Optimización de la triple terapia en el tratamiento del cáncer de próstata hormonosensible metastásico

Optimizing triple therapy in patients with metastatic hormone-sensitive prostate cancer

e17082 Background: Severalguidelines recommended the use of androgen receptor pathway inhibitors (ARPIs) and/or docetaxel along with ADT for mHSPC based on improved clinical outcomes demonstrated in clinical trials. Given the evolving treatment landscape since 2016, there is a need to understand the translation of clinical evidence and guidelines into clinical practice. Therefore, we examined the use of, and factors associated with intensification beyond ADT in men with mHSPC. Methods: A retrospective cohort of men treated for mHSPC was selected from private insurance claims of the Komodo Research Dataset (Jan 2017-Sep 2023). Men with mHSPC were identified based on their earliest claim for metastasis on or after prostate cancer diagnosis date without evidence of castration resistance. Index date was the earliest claim of ADT following mHSPC. Continuous insurance coverage for ≥ 12 months pre- (baseline) and ≥ 4 months post-index was required. Intensification beyond ADT was defined as the addition of ARPIs, docetaxel or both within ±4 months of the index date. Multinomial regression was conducted to examine factors associated with ADT intensification. Results: The study cohort comprised of 10,717 men with mHSPC with a median age of 65 years. Most had de novo mHSPC (62%), bone-only metastases (49%), hypertension (68%), diabetes (29%), and received opioids (59%) at baseline. Overall, in addition to ADT, 28% received ARPI (abiraterone: 18%, androgen receptor inhibitors: 10%), 9% docetaxel and 2.5% ARPI + docetaxel. From 2017 to 2023, there has been an increase in the intensification of ADT with ARPI from 13% to 47% and with docetaxel + ARPI from 0.8% to 15%, while the use of ADT + docetaxel declined from 12% to 3% and ADT alone from 74% to 36%. Key factors (age, comorbidity, de novo mHSPC, bone metastases) associated with intensification with either docetaxel or ARPI are listed in Table. Conclusions: There was a linear increase in intensification with ARPI and/or docetaxel in mHSPC between 2017-2023 in the US. Findings highlight a gradual uptake of guideline-recommended treatment for men with mHSPC, while over a third are still receiving ADT alone. [Table: see text]

Metastatic Burden in Hormone-Naive Prostate Cancer: A Tale of Two Subgroups

To conduct a systematic literature review of real-world data (RWD) studies to summarise treatment patterns among men with metastatic hormone-sensitive prostate cancer (mHSPC).While androgen-deprivation therapy (ADT) is a primary treatment strategy for mHSPC, ADT intensification with androgen receptor pathway inhibitors (ARPIs) and/or chemotherapy is recommended by current guidelines and has improved clinical outcomes in the last decade. We searched electronic databases (PubMed; Excerpta Medica dataBASE [EMBASE]) for eligible studies (retrospective or prospective observational RWD studies examining mHSPC treatment patterns) between database inception and July 2023, and manually screened the past 2 years of relevant conference proceedings. Of 2336 retrieved citations, 29 studies met the inclusion criteria, covering North America (United States, n = 21; Canada, n = 2), Europe (n = 8), and Asia (n = 6). Most studies utilised retrospective cohorts (n = 26) and included men with a median age of ≥70 years (n = 20). ADT monotherapy was predominantly used across geographies, followed by ADT + ARPI and ADT + docetaxel in the United States and Europe but not in Asia, where use of each combination remained low. Studies with recent electronic medical record data from cancer centres/registries showed >40% use of ADT + ARPI in the United States and Europe. Abiraterone was the most frequently used ARPI, followed by enzalutamide. Quantitative factors associated with ADT intensification were high disease burden, younger age, Eastern Cooperative Oncology Group performance status score of 0 to 1, fewer comorbidities, and oncologist physician specialty; qualitative factors were patient preference, unsatisfactory response to ADT, ability to tolerate adverse events, and absence of cost barriers. While there was an increasing trend in ADT intensification for mHSPC over the study period across geographies, use remained suboptimal considering the high proportion of patients who were still receiving ADT monotherapy only. These findings highlight the need for interventions to further optimise current mHSPC therapies with high guideline concordance.

Real-world Evidence on Baseline Characteristics and Treatment in Metastatic Hormone-sensitive Prostate Cancer: Findings from the PIONEER 2.0 Big Data Investigation Group

Observational Health Data Analysis of the Cardiovascular Adverse Events of Systemic Treatment in Patients with Metastatic Hormone-sensitive Prostate Cancer: Big Data Analytics Using the PIONEER Platform.

Background: Treatment intensification strategies with an androgen receptor pathway inhibitor (ARPI) and/or docetaxel chemotherapy in addition to androgen deprivation therapy (ADT) are guideline recommended treatment options for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Prevalence of guideline concordant care for mHSPC patients in the US and its changes over time are not well characterized. Methods: The International Registry for Men with Advanced Prostate Cancer (IRONMAN) is a prospective cohort study of patients with newly diagnosed mHSPC and castration-resistant prostate cancer (CRPC). Therapies are captured by site personnel and by directly capturing data from treating physicians via physician questionnaires (PQ). We included all US patients with mHSPC enrolled from 2018 to January 1, 2023 with a completed PQ at enrollment. We examined patient characteristics, first-line treatments for mHSPC, and guideline concordance of first-line treatments. Guideline concordance was defined as a treatment regimen listed in the first National Comprehensive Cancer Network guidelines version for the year prior to treatment. Patients enrolled in clinical trials were excluded from analysis of treatment guideline concordance. Results: Among the 636 US participants with mHSPC, physicians completed PQs for 458 participants (72%). Participants had a median age of 68 years (interquartile range 62 - 75). Three hundred eight (78%) were White, 72 (18%) were Black, 13 (3%) were other races/ethnicities: 65 did not report race. First-line treatment for mHSPC based on the PQ was most commonly ADT + ARPI (59%) followed by ADT + docetaxel (17%), ADT monotherapy (14%), ADT + first-generation antiandrogen (3%), ADT + ARPI + docetaxel (3%), and other treatments (5%). Overall, 384 (86%) participants received first-line treatment that was guideline concordant at the time of treatment. Treatment guideline concordance was highest in 2018 (99%) when ADT monotherapy was considered as guideline concordant but then decreased to 80% in 2019 and remained largely stable from 2019 to 2022 (85%). Overall, rates of guideline concordance were similar when stratified by race (88% for White patients vs 85% for Black patients), age (90% for patients <65 years old vs 85% for patients ≥65 years old), and treatment at a Comprehensive Cancer Center (CCC) (87% at CCC vs 86% at non-CCC). Conclusion: Among patients with mHSPC treated in the US at 38 cancer centers, proportions of guideline concordant first-line treatment were high and remained stable over time, despite changes in approved therapies. Future efforts to understand reasons for treatment decisions will be important to better understand the relatively uncommon situations in which guidelines and actually received treatments differ for patients with mHSPC. Citation Format: Hannah Dzimitrowicz McManus, Lauren Howard, Kerri-Anne Crowell, Terry Hyslop, Jake Vinson, Dana E. Rathkopf, Philip Kantoff, Lorelei A. Mucci, Daniel George, Konrad Stopsack. Treatment guideline concordance for patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the United States in IRONMAN, the International Registry for Men with Advanced Prostate Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3812.

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 <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 >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 <0.2 ng/mL was achieved in 40% (n=554) at 6 months and 51% (n=702) at 12 months. Rates of PSA nadir <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 <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 <0.2 ng/mL in 6 months. Conclusions: In this non-randomized, real-world registry, patients with mHSPC who achieved a PSA nadir <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 <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 <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 <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]

Prostate Radiotherapy in Low-volume Metastatic Hormone-sensitive Prostate Cancer: A Network Meta-analysis

5092 Background: Combination therapy has improved treatment of metastatic hormone sensitive prostate cancer (mHSPC). Doublets include androgen deprivation therapy (ADT) plus docetaxel (DOC) or the androgen receptor pathway inhibitors (ARPIs) abiraterone, enzalutamide, apalutamide, or darolutamide. There have been no large clinical trials that compare DOC to ARPIs in mHSPC. This study evaluates overall survival and time to castration-resistance in patients with de novo (synchronous) mHSPC in the Veterans Health Administration treated with combination therapy. Methods: Veterans were identified with initial diagnosis of ‘distant’ prostate cancer. All veterans had ADT initiated within 4 months of diagnosis and followed until September 2023. First combination therapy with DOC from 7/2016-6/2021 or ARPI from 7/2017-6/2021 were included if initiated within 4 months after ADT. Volume of disease was determined from chart review and castration-resistance (mCRPC) by a combination of natural language processing and administrative data. Real-world progression-free survival (rwPFS) was determined as time to mCRPC or death. Kaplan-Meier time to event analyses and Cox proportional hazard modeling with age, Black race, Charlson comorbidity index, prostate specific antigen, body mass index, and weight change in the year prior was used for analyses. Results: 1,226 patients with de novo mHSPC were identified with median age of 71.5 years and 349 (28.6%) were Black. High volume disease was identified in 929 (76.0%) and low volume in 293 (24.0%). DOC was used in 341 (27.9%) and ARPIs in 881 (72.1%). Veterans with high volume disease had shorter overall survival (OS) than low volume (23.8 vs. 64.1 months, p<0.001). Overall, there was no difference in OS between DOC and ARPI (36.4 vs. 38.9 months, p=0.68), however DOC was associated with a shorter rwPFS (16.5 vs 22.1 months, p<0.001). In high volume disease, there was no difference in OS between DOC and ARPI (33.8 vs. 32.5 months, p=0.68), however DOC was associated with a shorter rwPFS (14.9 vs 19.2 months, p=0.002). In a multivariable model of patients with high volume disease, there was no difference in OS observed between initial treatment with DOC and ARPIs (aHR 0.83, 95% CI 0.69-1.00). Conclusions: In veterans with de novo mHSPC, no difference in OS were observed between combination treatment with DOC or ARPI in patients with low or high-volume mHSPC. ARPIs were associated with longer progression free survival. Due to a lack of clinical trials comparing DOC and ARPI therapy, these data may guide selection of combination therapy for mHSPC.[Table: see text]

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]

5097 Background: Docetaxel (DOC) continues to demonstrate efficacy in metastatic hormone sensitive prostate cancer (mHSPC), particularly in combination with androgen deprivation therapy (ADT) ± androgen receptor pathway inhibitors (ARPI). However, a paucity of data exists evaluating treatment sequencing with DOC for patients with high volume disease. We assessed overall survival (OS) of patients with mHSPC treated with either DOC followed by ARPIs or ARPIs followed by DOC. Methods: A nationwide retrospective study of 696 US Veterans with de novo (synchronous) mHSPC who received both DOC and an ARPI in combination with ADT in the Veterans Health Administration between 2015-2023. Of these, 581 (83.5%) had high-volume disease. Patients either received DOC (1) within 4 months of and (2) greater than 4 months after ADT. The early DOC group received an ARPI after the initial 4 months while the late DOC group received an ARPI within 4 months of ADT. Age, baseline PSA, Charlson comorbidity index (CCI) and BMI values were acquired for each patient. Survival analysis was performed using the Kaplan-Meier method. Results: Of the 581 Veterans with high-volume disease, 400 received DOC early (68.8%) and 181 received DOC later (31.2%). Patients who received DOC early had a significantly longer OS than those who received it later (median 36.3 vs 29.3 months, p<0.001, HR 0.65, 95% CI 0.53-0.80). Findings were similar when adjusted for age, baseline PSA, and CCI (aHR 0.69, 95% CI 0.56-0.85). Additionally, patients who received DOC early had a significantly longer rwPFS than those who received it later (median 17.0 vs 12.5 months, p<0.001, HR 0.63, 95% CI 0.52-0.76). Findings were similar when adjusted for age, baseline PSA, and CCI (aHR 0.64, 95% CI 0.53-0.78). Evaluation of baseline characteristics between DOC vs ARPI combination therapy showed that the early DOC group was younger (mean 66.4 vs 69.6 years, p<0.001). However, no other statistically significant differences were found between the two groups when comparing baseline PSA, BMI, and CCI. Conclusions: Initial DOC in Veterans with de novo high volume mHSPC was associated with longer survival. While all patients were candidates for chemotherapy, the Veterans who were treated early with DOC were younger. These finding support early docetaxel in patients with aggressive disease that are likely to develop castration-resistance and require subsequent therapies. Patient characteristics. Docetaxel Early (n=400) Docetaxel Late (n=181) p-value Age (mean) 66.4 69.6 < 0.001 Baseline PSA (median) 174 217 0.23 Creatinine Value (median) 1.00 1.02 0.1 BMI (mean) 28.7 28.0 0.06 Charlson Comorbidity Index (mean) 1.66 1.90 0.36

20 Background: Clinical features of people with mHSPC may affect their outcomes from the addition of ARPIs to androgen deprivation therapy (ADT). The STOPCAP Collaboration is seeking IPD to reliably investigate potential ARPI effect modifiers and determine who benefits more from an ARPI vs docetaxel plus ADT doublet. Methods: Full methods are in registered protocols (CRD42023431331; CRD4202540066). We sought IPD for completed trials examining effects of ARPIs for mHSPC. Initially, we examined ARPI effects using intention-to-treat, two-stage, common-effect meta-analysis of hazard ratios (HRs), adjusted for a core set of covariates and use of concomitant docetaxel. Main effects were based on overall survival (OS). Interaction effects were based on progression-free survival (PFS) to maximise power, then OS whenever PFS interactions were found (P<0.10). Within clinically-relevant subgroups, ARPI and docetaxel doublet effects were compared using two-stage, contrast-based, random-effects network meta-analysis (NMA). Results: By October 2024, we had updated IPD from five trial comparisons: LATITUDE, STAMPEDE A vs G, SWOG-1216, ENZAMET, and STAMPEDE A vs J. Based on these (2882 events/5472 pts), adding an ARPI to ADT improved OS (HR=0.69, 95% CI=0.64-0.74). Four trial comparisons (excluding SWOG-1216) provided PFS data (2781 events/4161 pts) and showed improved PFS (HR=0.49, 95% CI=0.45-0.53). The relative benefit of ARPIs on PFS increased with younger age (interaction p=0.034), higher BMI (interaction p=0.048), and lower burden of metastases (interaction p=0.096). These effects were similar for OS (age interaction p=0.035; BMI interaction p=0.031; volume interaction p=0.25). The age effect was most pronounced in the abiraterone trials. Combining IPD from the ARPI + ADT and docetaxel + ADT trials (GETUG-AFU-15, CHAARTED, STAMPEDE A vs C) in NMA suggested that overall, an ARPI doublet may improve OS more than a docetaxel doublet (HR=0.85, 95% CI=0.70-1.03). However, when the NMA was confined to participants with high-volume, synchronous disease, where docetaxel is most efficacious (but excluding SWOG-1216, for which these data were not available), effects on OS were: HR=0.89, 95% CI=0.74-1.06. Conclusions: Our preliminary results suggest that people with mHSPC who are younger, have a higher BMI, or have low volume disease, may benefit more from ARPIs. ARPI and docetaxel doublets seem similarly effective in high-volume, synchronous disease. We will present updated analyses, incorporating recently received PEACE 1 IPD, for a clearer picture of ARPI effects, including subgroup-specific effects. Ongoing collection of IPD from other key trials will allow robust comparison of ARPI doublet with triplet therapy (including docetaxel), guiding more personalised treatment.

169 Background: Combination therapies, such as androgen deprivation therapy (ADT) + androgen receptor pathway inhibitor (ARPI) +/- docetaxel, were shown to improve overall survival (OS) in pts with mHSPC. However, some pts are still characterized by EP. EMETPRO study analyzed these pts and their response to treatments administered at progression. Methods: EMETPRO is a multicenter, retrospective registry of pts with EP mHSPC defined as pts who have progression ≤ 6 months (m) under combination therapies (ADT + docetaxel or ADT + ARPI) or ≤ 9 m from ADT alone start. The primary endpoint is progression-free survival (PFS) calculated from the start of first-line (1°L) treatment for mCRPC in the entire population and in the different treatments sub-cohorts based on the treatment received in mHSPC. Secondary endpoints included OS calculated from the start of treatment for mHSPC and from the start of 1°L treatment for mCRPC. Results: From May 2005 to May 2023 431 pts were enrolled in the study. Median age was 69 years. Molecular analyses were available in 195 (45.2%) pts (Table). 206 (47.8%) pts received ADT alone for mHSPC while 123 (28.6%) and 77 (17.8%) pts received ADT + docetaxel and ADT + ARPI, respectively. 80 (38.8%) and 66 (32.0%) pts treated with ADT alone in mHSPC received ARPI or docetaxel as 1°L mCRPC treatment, respectively. 77 (62.6%) and 13 (10.6%) pts treated with ADT+ docetaxel in mHSPC received ARPI or cabazitaxel in mCRPC, respectively. 46 (59.7%) and 7 (9.1%) pts treated with ADT+ ARPI in mHSPC received docetaxel or a second ARPI in mCRPC, respectively. 14 pts (3.2%) received olaparib or radioligand treatments as 1°L mCRPC therapy. The median PFS from the start of 1°L treatment for mCRPC was 6.5, 4.9, and 5.4 m for pts that received ADT, ADT + docetaxel and ADT + ARPI, respectively. The median OS from mHSPC was 27.0, 20.0, and 19.5 m, in the same groups while the median OS from 1°L treatment for mCRPC was 18.5, 12 and 14.6 m, respectively. The 1°L therapy received in the mCRPC setting and the molecular profile did not correlate with PFS or OS. Conclusions: Pts with EP mHSPC are characterized by poor outcomes regardless of treatment received at progression. The best 1°L mCRPC therapy to use in these pts remains a crucial unmet clinical need. Future studies evaluating novel mechanisms (e.g. olaparib or lutetium PSMA) or intensification strategies (e.g. cabazitaxel and/or carboplatin) in this setting are urgently needed. Baseline characteristics. Number (N°) of pts 431 GS≥8 at mHSPC, N° (%) 278 (64.5) High-volume disease (CHAARTEED), N° (%) 302 (70.1) N° of pts with germline testing results 63 Alterations detected, N° (%) 24 (38.1) BRCA alterations detected, N° (%) 13 (20.6) N° of pts with somatic testing results 181 DNA damage response and repair gene alterations, No. (%) 47 (26.0) At least one TP53/PTEN/RB1 gene mutation detected, No. (%) 84 (46.4)

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). 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. 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. In select subgroups, early treatment intensification with combination therapy leads to improved survival, though it can be associated with long-term toxicity.