI National Clinical Trials Network. This study investigates whether adding docetaxel prior to development of CRPC, regardless of disease volume, will improve OS in ARPI-treated mCSPC pts that show evidence of suboptimal response. Methods: This international, open-label, randomized phase III trial compares standard ADT + ARPI against the addition of docetaxel to ADT + ARPI in mCSPC pts with suboptimal PSA response, defined as PSA ≥0.2 ng/mL after 6-12 months of ADT and ≥4 months of ARPI. Stratification will be based on PSA levels, ARPI type, presence of liver metastasis, disease recurrence status, and time since ADT initiation. Arm 1 will continue standard ADT + ARPI (abiraterone acetate with prednisone, apalutamide, enzalutamide or darolutamide). Arm 2 will receive docetaxel 75mg/m 2 IV every 3 weeks for up to 6 cycles in addition to continuing standard ADT + ARPI. Sample size is 830 pts in order to detect a targeted 33% improvement in overall survival (hazard ratio 0.75) using a 1-sided 0.025 level test with 85% power. Key eligibility criteria are: ≥18 years, histologically confirmed prostate adenocarcinoma, metastatic disease present and confirmed by conventional imaging (CT and/or bone scan), PSA ≥5.0 ng/mL prior to ADT, receipt of ADT for 6-12 months and ARPI for ≥4 months, PSA ≥0.2 ng/mL within 14 days of enrolment, adequate organ and marrow function, ECOG performance status 0-2, eligible for docetaxel chemotherapy, no evidence of disease progression or biochemical progression on ADT prior to enrolment. Primary endpoint is overall survival. Secondary endpoints include PSA response, PSA kinetics, and clinical progression free-survival. Correlative studies will explore the prognostic and predictive value of circulating tumor DNA (ctDNA) and the association between molecular signatures in primary prostate cancer tissue and clinical outcomes. Enrolment has been initiated in January 2025 and is ongoing. Clinical trial information: NCT06592924 .