Implications of metastatic stage at presentation in docetaxel naïve metastatic castrate resistant prostate cancer.

BACKGROUND: We performed a secondary analysis of ACIS study to determine if synchronous versus metachronous metastatic presentation has any association with survival and treatment response to dual androgen receptor axis-targeted therapy (ARAT) in docetaxel naïve metastatic castrate resistant prostate cancer (mCRPC). METHODOLOGY: In this phase III randomized controlled trial, docetaxel naïve mCRPC patients were randomized to either apalutamide or placebo combined with abiraterone and prednisone. Multivariable Cox regression models were applied to determine the adjusted association of M-stage with radiographic progression-free survival (rPFS) and overall survival (OS). To determine the heterogeneity of treatment effect based on metastatic stage (M-stage) at presentation, Cox regression was applied with interaction terms between M-stage and treatment. RESULTS: Among 972 patients, 432 had M0, 334 had M1, while M-stage at presentation was unknown in 206. There was no association of M-stage at presentation with rPFS in patients with prior local therapy (LT) (hazard ratio for M1-stage: 1.22 [95% confidence interval: 0.82-1.82]; unknown: 1.03 [0.77-1.38]) or without prior LT (M1-stage: 0.87 [0.64-1.19]; unknown: 1.15 [0.77-1.72]) with no significant heterogeneity. Similarly, there was no association of M-stage with OS in patients with prior LT (M1-stage: 1.04 [0.81-1.33]; unknown: 0.98 [0.79-1.21]) or without prior LT (M1-stage: 0.95 [0.70-1.29]; unknown: 1.17 [0.80-1.71]) with no significant heterogeneity. Based on M-stage at presentation, we did not find any significant heterogeneity in treatment effect on rPFS (interaction p = 0.13), and OS (interaction p = 0.87). CONCLUSION: M-stage at presentation had no association with survival in chemotherapy-naïve mCRPC. We did not find any statistically significant heterogeneity in efficacy of dual ARAT based on synchronous versus metachronous presentation.

Real-world effectiveness of third-line cabazitaxel in patients with metastatic castration-resistant prostate cancer: CARD-like analysis of data from a post-marketing surveillance in Japan.

BACKGROUND: The CARD trial was conducted in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received docetaxel and experienced disease progression within 1 year on an androgen receptor-axis-targeted therapy (ARAT). Subsequent treatment with cabazitaxel had improved clinical outcomes compared with an alternative ARAT. This study aims to confirm the effectiveness of cabazitaxel in real-world patients in Japan and compare their characteristics with those of patients from the CARD trial. METHODS: This was a post-hoc analysis of a nationwide post-marketing surveillance registering all patients who were prescribed cabazitaxel in Japan between September 2014 and June 2015. Included patients had received docetaxel and ≤ 1 year of an ARAT (abiraterone or enzalutamide) prior to receiving cabazitaxel or an alternative ARAT, as their third-line therapy. The primary effectiveness endpoint was the time to treatment failure (TTF) of the third-line therapy. Patients were matched (1:1) from the cabazitaxel and second ARAT arms based on propensity score (PS). RESULTS: Of the 535 patients analysed, 247 received cabazitaxel and 288 the alternative ARAT as their third-line therapy, of which, 91.3% (n = 263/288) received abiraterone and 8.7% (n = 25/288) received enzalutamide as their second third-line ARAT. Patients in the cabazitaxel and second ARAT arms had TNM classification of M1 or MX in 73.3% and 68.1%, Gleason score of 8-10 in 78.5% and 79.2% and mean (standard deviation) serum PSA levels of 483 (1370) and 594 (1241) ng/mL, respectively. Initial cabazitaxel dose was ≤ 20 mg/m2 in 61.9% (n = 153/247) of the patients in the cabazitaxel arm. The median TTF (95% confidence interval [CI]) of the third-line therapy was 109 (94-128) days for cabazitaxel and 58 (57-66) days for the second ARAT, with a hazard ratio (95% CI) of 0.339 (0.279-0.413) favouring cabazitaxel. Similar results were obtained after PS-matching, with a hazard ratio (95% CI) of 0.323 (95% CI 0.258-0.402) favouring cabazitaxel. CONCLUSIONS: Consistent with the CARD trial, cabazitaxel demonstrated superior effectiveness over a second alternative ARAT in a real-world patient population in Japan, despite the population having more advanced disease status and a lower dose of cabazitaxel being more frequently administered, than in the CARD trial.

TOward a comPrehensive supportive Care intervention for Older men with metastatic Prostate cancer (TOPCOP3): A pilot randomized controlled trial and process evaluation.

INTRODUCTION: Current management of metastatic prostate cancer (mPC) includes androgen receptor axis-targeted therapy (ARATs), which is associated with substantial toxicity in older adults. Geriatric assessment and management and remote symptom monitoring have been shown to reduce toxicity and improve quality of life in patients undergoing chemotherapy, but their efficacy in patients being treated with ARATs has not been explored. The purpose of this study is to examine whether these interventions, alone or in combination, can improve treatment tolerability and quality of life (QOL) for older adults with metastatic prostate cancer on ARATs. MATERIALS AND METHODS: TOPCOP3 is a multi-centre, factorial pilot clinical trial coupled with an embedded process evaluation. The study includes four treatment arms: geriatric assessment and management (GA + M); remote symptom monitoring (RSM); geriatric assessment and management plus remote symptom monitoring; and usual care and will be followed for six months. The aim is to recruit 168 patients between two cancer centres in Toronto, Canada. Eligible participants will be randomized equally via REDCap. Participants in all arms will complete a comprehensive baseline assessment upon enrollment following the Geriatric Core dataset, as well as follow-up assessments at 1.5, 3, 4.5, and 6 months. The co-primary outcomes will be grade 3-5 toxicity and QOL. Toxicities will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. QOL will be measured by patient self-reporting using the EuroQol 5 dimensions of health questionnaire. Secondary outcomes include fatigue, insomnia, and depression. Finally, four process evaluation outcomes will also be observed, namely feasibility, fidelity, and acceptability, along with implementation barriers and facilitators. DISCUSSION: Data will be collected to observe the effects of GA + M and RSM on QOL and toxicities experienced by older adults receiving ARATs for metastatic prostate cancer. Data will also be collected to help the design and conduct of a definitive multicentre phase III randomized controlled trial. This study will extend supportive care interventions for older adults with cancer into new areas and inform the design of larger trials. TRIAL REGISTRATION: The trial is registered at clinicaltrials.gov (registration number: NCT05582772).

H19 in Serum Extracellular Vesicles Reflects Resistance to AR Axis-targeted Therapy Among CRPC Patients.

BACKGROUND/AIM: We aimed to evaluate the changes of androgen receptor (AR) signaling-related long non-coding RNAs (lncRNAs) in serum extracellular vesicles (EVs) from prostate cancer (PC) patients, in order to identify novel biomarkers for AR axis-targeted therapy (ARAT)-resistance among castration-resistant PC (CRPC) patients. PATIENTS AND METHODS: EVs were isolated from 2 patients before and after acquiring ARAT-resistance. RNA profiling of EVs was performed by RNA-sequencing. The expression levels of selected lncRNAs in EVs were analyzed by digital droplet PCR (ddPCR) in 58 localized and 14 metastatic PC patients at diagnosis, 7 ARAT-naïve and 6 ARAT-resistant CRPC patients. LncRNA H19 expression in PC tissue was examined using published data. In order to analyze the role of H19, the prognosis was analyzed in PC patients and proteomic analysis was performed in 22Rv1 PC cells. RESULTS: RNA-sequencing revealed that AR-regulated RNAs were most enriched in EVs after acquiring ARAT-resistance. Among them, up-regulation of AR signaling-related lncRNAs (PCAT1, H19, HOXA-11AS, ZEB1-AS1, ARLNC1, PART1, CTBP1-AS and PCA3) was confirmed by ddPCR. H19 contained in EVs (EV-H19) was significantly increased among ARAT-resistant patients compared to ARAT-naïve CRPC or metastatic PC patients. In PC tissue, H19 was negatively correlated with AR protein and AR-activity score and up-regulated in neuroendocrine CRPC tissue with low AR expression. Furthermore, EV-H19 expression was significantly associated with worse outcome to androgen-deprivation therapy. Proteomic analysis demonstrated that H19 knockdown enhanced PC-related protein expression. CONCLUSION: EV-H19 may negatively correlate with AR-signaling activity and could be a marker to diagnose ARAT-resistance among CRPC patients.

Survival of Patients with Metastatic Prostate Cancer After Disease Progression on an Androgen Receptor Axis-Targeted Therapy Given in the Metastatic Castration-Sensitive Versus Metastatic Castration-Resistant Prostate Cancer Setting.

Androgen receptor axis-targeted therapies (ARATs; androgen receptor or androgen synthesis inhibitors) have been approved for the treatment of patients with metastatic castration-sensitive and castration-resistant prostate cancer (mCSPC and mCRPC) on the basis of improved overall survival (OS) in randomized clinical trials. However, it is not clear whether the OS for patients after progression on first-line ARAT differs if the first ARAT was administered in the mCSPC versus mCRPC setting and what its estimates are. We assessed the OS after disease progression on ARAT given as first-line therapy in mCSPC versus mCRPC. Patient-level data were collected retrospectively, and only those treated with first-line ARAT for mCSPC or mCRPC were included. For patients receiving ARAT in the mCRPC setting, no prior ARAT was allowed in the mCSPC setting. The median OS and hazard ratio (HR) were determined via Kaplan-Meier analysis from the time of progression on ARAT. Of 382 patients treated with first-line ARAT, 172 (44 mCSPC and 128 mCRPC) had experienced disease progression and were included in the analysis. Median OS was similar in the mCSPC (23 mo) and mCRPC (17 mo) settings (HR 0.99, 95% confidence interval 0.62-1.56; p = 0.95). A total of 138 patients received subsequent systemic therapy after progression. Our results suggest that median OS is similar after progression on one ARAT, whether given in the first-line mCSPC or first-line mCRPC setting, and is estimated to be <2 yr. These data have implications for patient prognostication and the design of clinical trials in the post-ARAT setting for further drug development. PATIENT SUMMARY: We investigated whether the survival benefit differs between metastatic castration-sensitive and castration-resistant prostate cancer for patients who have already experienced cancer progression after first-line treatment with one drug targeting the androgen receptor pathway  (called ARAT). We found that the median survival benefit was less than 2 years and was similar for the two groups.

A transcriptional biosensor to monitor single cancer cell therapeutic responses by bioluminescence microscopy.

When several life-prolonging drugs are indicated for cancer treatment, predictive drug-response tumor biomarkers are essential to guide management. Most conventional biomarkers are based on bulk tissue analysis, which cannot address the complexity of single-cell heterogeneity responsible for drug resistance. Therefore, there is a need to develop alternative drug response predictive biomarker approaches that could directly interrogate single-cell and whole population cancer cell drug sensitivity. In this study, we report a novel method exploiting bioluminescence microscopy to detect single prostate cancer (PCa) cell response to androgen receptor (AR)-axis-targeted therapies (ARAT) and predict cell population sensitivity. Methods: We have generated a new adenovirus-delivered biosensor, PCA3-Cre-PSEBC-ITSTA, which combines an integrated two-step transcriptional amplification system (ITSTA) and the activities of the prostate cancer antigen 3 (PCA3) and modified prostate-specific antigen (PSEBC) gene promoters as a single output driving the firefly luciferase reporter gene. This system was tested on PCa cell lines and on primary PCa cells. Single cells, exposed or not to ARAT, were dynamically imaged by bioluminescence microscopy. A linear discriminant analysis (LDA)-based method was used to determine cell population sensitivities to ARAT. Results: We show that the PCA3-Cre-PSEBC-ITSTA biosensor is PCa-specific and can dynamically monitor single-cell AR transcriptional activity before and after ARAT by bioluminescence microscopy. After biosensor transduction and bioluminescence microscopy single-cell luminescence dynamic quantification, LDA analysis could discriminate the cell populations overall ARAT sensitivity despite heterogeneous single-cell responses. Indeed, the biosensor could detect a significant decrease in AR activity following exposure to conventional ARAT in hormone-naive primary PCa cells, while in castration-resistant PCa patients, treatment response correlated with the observed clinical ARAT resistance. Conclusion: The exploitation of bioluminescence microscopy and multi-promoter transcriptionally-regulated biosensors can aptly define the overall treatment response of patients by monitoring live single cell drug response from primary cancer tissue. This approach can be used to develop predictive biomarkers for drug response in order to help clinicians select the best drug combinations or sequences for each patient.

Addition of Docetaxel to Androgen Receptor Axis-targeted Therapy and Androgen Deprivation Therapy in Metastatic Hormone-sensitive Prostate Cancer: A Network Meta-analysis.

CONTEXT: Randomized controlled trials (RCTs) have shown that addition of docetaxel or androgen receptor axis-targeted therapy (ARAT) to androgen deprivation therapy (ADT) or addition of ARAT to ADT and docetaxel improves overall survival (OS) in metastatic hormone-sensitive prostate cancer (mHSPC). However, it is unknown whether docetaxel, when given as part of triplet therapy, has an independent OS benefit. OBJECTIVE: To compare the efficacy of ADT plus ARAT with the triplet of ADT, ARAT, and docetaxel through a network meta-analysis (NMA) of RCTs in mHSPC. EVIDENCE ACQUISITION: Bibliographic databases and conference proceedings were searched in March 2022 for RCTs that evaluated the addition of docetaxel, ARAT, or both to ADT in mHSPC. The primary endpoint was OS. Standard random-effect NMA and Bayesian analyses were performed to compare ADT plus ARAT with triplet therapy. EVIDENCE SYNTHESIS: Eleven RCTs (n = 11 546) were eligible. Compared with ADT plus ARAT, the triplet had a nonsignificant OS benefit (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.68-1.16), while ADT plus docetaxel (HR 1.16 [0.94-1.43]) and ADT alone (HR 1.46 [1.30-1.64]) had an increased risk of death. By P-score ordering, the triplet was the most effective treatment strategy (P score = 0.936) followed by ADT plus ARAT (P score = 0.704). The triplet had a 77% likelihood of being the best treatment strategy compared with a 23% likelihood for ADT plus ARAT. CONCLUSIONS: The triplet of ADT, ARAT, and docetaxel was the highest ranked treatment strategy, but it did not confer a statistically significant OS benefit over ADT plus ARAT. This NMA provides the highest-level comparative evidence for these treatment approaches in the initial management of mHSPC. PATIENT SUMMARY: We synthesized the available evidence from clinical trials conducted in newly diagnosed metastatic prostate cancer to compare the survival of patients receiving triplet therapy (androgen receptor axis-targeted therapy [ARAT], androgen deprivation therapy [ADT], and docetaxel) with those receiving only ARAT and ADT. We conclude that the triplet is a somewhat more effective treatment approach.