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Until 2010, docetaxel was the only agent with proven survival benefit for castration-resistant prostate cancer. The development of cabazitaxel, abiraterone acetate, enzalutamide, radium-223, and sipuleucel-T has increased the number of treatment options. Because these agents were developed concurrently within a short period of time, prospective data on their sequential use efficacy are scarce. The challenge now is to reach a consensus on the best way to sequence effective treatments, ideally by the use of an approach specific to patient subgroups. However, the absence of robust surrogates of survival and the lack of predictive biomarkers makes data for the sequential use of these agents difficult to obtain and interpret.

Key Points The discovery of androgen dependence in prostate cancer in 1941 by Huggins and colleagues still remains the backbone for the treatment of advance-staged prostate cancer Over the past decade, the better understanding of the mechanisms driving resistance to castration has led to development of abiraterone acetate and enzalutamide, two next-generation androgen receptor (AR) targeting agents Several challenges remain including resistance to continued blocking of the AR axis, cross-resistance between agents, ideal sequence of administration, combination strategies, and coordination with other treatments Molecular characterization of patients, through next-generation sequencing or transcriptome analysis, will help to dissect mechanisms of resistance and to identify biomarkers allowing the selection of patients for specific treatment The improved understanding of intra-patient molecular heterogeneity and of the multiple, redundant and compensatory signalling networks in cancers supports a role for rational combinatorial, targeted therapeutic approaches Over 70 years ago, Huggins and Hodges discovered that prostate cancer depends on androgens. Since then, targeting the androgen receptor signaling pathway has remained the backbone of prostate cancer treatment. This Review discusses the past, present and future of androgen receptor targeting therapeutics. The discovery of androgen dependence in prostate cancer in 1941 by Huggins and colleagues has remained the backbone for the treatment of this disease. However, although many patients initially respond to androgen depletion therapy, they almost invariably relapse and develop resistance with transition of the disease to a castration-resistant state. Over the past decade, the better understanding of the mechanisms that drive resistance to castration has led to the development of next-generation androgen receptor targeting agents such as abiraterone acetate and enzalutamide. This Review aims to revisit the discovery and evolution of androgen receptor targeting therapeutics for the treatment of advanced-stage prostate cancer over the years and to discuss the upcoming future and challenges in the treatment of this common cancer.

Tumor heterogeneity in metastatic prostate cancer (mPC) is well established, but comprehensive characterization using routine sampling remains challenging. Autopsy-based research addresses this obstacle by enabling broad tissue collection within individual patients after treatment. In this issue of the JCI, Roudier et al. analyzed samples from a mPC research autopsy cohort, revealing extensive inter- and intratumor heterogeneity across patients and at the cellular level. The authors associated this variability with genomic, phenotypic, and clinical features and explored the importance of tumors expressing both androgen receptor and neuroendocrine markers. Their findings demonstrate heterogeneity across metastatic sites that may influence treatment response and clinical outcomes, informing future therapeutic strategies in mPC.

STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL). Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively. Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC. ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544.

The survival benefit in these two gene subgroups is consistent with the improvement in rPFS observed in an individual patient meta-analysis, 12 which included the TALAPRO-2 trial, investigating PARP inhibition in this disease setting. Because crossover to PARP inhibition was not performed as part of the trial for the placebo group, TALAPRO-2 did not directly test whether the longer and earlier exposure to talazoparib improves survival versus potentially shorter durations of treatment after progression. [...]PARP inhibitor plus ARPI combinations could be primarily administered at start of androgen deprivation therapy for metastatic castration-sensitive prostate cancer. 15 This setting has the additional advantage that tumour genomic sequencing is more likely to be successful. [...]TALAPRO-2 shows a clear benefit for enzalutamide plus talazoparib in patients with tumours that have DNA damage repair gene defects that sensitise to PARP inhibitors, by a process known as synthetic lethality.

The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC. ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone–prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone–prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov, number NCT02257736. 982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone–prednisone; 490 to abiraterone–prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0–28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4–27·4) in the apalutamide plus abiraterone–prednisone group versus 16·6 months (13·9–19·3) in the abiraterone–prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58–0·83; p<0·0001). At the updated analysis (final analysis for overall survival; median follow-up 54·8 months [IQR 51·5–58·4]), median radiographic progression-free survival was 24·0 months (95% CI 19·7–27·5) versus 16·6 months (13·9–19·3; HR 0·70, 95% CI 0·60–0·83; p<0·0001). The most common grade 3–4 treatment-emergent adverse event was hypertension (82 [17%] of 490 patients receiving apalutamide plus abiraterone–prednisone and 49 [10%] of 489 receiving abiraterone–prednisone). Serious treatment-emergent adverse events occurred in 195 (40%) patients receiving apalutamide plus abiraterone–prednisone and 181 (37%) patients receiving abiraterone–prednisone. Drug-related treatment-emergent adverse events with fatal outcomes occurred in three (1%) patients in the apalutamide plus abiraterone–prednisone group (2 pulmonary embolism, 1 cardiac failure) and five (1%) patients in the abiraterone–prednisone group (1 cardiac failure and 1 cardiac arrest, 1 mesenteric arterial occlusion, 1 seizure, and 1 sudden death). Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone–prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC. Janssen Research & Development.

Although androgen deprivation therapy is typically given long-term for men with metastatic prostate cancer, second-generation hormone therapies are generally discontinued before the subsequent line of treatment. We aimed to evaluate the efficacy of continuing enzalutamide after progression in controlling metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel and prednisolone. PRESIDE was a two-period, multinational, double-blind, randomised, placebo-controlled, phase 3b study done at 123 sites in Europe (in Austria, Belgium, Czech Republic, France, Germany, Greece, Italy, Netherlands, Norway, Poland, Russia, Spain, Sweden, Switzerland, Turkey, and the UK). Patients were eligible for period 1 (P1) of the study if they had histologically confirmed prostate adenocarcinoma without neuroendocrine differentiation or small-cell features, serum testosterone concentrations of 1·73 nmol/L or less, and had progressed during androgen deprivation therapy with a luteinising hormone-releasing hormone agonist or antagonist or after bilateral orchiectomy. In P1, patients received open-label enzalutamide 160 mg per day orally. At week 13, patients were assessed for either radiographic or prostate-specific antigen (PSA) progression (25% or more increase and 2 ng/mL or more above nadir). Patients who showed any decline in PSA at week 13 and subsequently progressed (radiographic progression, PSA progression, or both) were screened and enrolled in period 2 (P2), during which eligible patients were treated with up to ten cycles of intravenous docetaxel 75 mg/m2 every 3 weeks and oral prednisolone 10 mg/day, and randomly assigned (1:1) to oral enzalutamide 160 mg/day or oral placebo. Patients were stratified by type of disease progression. The block size was four and the overall number of blocks was 400. Patients, investigators, and study organisers were masked to treatment assignment. The primary endpoint was progression-free survival analysed in all patients in P2. This trial is registered with ClinicalTrials.gov, NCT02288247, and is no longer recruiting. Between Dec 1, 2014, and Feb 15, 2016, 816 patients were screened for P1 of the study. 688 patients were enrolled in P1 and 687 received open-label enzalutamide. In P2, 271 patients were randomly assigned at 73 sites to receive enzalutamide (n=136) or placebo (n=135). The data cutoff for analysis was April 30, 2020. Median progression-free survival with enzalutamide was 9·5 months (95% CI 8·3–10·9) versus 8·3 months (6·3–8·7) with placebo (hazard ratio 0·72 [95% CI 0·53–0·96]; p=0·027). The most common grade 3 treatment-emergent adverse events were neutropenia (17 [13%] of 136 patients in the enzalutamide group vs 12 [9%] of 135 patients in the placebo group) and asthenia (ten [7%] vs six [4%]). The most common grade 4 treatment-emergent adverse event in P2 was neutropenia (23 [17%] of 136 patients in the enzalutamide group vs 28 [21%] of 135 patients in the placebo group). Serious treatment-emergent adverse events were reported in 67 (49%) of 136 patients in the enzalutamide group and 52 (39%) of 135 patients in the placebo group. Two (15%) of 13 deaths in the enzalutamide group (caused by septic shock and haematuria) and one (14%) of seven deaths in the placebo group (caused by actue kidney injury) were associated with docetaxel. PRESIDE met its primary endpoint and showed that continuing enzalutamide with docetaxel plus androgen deprivation therapy delayed time to progression compared with docetaxel plus androgen deprivation therapy alone, supporting the hypothesis that enzalutamide maintenance could control persistent androgen-dependent clones in men with mCRPC who progress after treatment with enzalutamide alone. Astellas Pharma and Pfizer.

RECONCILE (ClinicalTrials.gov:NCT04340245) will identify molecular and radiomic markers associated with clinical progression and radiological progression events in a cohort of localised, newly diagnosed Gleason 3 + 4 tumours. Molecular markers will be correlated against standard of care MRI-targeted histology and oncological outcomes. RECONCILE is an ethics approved (20/LO/0366) single centre, prospective, longitudinal, observational cohort study of recently diagnosed (within 12 months), organ-confined Gleason 3 + 4 cancers (MCCL ≤10mm) currently under active surveillance. 60 treatment-naïve participants with a concordant MRI lesion (Likert score 4 or 5) and PSA ≤ 15 ng/ml will be recruited. Blood, urine and targeted prostate tissue cores will be subject to next generation sequencing at baseline and one year in all participants. Semen will be collected from a specified sub-population. Baseline and interval MR images will be extracted from standard of care prostate MRI ahead of radiomic analysis. Data extracted from radiological and biological samples will be used to derive the association of molecular change and radiological progression, the primary outcome of the study. To compensate for spatial intratumoral heterogeneity and inherent sampling bias, a molecular index will be derived for each participant using the molecular profile of tumour tissue at both baseline (MolBL) and one year (MolFU). We will extract a ΔMolBL:MolFU score for each participant. Molecular progression will be defined as a MolBL:MolFU score >95% CI of the combined ΔMolBL scores. Radiological progression is defined as a PRECISE score of 4 or 5. The study is powered to detect an association with a statistical power of 80%. Recruitment began in July 2020 (n = 62). To date, 37 participants have donated tissue for analysis. We have designed and implemented a prospective, longitudinal study to evaluate the underlying molecular landscape of intermediate risk, MR-visible prostate tumours. Recruitment is ongoing.

Background In a Phase 2 clinical trial, we aimed to determine the lutetium-177 [ 177 Lu]-PSMA-617 activity and the clinical utility of levels of plasma androgen receptor (AR) gene in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). Methods We determined AR copy number in pretreatment plasma samples. We used logistic regression to estimate the odds ratio (OR) and 95% confidence intervals (95% CIs) in order to evaluate the independent relevance of AR status and to evaluate patients with early progressive disease (PD) defined as treatment interruption occurring within 4 months after the start of 177 Lu-PSMA-617. Results Twelve of the 15 (80%) with AR gene gain and 5 of the 25 (20%) patients with no gain of AR had early PD ( p  = 0.0002). The OR for patients without PSA response having AR gain was 3.69 (95% CI 0.83–16.36, p  = 0.085). The OR for patients with early PD having AR gain was 16.00, (95% CI 3.23–79.27, p  = 0.0007). Overall, median PFS and OS were 7.5 and 12.4 months, respectively. AR -gained had a significant shorter OS compared to AR -normal patients (7.4 vs 19.1 months, p  = 0.020). No treatment interruptions due to adverse effects were reported. Discussion Plasma AR status helped to indicate mCRPC with early resistance to 177 Lu-PSMA-617. Trial registration NCT03454750.

ABSTRACT Background Plasma tumour DNA (ptDNA) levels on treatment are associated with response in a variety of cancers. However, the role of ptDNA in prostate cancer monitoring remains largely unexplored. Here we characterised on-treatment ptDNA dynamics and evaluated its potential for early assessment of therapy efficacy for metastatic castration-resistant prostate cancer (mCRPC). Methods Between 2011 and 2016, 114 sequential plasma samples from 43 mCRPC abiraterone-treated patients were collected. Targeted next-generation sequencing was performed to determine ptDNA fraction. ptDNA progressive disease was defined as a rise in the fraction compared to the pre-treatment. Results A ptDNA rise in the first on-treatment sample (interquartile range (IQR) 2.6–3.7 months) was significantly associated with increased risk of early radiographic or any prostate-specific antigen (PSA) rise (odds ratio (OR) = 15.8, 95% confidence interval (CI) 3.5–60.2, p  = 0.0002 and OR = 6.0, 95% CI 1.6–20.0, p  = 0.01, respectively). We also identified exemplar cases that had a rise in PSA or pseudoprogression secondary to bone flare but no rise in ptDNA. In an exploratory analysis, initial ptDNA change was found to associate with the duration of response to prior androgen deprivation therapy ( p  < 0.0001) but not to prior taxanes ( p  = 0.32). Conclusions We found that ptDNA assessment for therapy monitoring in mCRPC is feasible and provides data relevant to the clinical setting. Prospective evaluation of these findings is now merited.