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Purpose: to assess the utility of response monitoring to enzalutamide by using [68Ga]Ga-PSMA PET in mCRPC patients treated with enzalutamide as first-line therapy. Methods: patients underwent [68Ga]Ga-PSMA PET less than 8 weeks before and 3 months after starting enzalutamide. On the basis of EAU/EANM criteria, patients were categorized as PSMA responders (PET-R) or PSMA non-responders (PET-NR), whilst, based on PSA, they were classified as biochemical responders (PSA-R) or non-responders (PSA-NR). Survival analysis was performed using the Cox regression hazard model and the Kaplan-Meier method. Results: 69 patients were considered fully evaluable. We observed 47.8% of concordance between [68Ga]Ga-PSMA PET and PSA monitoring at 3 months after starting enzalutamide. For discordant cases, the PSA reduction has a weak impact on PFS and a significant impact on OS in PET-NR patients, whilst this change has no impact either for PFS and OS in PET-R ones. Conclusions: [68Ga]Ga-PSMA PET could be a useful imaging tool for monitoring response to enzalutamide in mCRPC patients, being more informative than PSA in this setting, and possibly better guiding clinicians in therapeutic decisions. [ABSTRACT FROM AUTHOR]

Introduction: Plasma androgen receptor (AR) copy number (CN) status identifies castration-resistant prostate cancer (CRPC) patients with worse outcome on abiraterone/enzalutamide. However, the impact of AR CN changes on clinical outcome in CRPC is unknown. Materials and Methods: Plasma samples from 73 patients treated with abiraterone or enzalutamide were collected at baseline and at the time of progression disease (PD). Droplet digital polymerase chain reaction was used to assess AR CN status. Results: We showed that 11 patients (15.1%) changed AR CN status from baseline to PD (9 patients from normal to gain, 2 from gain to normal). Patients changing AR CN status from normal at baseline to gain at PD had intermediate median overall survival (OS) of 20.5 months (95% CI = 8.0–44.2) between those who remained AR CN normal from baseline to PD (27.3 months [95% CI = 21.9–34.4]) and those who remained AR CN gain from baseline to PD (9.1 months [95% CI = 3.8–14.5], p < 0.0001). Patients changing AR CN from normal at baseline to gain at PD had a median progression-free survival (PFS) of 9.2 months (95% CI = 2.0–14.7), patients who remained AR CN normal had a median PFS of 9.1 months (95% CI = 7.2–10.1), and patients who remained AR CN gain had a median PFS of 5.4 (95% CI = 3.6–6.5, p = 0.0005). Both OS and PFS were not significantly different between patients with AR CN that changes from normal to gain and patients with stable AR CN normal. Conclusions: We showed that CRPC patients changing AR CN status from baseline to progression time point had intermediate OS and we suggested that AR CN evaluation at baseline could be the most informative for clinical outcome of CRPC patients treated with abiraterone or enzalutamide. Larger prospective studies are warranted. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy (ADT) is a cornerstone of treatment for prostate cancer and, in recent years, androgen receptor (AR)-targeted therapies (abiraterone and enzalutamide) have both been used for the treatment of castration-resistant prostate cancer (CRPC). In our study, we sought to investigate the association between ADT and immune disorders, considering a potential role of androgens in the immune modulation. We retrospectively evaluated CRPC patients treated with abiraterone/enzalutamide between July 2011 and December 2018. We assessed the risk of developing immune alterations and their impact on outcome. We included 844 CRPC patients receiving AR-directed therapies, of whom 36 (4.3%) had autoimmune diseases and 47 (5.6%) second tumors as comorbidities. Median age was 70 years [interquartile range (IQR) = 63–75)]. We showed higher significant incidence of autoimmune diseases during their hormone sensitive status (p = 0.021) and the presence of autoimmune comorbidities before starting treatment with abiraterone/enzalutamide was significantly associated with worse overall survival (OS) (10.1 vs. 13.7 months, HR = 1.59, 95% CI 1.03–2.27, p = 0.038). In a multivariate analysis, the presence of autoimmune disorders was an independent predictor of OS (HR = 1.65, 95% CI 1.05–2.60, p = 0.031). In conclusion, CRPC patients with autoimmune alterations before starting AR-directed therapies may have worse prognosis. Further prospective studies are warranted to assess the role of immune modulation in the management of prostate cancer patients. [ABSTRACT FROM AUTHOR]

Pre-clinical data suggest that docetaxel and enzalutamide interfere with androgen receptor translocation and signalling. The aim of this study is to assess the efficacy of their concurrent administration in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC). In this open-label, randomised, phase II trial, previously untreated mCRPC patients were randomised 1:1 to receive eight 21-d courses of docetaxel 75 mg/m2, oral prednisone 5 mg twice daily and oral enzalutamide 160 mg/d (arm DE), or the same treatment without enzalutamide (arm D). The primary end-point was the percentage of patients without investigator-assessed disease progression 6 months after the first docetaxel administration. The 246 eligible patients were randomly assigned to receive docetaxel, prednisone and enzalutamide (n = 120) or docetaxel and prednisone (n = 126). The 6-month progression rate was 12.5% (95% confidence interval [CI] 8.1–20.6) in arm DE and 27.8% (95% CI 22.8–39.4) in arm D (chi-squared test 10.01; P = 0.002). The most frequent grade III–IV adverse events were fatigue (12.5% in arm DE versus 5.6% in arm D), febrile neutropenia (9.3% versus 4.0%) and neutropenia (7.6% versus 5.6%). The combination of enzalutamide and docetaxel appears to be more clinically beneficial than docetaxel alone in previously untreated mCRPC patients, although serious adverse events were more frequent. Our findings suggest that first-line treatment with this combination could lead to an additional clinical benefit when prompt and prolonged disease control is simultaneously required. Clearly, these results should be considered cautiously because of the study's phase II design and the absence of an overall survival benefit. EudraCT 2014-000175-43 – NCT02453009. [Display omitted] • Docetaxel (D) and enzalutamide (E) have different mechanism of action. • They are efficacious in metastatic castration-resistant prostate cancer (mCRPC). • We compared their combination versus docetaxel alone in first-line mCRPC. • This combination increased the 6-month disease control rate by 15.3%. • We observed more grade III- toxicities in DE arm than in D arm. [ABSTRACT FROM AUTHOR]

Background Metabolic syndrome (MS) and inflammation (INF) alterations are among the factors involved in cancer progression. The study aimed to assess the relationship between MS and INF and its effect on progression-free/overall survival (PFS/OS) in metastatic castration-resistant prostate cancer (mCRPC) treaed with abiraterone or enzalutamide. Methods We, retrospectively, evaluated patients with mCRPC in 7 Italian Institutes between March 2011 and October 2016. MS was defined by modified adult treatment panel-III criteria. INF was characterized by at least one of these criteria: neutrophil to lymphocyte ratio ≥ 3, elevated erythrocyte sedimentation rate or C-reactive protein. Results Eighty-three of 551 (15.1%) patients met MS criteria at baseline and 34 (6.2%) during treatment. MS patients (MS+) presented a greater INF profile compared to MS− ( P <0.0001). Median PFS was 3.7 for MS+ vs. 8.7 months for MS− (hazard ratio [HR] = 2.77; 95% CI: 2.12–3.61; P <0.0001). Median OS was 6.9 and 19 months in MS+ and MS−, respectively (HR = 3.43; 95% CI: 2.56–4.58; P <0.0001). We also demonstrated INF led to shorter PFS and OS (4.5 vs. 8.5 months, HR = 1.48, 95% CI: 1.15–1.90, P = 0.002, and 11.2 vs. 18.8 months, HR =1.66, 95% CI: 1.26–2.18, P = 0.0003, respectively). The combination of MS with INF provided the identification of high-risk prognostic group (MS+/INF+ vs. MS−/INF−) with worse PFS (3.7 vs. 9 months, HR = 2.7, 95% CI: 1.88–3.89, P <0.0001) and OS (6.3 vs. 20.4 months, HR = 4.04, 95% CI: 2.75–5.93, P <0.0001). Multivariable analysis confirmed that MS was independently associated with PFS (HR = 2.07; 95% CI: 1.03–4.18; P = 0.041) and OS (HR = 4.87; 95% CI: 2.36–10.03; P <0.0001). The absence of INF as an independent predictor of survival underlined the correlation between MS/INF. Conclusions Pretreatment identification of MS and INF alterations might represent an available and easy tool for better prognostication of patients with mCRPC. A prospective evaluation is warranted. [ABSTRACT FROM AUTHOR]