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Inhibitors of fibroblast growth factor receptor (FGFR) represent an outstanding treatment approach for selected patients with urothelial cancer (UC). These agents are changing the clinical approach to a subgroup of UC, the luminal-papillary subtype, characterized by FGFR mutations, fusions, or amplification. In this review, we provide an overview of the results of recent clinical trials on FGFR tyrosine kinase inhibitors (TKIs) currently in clinical development for the treatment of UC: erdafitinib, rogaratinib, infigratinib, and the monoclonal antibody vofatamab. The Food and Drug Administration recently granted accelerated approval to erdafitinib for patients with advanced UC with alterations of FGFR2 or FGFR3 after progression on platinum-based chemotherapy. We also look at future therapeutic options of combination regimens with immune-checkpoint inhibitors as strategies for improving the antitumor effects of this class of drug, and for preventing or delaying the development of resistance.

Prostate cancer (PCa) is one of the main causes of cancer-related death in men. In the present immunotherapy era, several immunotherapeutic agents have been evaluated in PCa with poor results, possibly due to its low mutational burden. The recent development of chimeric antigen receptor (CAR)-T cell therapy redirected against cancer-specific antigens would seem to provide the means for bypassing immune tolerance mechanisms. CAR-T cell therapy has proven effective in eradicating hematologic malignancies and the challenge now is to obtain the same degree of in solid tumors, including PCa. In this study we review the principles that have guided the engineering of CAR-T cells and the specific prostatic antigens identified as possible targets for immunological and non-immunological therapies. We also provide a state-of-the-art overview of CAR-T cell therapy in PCa, defining the key obstacles to its development and underlining the mechanisms used to overcome these barriers. At present, although there are still many unanswered questions regarding CAR-T cell therapy, there is no doubt that it has the potential to become an important treatment option for urological malignancies.

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.

Background Cabazitaxel improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients progressing after docetaxel. In this prospective study, we evaluated the prognostic role of CTC gene expression on cabazitaxel-treated patients and its association with plasma androgen receptor ( AR ) copy number (CN). Methods Patients receiving cabazitaxel 20 or 25 mg/sqm for mCRPC were enrolled. Digital PCR was performed to assess plasma AR CN status. CTC enrichment was assessed using the AdnaTest EMT-2/StemCell kit. CTC expression analyses were performed for 17 genes. Data are expressed as hazard ratio (HR) or odds ratio (OR) and 95% CI. Results Seventy-four patients were fully evaluable. CTC expression of AR-V7 (HR=2.52, 1.24–5.12, p =0.011), AKR1C3 (HR=2.01, 1.06–3.81, p =0.031), AR (HR=2.70, 1.46–5.01, p =0.002), EPCAM (HR=3.75, 2.10–6.71, p < 0.0001), PSMA (HR=2.09, 1.19–3.66, p =0.01), MDK (HR=3.35, 1.83–6.13, p < 0.0001), and HPRT1 (HR=2.46, 1.44–4.18, p =0.0009) was significantly associated with OS. ALDH1 (OR=5.50, 0.97–31.22, p =0.05), AR (OR=8.71, 2.32–32.25, p =0.001), EPCAM (OR=7.26, 1.47–35.73, p =0.015), PSMA (OR=3.86, 1.10–13.50, p =0.035), MDK (OR=6.84, 1.87–24.98, p =0.004), and HPRT1 (OR=7.41, 1.82–30.19, p =0.005) expression was associated with early PD. AR CN status was significantly correlated with AR-V7 ( p =0.05), EPCAM ( p =0.02), and MDK ( p =0.002) expression. In multivariable model, EPCAM and HPRT1 CTC expression, plasma AR CN gain, ECOG PS=2, and liver metastases and PSA were independently associated with poorer OS. In patients treated with cabazitaxel 20 mg/sqm, median OS was shorter in AR-V7 positive than negative patients (6.6 versus 14 months, HR=3.46, 1.47–8.17], p =0.004). Conclusions Baseline CTC biomarkers may be prognosticators for cabazitaxel-treated mCRPC patients. Cabazitaxel at lower (20 mg/sqm) dose was associated with poorer outcomes in AR-V7 positive patients compared to AR-V7 negative patients in a post hoc subgroup analysis. Trial registration Clinicaltrials.gov NCT03381326 . Retrospectively registered on 18 December 2017.

Over the years, an increasing proportion of metastatic prostate cancer patients has been found to experience an initial bone flare phenomenon under both standard therapies (androgen deprivation therapy, chemotherapy, radiotherapy, abiraterone, enzalutamide) and novel agents (immunotherapy, bone-targeting radioisotopes). The underlying biological mechanisms of the flare phenomenon are still elusive and need further clarification, particularly in relation to different types of treatment and their treatment response assessment. Flare phenomenon is often underestimated and, in some cases, can negatively affect clinical outcome. In cases with suspected bone flare, the treatment should be continued for a minimum of 12 more weeks before further decisions about efficacy can be taken. Physicians and patients should be aware of this effect to avoid unwarranted anxiety and inadequate early discontinuation of treatment. This review aims at highlighting new evidence on flare phenomenon arising after the introduction of new drugs extending across the biochemical, radiographic and clinical spectrum of the disease.

Germ cell tumors (GCTs) represent a heterogeneous neoplasm family affecting gonads and rarely occurring in extragonadal areas. Most of patients have a good prognosis, often even in the presence of metastatic disease; however, in almost 15% of cases, tumor relapse and platinum resistance are the main challenges. Thus, novel treatment strategies with both improved antineoplastic activity and minor treatment-related adverse events compared with platinum are really expected. In this context, the development and the high activity demonstrated by immune checkpoint inhibitors in solid tumors and, subsequently, the interesting results obtained from the use of chimeric antigen receptor (CAR-) T cell therapy in hematological tumors, have stimulated research in this direction also in GCTs. In this article, we will analyze the molecular mechanisms underlying the immune action in the development of GCTs, and we will report the data from the studies that tested the new immunotherapeutic approaches in these neoplasms.

Purpose To evaluate adherence to abiraterone or enzalutamide for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Methods In an observational prospective cohort study, we monitored patients with mCRPC for their adherence to abiraterone or enzalutamide in the pre- or post-chemotherapy setting. Results Fifty-eight patients with median age of 76 years (range 56–94), age-adjusted Charlson comorbidity score of 10 (range, 4–15), and geriatric G8 score of 14 (range, 6–17) were enrolled. Twenty-two (38%) patients were treated with abiraterone and 36 (62%) with enzalutamide, while forty-two (72%) were in the pre-chemotherapy setting. Forty-seven patients (81%) had a caregiver. Based on the pill counting, a non-adherence rate of 4.8% and 6.2% was observed for the whole period and the first 3 months, respectively, without a statistically significant difference between abiraterone and enzalutamide cohorts. A lower non-adherence rate (1.3%) was reported by patients during the whole period, mainly due to a misperception (77%) and forgetfulness (19%). Non-adherence rate to the fulfilling of the clinical diary was 38% for the whole period. Non-adherence in the whole period was related to the radiological response ( p  = 0.03) and geriatric G8 score ( p  = 0.005). By the receiver operating characteristic (ROC) curve based on the radiological response, non-adherence cut-off was 1.87% ( p  = 0.04). By this non-adherence cut-off, the G8 cut-off was 14.75 ( p  = 0.0003). Conclusion Non-adherence to abiraterone or enzalutamide for mCRPC may have an impact on disease response and be related to patients’ frailty, suggesting their geriatric assessment and clinical interventions to monitor and increase their adherence.

Plasma tumour DNA (ptDNA) is a potential early noninvasive biomarker of treatment outcome in metastatic castration‐resistant prostate cancer (mCRPC). Herein, we investigated whether pretreatment ptDNA levels reflect metabolic tumour burden in mCRPC and better predict treatment outcome in combination with functional imaging. Targeted next‐generation sequencing was performed to estimate the ptDNA fraction from 102 mCRPC patients receiving abiraterone or enzalutamide. The maximum standardized uptake value (SUVmax), total lesion activity (TLA) and metabolic tumour volume (MTV) were evaluated on 18F‐fluorocholine positron emission tomography/computed tomography. We assessed a Weibull multiple regression model to determine the combined impact of clinical, molecular and imaging characteristics on overall survival (OS) and progression‐free survival (PFS), and to obtain prognostic scores. A significant association was seen between ptDNA and SUVmax, MTV and TLA. For survival analysis, patients were randomly allocated into a training (n = 68) and a validation (n = 34) set. In the training set, multivariable analyses showed that ptDNA, MTV and serum lactate dehydrogenase together with visceral metastasis were independent predictors of both OS and PFS. Prognostic scores were generated, with the identification of three groups of patients with significantly different median OS (29.2, 15.9 and 8.7 months) and PFS (13.3, 7.7 and 3.2 months) probabilities. The differences in median survival between risk groups were confirmed in the validation cohort for both OS and PFS. In our study, we showed that integrating plasma DNA analysis with functional imaging may improve prognostic risk stratification and treatment selection in mCRPC. Plasma tumour DNA (ptDNA) has been recently demonstrated as a potential early noninvasive biomarker in patients affected with metastatic castration‐resistant prostate cancer receiving androgen receptor signalling inhibitors. In our study, we initially showed that ptDNA reflected tumour metabolic activity. Additionally, integrating ptDNA analysis with functional imaging and clinical features showed potential for an improved outcome prediction as well as for a better treatment selection in these patients.

There is an urgent need of biomarkers to personalize metastatic castration-resistant prostate cancer (mCRPC) treatment. A new prognostic model described by our group combines molecular characteristics (ptDNA levels), metabolic features from PET-scans (metabolic tumor volume), clinical parameters (visceral metastases), and lab tests (lactate-dehydrogenase levels) in abiraterone or enzalutamide-treated patients. This study aims to validate the score on mCRPC patients undergoing taxane treatment. Twenty-eight patients affected by mCRPC, pre-treated with abiraterone or enzalutamide, candidate for taxane-based treatments, have been prospectively evaluated. All patients underwent a basal PET/CT scan with F-choline and blood samples. The prognostic model previously described was applied to this population; based on the partial results of the parameters, we assigned the patients into three risk groups. In the 28 patients evaluated, we observed a different median OS among the three risk groups (risk group I, 18.1 months [95% CI: 15.2-33.1 months]; risk group II, 12.7 months [4.9-18.6 months]; and risk group III, 10.1 months [3.4-15.4 months]; p = 0.012). Statistically significant differences were also observed for PFS. The prognostic score has confirmed to be a good prognostic tool also in a more advanced cohort of patients treated with taxanes. This tool may represent a valid method to refine prognostication and treatment selection in a cohort of patients where biomarkers are scarce.

Mediastinal germ cell tumors (MGCTs) share histologic, molecular and biomarkers features with testicular GCTs; however, nonseminomatous MGCTs are usually more aggressive and have poorer prognosis than nonseminomatous TGCTs. Most nonseminomatous MGCT cases show early resistance to platinum-based therapies and seldom have been associated with the onset of one or more concomitant somatic malignancies, in particular myeloid neoplasms with recent findings supporting a common, shared genetic precursor with the primary MGCT. Genomic, transcriptomic and epigenetic features of testicular GCTs have been extensively studied, allowing for the understanding of GCT development and transformation of seminomatous and nonseminomatous histologies. However, MGCTs are still lacking proper multi-omics analysis and only few data are reported in the literature. Understanding of the mechanism involved in the development, in the progression and in their higher resistance to common therapies is still poorly understood. With this review, we aim to collect all molecular findings reported in this rare disease, resuming the similarities and disparities with the gonadal counterparts.