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Metastatic castration resistant prostate cancer (CRPC) is an inevitably fatal disease. However, in recent years, several treatments have been shown to improve the outcome of CRPC patients both in the non-metastatic (nmCRPC) as well as the metastatic setting (mCRPC). In nmCRPC patients with a PSA doubling time < 10 months, the addition of enzalutamide, apalutamide and darolutamide to androgen deprivation therapy (ADT) compared to ADT alone resulted in improved metastases free (MFS) and overall survival (OS). For mCRPC patients, several treatment options have been shown to be effective: two taxane based chemotherapies (docetaxel and cabazitaxel), two androgen-receptor pathway inhibitors (ARPI) (abiraterone and enzalutamide), two radiopharmaceutical agents (radium 223 and 177Lutetium-PSMA-617), one immunotherapy treatment (sipuleucel-T) and two poly ADP-ribose polymerase (PARP) inhibitors (olaparib and rucaparib). Pembrolizumab is US Food and Drug Administration (FDA) approved in all MSI high solid tumors, although a very small proportion of prostate cancer patients harboring this characteristic will benefit. Despite having a broad variety of treatments available, there are still several unmet clinical needs for CRPC. The objective of this review was to describe the therapeutic landscape in CRPC patients, to identify criteria for selecting patients for specific treatments currently available, and to address the current challenges in this setting.

In the phase 3 PROpel trial (NCT03732820) patients with metastatic castration‐resistant prostate cancer (mCRPC) treated with olaparib plus abiraterone in the first‐line setting showed significantly prolonged radiographic progression‐free survival (rPFS; primary data cutoff [DCO]: 30 July 2021; hazard ratio [HR] 0.66, 95% confidence interval [CI], 0.54–0.81; p < 0.001), and at prespecified final OS analysis DCO (12 October 2022) numerically prolonged overall survival (OS; HR 0.81, 95% CI, 0.67–1.00; p = 0.054), versus placebo plus abiraterone for the global population. Here, we report efficacy, safety, and patient‐reported outcome data for the Asian subset in PROpel. Eligible patients were randomly assigned (1:1) to either olaparib (300 mg twice daily) or placebo in combination with abiraterone (1000 mg once daily). The primary endpoint was investigator‐assessed rPFS, and a key secondary endpoint was OS. In the Asian subset (n = 133) at primary analysis, median rPFS was 27.6 months in the olaparib plus abiraterone arm (n = 63), compared with 19.3 months in the placebo plus abiraterone arm (n = 70; HR 0.55, 95% CI, 0.32–0.95). Median OS at the final analysis was not reached in the olaparib plus abiraterone arm versus 43.7 months in the placebo plus abiraterone arm (HR 0.59, 95% CI, 0.32–1.06). The safety profile was generally similar in the Asian subset and the global population. Efficacy and safety results for olaparib plus abiraterone in the Asian subset were generally consistent with the global PROpel population supporting the combination of olaparib plus abiraterone as an important first‐line treatment for consideration in Asian patients with mCRPC. Trial Registration: Clinicaltrials.gov identifier: NCT03732820 In the phase 3 PROpel trial (NCT03732820), first‐line treatment with olaparib plus abiraterone significantly prolonged radiographic progression‐free survival (rPFS) and numerically prolonged overall survival (OS) versus placebo plus abiraterone in patients with metastatic castration‐resistant prostate cancer (mCRPC). Results of preplanned subgroup analyses of efficacy and safety in the Asian subset of PROpel (n = 133; rPFS hazard ratio [HR] 0.55, 95% CI 0.32–0.95; OS HR 0.59, 95% CI 0.32–1.06) were generally consistent with the global population. Our findings support consideration of the combination of olaparib plus abiraterone as an important first‐line treatment for Asian patients with mCRPC.

Background Metastatic castration‐resistant prostate cancer (mCRPC) patients have a poor prognosis, and curcumin is known to have antineoplastic properties. On the basis of previous phase I and phase II studies, we investigated whether the association of curcumin with docetaxel could improve prognosis among mCRPC patients. Methods A total of 50 mCRPC patients (included from June 2014 to July 2016) treated with docetaxel in association with oral curcumin (6 g/d for 7 days every 3 weeks) versus placebo were included in this double‐blind, randomized, phase II study. The primary endpoint was to evaluate the time to progression. Among the secondary endpoints, compliance, overall survival, prostate‐specific antigen (PSA) response, safety, curcumin absorption, and quality of life were investigated. An interim analysis was planned in the modified intention‐to‐treat population with data at 6 months (22 patients per arm). Results Despite good compliance and a verified absorption of curcumin, no difference was shown for our primary endpoint: progression‐free survival (PFS) between the placebo and curcumin groups was, respectively, 5.3 months versus 3.7 months, p = 0.75. Similarly, no difference was observed for the secondary objectives: PSA response rate (p = 0.88), overall survival (p = 0.50), and quality of life (p = 0.49 and p = 0.47). Conclusion Even though our previous studies and data in the literature seemed to support an association between curcumin and cancer therapies in order to improve patient outcome and prognosis, the results from this interim analysis clearly showed that adding curcumin to mCRPC patients’ treatment strategies was not efficacious. The study was discontinued on the grounds of futility. In this manuscript, we present the result of the interim analysis of our study conducted in metastatic castration‐resistant prostate cancer (mCRPC) patients. According to previous studies, we investigated whether the association of curcumin to docetaxel could improve prognosis among patients. This study is the first one to explore the efficacy of curcumin in mCRPC treated with docetaxel, with the assessment of serum curcumin levels. The results from this phase II study with such a posology lead us to conclude that curcumin in association with docetaxel does not improve mCRPC patients, nor does it improve progression‐free survival or overall survival.

Metastatic castration‐resistant prostate cancer (mCRPC) is a heterogeneous disease. Several studies have identified transcriptional subtypes of mCRPC, but comprehensive analysis of prognostic gene expression pathways has been limited. Therefore, we aggregated a cohort of 1012 mCRPC tissue samples from 769 patients and investigated the association of gene expression‐based pathways with clinical outcomes and intrapatient and intratumor heterogeneity. Survival data were obtained for 272 patients. Pathway‐level enrichment was evaluated using gene set variation analysis. scRNA‐seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. We identified five pathway clusters: (a) Immune response/WNT/TGF‐beta signaling, (b) AR signaling/luminal signatures, (c) mTOR signaling and glycolysis, (d) cell proliferation, and (e) neuroendocrine differentiation. Proliferation, AR signaling loss, and glycolysis/mTOR signaling were independently prognostic. Adverse prognostic pathway scores decreased on treatment with AR signaling inhibitors, but not at progression, suggesting failure to permanently target these pathways. scRNA‐seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. Our results suggest loss of AR signaling, high proliferation, and a glycolytic phenotype as adverse prognostic pathways in mCRPC that could be used in conjunction with clinical factors to prognosticate for treatment decisions. We aggregated a cohort of 1012 mCRPC tissue samples from 769 patients and investigated the association of gene expression‐based pathways with clinical outcomes. Loss of AR signaling, high proliferation, and a glycolytic phenotype were independently prognostic for poor outcomes, and an adverse transcriptional feature score incorporating these pathways added prognostic value to known clinical and genomic prognostic features.

The success of the PROfound, IPATential150, and TheraP trials promoted the transition from sequential treatment to therapeutic targets (TTs)‐guided precision treatment in metastatic castration‐resistant prostate cancer (mCRPC). The objective of this study was to evaluate the prevalence and prognostic value of TTs from these three trials. All included Chinese mCRPC patients underwent circulating tumor DNA (ctDNA) sequencing, PTEN status assessment, and dual‐tracer [68Ga‐prostate‐specific membrane antigen (PSMA) and 18F‐fluorodexyglucose (FDG)] positron emission tomography/computed tomography (PET/CT). Previous treatment with cabazitaxel, Lu‐PSMA or olaparib was unallowed. Patients with known significant sarcomatoid or spindle cell or neuroendocrine small cell components were also excluded. TTs were defined as positive as follows: (a) high PSMA and no PSMA−/FDG+ disease on dual‐tracer PET/CT scans; (b) defects in homologous recombination repair (HRR) genes in ctDNA; and (c) loss of PTEN immunohistochemistry staining in tumor tissue. The prevalence and prognostic value on progression‐free survival (PFS) of TTs were evaluated. A total of 106 consecutive mCRPC patients were included. The prevalence of positive PET/CT, HRR defect, and PTEN loss was 30%, 29% and 16%, respectively. Sixty‐three patients had at least one TT. Metastatic volume (odds ratio = 5.0; P = 0.017) was the only independent factor of positive TT in multivariate analysis. Seventy‐four patients received abiraterone after TT screening. Patients with positive PET/CT (P = 0.011) and HRR defect (P = 0.002) had a significantly shorter PFS after receiving abiraterone than patients with negative TTs. However, PTEN status was unrelated to PFS, which may be due to a less number of patients with PTEN loss (P = 0.952). Overall, patients with any positive TTs had a significantly shorter PFS after abiraterone than patients with negative TTs (P = 0.009). Nearly 60% of Chinese patients with mCRPC who had a poor prognosis on abiraterone were candidates for precision treatments based on the specific criteria of TTs. Results of the PROfound, IPATential150 and TheraP trials were evaluated to determine the frequency of mCRPC patients who had therapeutic targets. All included mCRPC patients underwent ctDNA sequencing, PTEN status assessment and dual‐tracer (68Ga‐PSMA and 18F‐FDG) PET/CT. Nearly 60% of patients had positive therapeutic targets. In addition, patients with positive therapeutic targets had a shorter progression‐free survival under abiraterone treatment.

Background This study aimed to identify the clinical predictors for the response of patients with mCRPC to ARATs. Materials and Methods We retrospectively collected data on consecutive patients who were diagnosed with mCRPC and underwent ARAT treatment during this stage of the disease. Clinical parameters were obtained through medical chart reviews. ARAT failure was defined as a continuous increase in the serum prostate‐specific antigen (PSA) level above nadir to > 2 ng/mL, accompanied by radiographic progression. ARAT failure‐free survival and overall survival were assessed through Kaplan–Meier survival analysis and Cox regression survival analysis. Nomogram analysis based on significant predictors of ARAT failure‐free survival was performed. Results In total, 319 patients with mCRPC who underwent ARAT were included. Multivariate analysis revealed that age, International Society of Urological Pathology (ISUP) grading, and chemotherapy‐naïve status were significant predictors of ARAT failure‐free survival. For overall survival, age, ISUP grading, and nadir PSA level during androgen deprivation therapy (ADT) were significant predictors. Through nomogram analysis based on age, ISUP grading, and chemotherapy‐naïve status, the likelihood of ARAT duration being more or less than 1 year could be predicted. Conclusion For mCRPC patients, being older, having ISUP Grade 5 cancer, and having a history of chemotherapy were associated with a shorter duration of response to next‐line ARATs. Therefore, other therapeutic agents should be prioritized for such patients. Notably, among the included patients, those who were older, had a higher ISUP grade and a higher nadir PSA level during ADT exhibited worse overall survival.

Background In the PROSELICA, a randomized controlled trial (RCT) comparing cabazitaxel 20 mg/m2 (C20) versus 25 mg/m2 (C25) in metastatic castration‐resistant prostate cancer (mCRPC), one‐variable‐at‐a‐time subgroup analysis suggested possible heterogeneity in treatment effect (HTE) of C25 versus C20 among study participants. Novel predictive HTE analysis approaches may provide an in‐depth understanding of such results. Methods We analyzed patient‐level data from 1200 patients with mCRPC who were randomized in the PROSELICA trial. Outcomes included overall survival (OS) and progression‐free survival (PFS). Using baseline characteristics, patients were stratified into quartiles based on either quantitative baseline risk of poor outcome (risk modeling) or predicted individualized treatment effect (ITE) using a causal survival forest algorithm (effect modeling). Treatment effects were measured as differences in restricted mean survival time (RMST). Results For risk modeling, the OS effect of C25 increased with risk quartiles: −0.07 months (95% CI, −1.60 to 1.46) in the lowest risk quartile and 1.67 months (95% CI, 0.25 to 3.10) in the highest risk quartile. For effect modeling, the OS effect ranged from −0.17 months (95% CI, −3.01 to 2.68) in the lowest ITE quartile to 0.57 months (95% CI, −2.27 to 3.41) in the highest ITE quartile. Both approaches demonstrated greater C25 benefit in patients with extensive previous treatment and baseline disease burden. PFS effects remained consistent across all quartiles. Conclusions The OS effect of C25 versus C20 may vary based on baseline characteristics in post‐docetaxel mCRPC. Patients with extensive treatment history and disease burden may benefit more from C25.

The global incidence of prostate cancer (PCa) is rising. Localized PCa can be managed through surgical intervention or radiotherapy, but certain patients may experience recurrence or develop metastatic disease following localized treatment. Despite aggressive therapeutic approaches, the majority of metastatic patients with PCa will eventually progress to metastatic castration-resistant PCa, with limited treatment alternatives and a dismal prognosis. The treatment options for advanced PCa are continuously evolving, yet there remains a demand for further innovative therapeutic approaches. Antibody-drug conjugates (ADCs) represent a novel class of targeted medications comprising a humanized monoclonal antibody, a linker and a cytotoxic payload. ADCs primarily bind to antigens that are upregulated on the surface of PCa cells but are minimally expressed on normal cells. At present, a variety of targets for ADCs have been identified in the treatment of PCa, encompassing prostate-specific membrane antigen, STEAP family member 1, trophoblast cell-surface antigen 2, CD46, B7-H3, tissue factor and delta-like protein 3, each with one or more specific ADC that has shown encouraging results in the PCa field. In the present review, the developmental course, composition and mechanism of action of ADCs are explored, with a specific focus on recently published studies and ongoing trials aimed at investigating the efficacy and safety of ADCs in treating PCa. Lastly, ongoing challenges in ADC development and corresponding strategies to combat them are discussed.

Background Low body mass index (BMI) and low serum albumin levels are suggested indicators of malnutrition and are associated with poor outcomes in cancer patients. Decreasing androgen can alter lipid metabolism, so the prognostic value of BMI may change in metastatic castration‐resistant prostate cancer (mCRPC) patients receiving abiraterone. We aimed to delineate the prognostic value of BMI, serum albumin, and BMI and serum albumin (ALB) combined. Materials and methods A post hoc analysis was performed on data from two randomized clinical trials evaluating the efficacy of abiraterone in chemotherapy‐pretreated and ‐naïve mCRPC patients. Survival analysis was conducted using Kaplan–Meier and Cox proportional hazard methods. Results A total of 2,205 mCRPC patients were included in this study. Low ALB independently predicted the OS in both cohorts (HR, 1.54; 95%CI, 1.34–1.78 and HR, 1.40; 95%CI, 1.21–1.64, respectively), while low BMI independently predicted the OS only in the post‐chemotherapy cohort (HR, 1.30; 95%CI, 1.12–1.50) but not in the pre‐chemotherapy cohort (HR, 1.19; 95%CI, 0.98–1.43). By combining BMI (<25 kg/m2 or ≥30 kg/m2) and ALB (<4 g/dl or >4 g/dl), the four groups were characterized and their HRs were 1, 0.60 (95%CI, 0.47–0.76, p < 0.001), 0.75 (95%CI,0.61–0.92 p = 0.006), and 0.49 (95%CI, 0.41–0.60, p < 0.001) in post‐chemotherapy patients and 1, 0.64 (95%CI, 0.46–0.89, p = 0.008), 0.75 (95%CI,0.58–0.98 p = 0.034), and 0.55 (95%CI, 0.42–0.72, p < 0.001) in chemotherapy‐naïve patients, respectively. Conclusions Our results demonstrate that the combination of BMI and ALB better characterizes the risk groups irrespective of previous chemotherapy. Patients with high BMI but low ALB have higher risk of death than patients with low BMI but high ALB. Combining BMI with ALB better predicts the outcome of mCRPC patients. High BMI/low ALB mCRPC patients may represent a poorly understood group of cachexia patients with worse outcome. Early nutritional intervention for high BMI/low ALB patients should be investigated to optimize their survival.

Patients with bone metastatic castration-resistant prostate cancer (mCRPC) might benefit from radium-223 (223Ra) combined with new-generation hormonal agents (NHAs) in terms of survival and quality of life (QoL). However, the safety of combination therapies remains unclear. Therefore, we aimed to perform a network meta-analysis by reviewing the literature about the combination of 223Ra with abiraterone acetate plus prednisone (AAP) or enzalutamide and to evaluate the safety of combination therapy in bone mCRPC patients. Ultimately, ten studies (2835 patients) were selected, including four randomized controlled trials (RCTs), five retrospective cohort studies, and one single-arm study. Overall, there was no difference in the incidence of fracture between the 223Ra+NHA combination group and the 223Ra monotherapy group (odds ratio [OR]: 1.46, 95% confidence interval [CI]: 0.91-2.34, P = 0.66), but the incidences in both the 223Ra+NHA combination group (OR: 3.22, 95% CI: 2.24-4.63, P < 0.01) and the 223Ra monotherapy group (OR: 2.24, 95% CI: 1.23-4.08, P < 0.01) were higher than that in the NHA monotherapy group. However, in the meta-analysis involving only RCTs, there was no difference between the 223Ra monotherapy group and the NHA monotherapy group (OR: 1.14, 95% CI: 0.22-5.95, P = 0.88), while the difference between the 223Ra+NHA combination group and the NHA monotherapy group remained significant (OR: 3.22, 95% CI: 2.24-4.63, P < 0.01). Symptomatic skeletal events (SSEs), SSE-free survival (SSE-FS), all grades of common adverse events (AEs), and ≥grade 3 AEs among all groups did not show any significant difference. Our results indicate that the combination of 223Ra with NHAs was well tolerated in bone mCRPC patients compared to 223Ra monotherapy, even though the incidence of fracture was higher in patients who received 223Ra than that among those who received NHA monotherapy. More evidence is needed to explore the safety and efficiency of 223Ra combination therapies.