AIM:Androgen receptor signaling inhibitors (ARSI) demonstrated to be efficacious as first-line therapy for mCRPC. The present real-world study aimed to identify the characteristics of the long-term responders (LTR) patients to first-line ARSI. METHODS:We retrospectively reviewed a consecutive series of 622 mCRPC patients treated with one ARSI as first line. Patients received standard doses of abiraterone (1000 mg daily plus prednisone 10 mg daily) or enzalutamide (160 mg daily) until progression. Patients with an ARSI exposure ≥ 36 months were considered as LTR. RESULTS:We identified 99 LTR patients who were compared to 523 no-LTR patients. At the multivariable analysis, LTR patients showed younger age (p < 0.0001), longer time to mCRPC (p < 0.0001), higher baseline levels of hemoglobin (p = 0.007), lower baseline PSA levels (p = 0.03), longer PSA doubling time (p = 0.03), low number of bone metastases (p = 0.01), and receivedenzalutamide (p = 0.01). The median overall survival (OS) of LTR was 78.2 months (95% CI 72.3-84.1 months) vs 27.7 months of no-LTR (95% CI 25.9-29.6 months). CONCLUSIONS:Several clinical and biological factors allow to identify those patients with higher probability of becoming LTR to ARSI in first-line mCRPC setting.

Renal cell carcinoma (RCC) is one of the most common types of urogenital cancer. The introduction of immune-based combinations, including dual immune-checkpoint inhibitors (ICI) or ICI plus tyrosine kinase inhibitors (TKIs), has radically changed the treatment landscape for metastatic RCC, showing varying efficacy across different prognostic groups based on the International Metastatic RCC Database Consortium (IMDC) criteria. This retrospective multicenter study, part of the ARON-1 project, aimed to evaluate the outcomes of favorable-risk metastatic RCC patients treated with immune-based combinations or sunitinib. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate. We carried out a survival analysis by a Cox regression model. A total of 524 favorable-risk patients were included in the analysis. After a median follow-up of 37.2 months, the median OS in the overall population was 56.1 months. There was no significant difference in OS between patients receiving sunitinib and those receiving TKI + ICI combinations (p = 0.761). Patients on TKI + ICI had significantly longer PFS compared to patient treated with sunitinib (30.7 vs 22.9 months, p = 0.007). Analysis of OS and PFS based on metastatic site revealed that patients with bone metastases benefited more from ICI plus TKI (56 patients with bone metastases receiving IO + TKI, 38 received pembrolizumab plus axitinib, 15 cabozantinib plus nivolumab and 3 pembrolizumab plus lenvatinib), while sunitinib was more effective for pancreatic and glandular metastases. Additionally, the number of metastatic sites played a role, with TKI plus ICI showing superiority in patients with a single metastatic site. The time from RCC diagnosis to metastatic disease also impacted outcomes, with TKI plus ICI being more effective in patients with a shorter interval (i.e., < 36 months). The choice between upfront combination or monotherapy for metastatic favorable prognosis RCC remains a current issue. While combination therapy offers prolonged PFS, it does not necessarily translate to improve OS compared to sunitinib. This real-world study supports the superiority in terms of PFS of TKI plus ICI vs TKI monotherapy but not in OS. Probable, other clinical factors should be taking into account to make clinical treatment decisions in this setting.

A retrospective study comparing a development to a validation cohort of mCRPC patients receiving ARSI found a new prognostic model. It included 7 clinical and baseline laboratory variables and confirmed its ability to prognosticate for OS. Introduction: Over the years, several prognostic models were developed in patients receiving chemotherapy for metastatic castration resistant prostate cancer (mCRPC), while data on androgen-receptor signaling inhibitors (ARSI) in a real-world setting are limited. Patients and methods: We compared a consecutive series of 565 mCRPC patients receiving first-line ARSI at 4 high-volume Italian Centers (development set) to an external series of 180 patients receiving the same treatment at another Italian high-volume Center (training set), between 2011 and 2022. Sixteen clinical and baseline laboratory variables were selected to develop a prognostic model. Patients were categorized into risk groups according to the number of independent factors positively associated with overall survival (OS). Results: In the development cohort, after a median follow-up of 21.1 months, the median OS was 30.4 months (95% CI 27.5-33.4). At the multivariate analysis, 7 variables [age, prostate specific antigen (PSA) doubling time, baseline levels of hemoglobin, PSA, time to castration resistance, ECOG PS and bone metastases number) were included into the final model. The median OS was 13.4, 25.7 and 46.4 months in poor (0-2 factors), intermediate (3-4 factors) and good ( >= 5 factors) prognosis group, respectively. The application of the model to the validation set confirmed its ability to prognosticate for OS. The model c-indexes were 0.68 (95% CI 0.64-0.72) and 0.75 (95% CI 0.68-0.81) in the development and validation cohort, respectively. Conclusions: Our model, based on clinical and laboratory variables readily assessable in clinical practice, might prognosticate the OS of mCRPC patients receiving first-line ARSI.

TPS494 Background: The combination of nivolumab plus ipilimumab (N+I) is able to increase the overall survival (OS), progression free survival (PFS) and overall response rate (ORR) compared to sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC) at intermediate or poor prognosis. However, the rate of pts with partial response to N+I (32%) is lower of that reported with the combination of axitinib plus pembrolizumab (51%). Moreover, analysis of outcome based on the depth of response strongly suggests a connection between response and survival. This study aims at investigating the efficacy of an intensified strategy with axitinib added to nivolumab in mRCC pts without complete response at the end of N+I induction. Methods: AxIn study (NCT05817903) is a randomized, open-label, multicenter, phase 2 trial evaluating in mRCC pts who completed induction with N+I without complete response or progressive disease, whether the intensification of therapy by adding axitinib to the standard nivolumab can increase the response rate and improve the survival compared to nivolumab alone. Eligible pts with partial response or stable disease after completion of N+I induction as first-line therapy, without any toxicity ≥ G2, and candidates to maintenance nivolumab as per standard clinical practice will be randomized 1:1 to intensification of therapy with axitinib in addition to nivolumab (Arm A) or nivolumab alone (Arm B). The primary endpoint is to assess the ORR of pts treated with the intensification of axitinib plus nivolumab compared to the standard of care of nivolumab monotherapy. Secondary endpoints include PFS, OS, depth of response, duration of response, quality of life, and safety. Exploratory biomarkers analysis will be performed. The trial is actively recruiting. Clinical trial information: NCT05817903 .

Background: Immune checkpoint inhibitors (ICIs) improve overall survival (OS) in advanced/metastatic urothelial cancer (a/mUC) patients. Preliminary evidence suggests a prognostic role of inflammatory biomarkers in this setting. We aimed to develop a disease-specific prognostic inflammatory index for a/mUC patients on ICIs. Methods: Fifteen variables were retrospectively correlated with OS and progression-free survival (PFS) in a development (D, n = 264) and a validation (V, n = 132) cohort of platinum-pretreated a/mUC pts receiving ICIs at L2 or further line. A nomogram and inflammatory prognostic index (U-IPI) were developed. The index was also tested in a control cohort of patients treated with chemotherapy only (C, n = 114). Results: The strongest predictors of OS were baseline platelet/lymphocyte (PLR) and neutrophil/lymphocyte (NLR) ratios, and lactate dehydrogenase (LDH), NLR, and albumin changes at 4 weeks. These were used to build the U-IPI, which can distinctly classify patients into good or poor response groups. The nomogram scoring is significant for PFS and OS (p < 0.001 in the D, V, and combined cohorts) for the immunotherapy (IO) cohort, but not for the control cohort. Conclusions: The lack of a baseline systemic inflammatory profile and the absence of early serum inflammatory biomarker changes are associated with significantly better outcomes on ICIs in a/mUC pts. The U-IPI is an easily applicable dynamic prognostic tool for PFS and OS, allowing for the early identification of a sub-group with dismal outcomes that would not benefit from ICIs, while distinguishing another that draws an important benefit.

Background: Although germline BRCA mutations have been associated with adverse outcomes in prostate cancer (PC), understanding of the association between somatic/germline alterations in homologous recombination repair (HRR) genes and treatment outcomes in metastatic castration-resistant PC (mCRPC) is limited. The aim of this study was to investigate the prevalence and outcomes associated with somatic/germline HRR alterations, particularly BRCA1/2, in patients initiating first-line (1L) mCRPC treatment with androgen receptor signalling inhibitors (ARSi) or taxanes. Patients and methods: Data from 729 mCRPC patients were pooled for CAPTURE from four multicentre observational studies. Eligibility required 1L treatment with ARSi or taxanes, adequate tumour samples and biomarker panel results. Patients underwent paired normal and tumour DNA analyses by next-generation sequencing using a custom gene panel including ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2, RAD51B and RAD54L. Patients were divided into subgroups based on somatic/germline alteration(s): with BRCA1/2 mutations (BRCA); with HRR mutations except BRCA1/2 (HRR non-BRCA); and without HRR alterations (non-HRR). Patients without BRCA1/2 mutations were classified as non-BRCA. Radiographic progression-free survival (rPFS), progression-free survival 2 (PFS2) and overall survival (OS) were assessed. Results: Of 729 patients, 96 (13.2%), 127 (17.4%) and 506 (69.4%) were in the BRCA, HRR non-BRCA and non-HRR subgroups, respectively. BRCA patients performed significantly worse for all outcomes than non-HRR or non-BRCA patients (P < 0.05), while PFS2 and OS were significantly shorter for BRCA than HRR non-BRCA patients (P < 0.05). HRR non-BRCA patients also had significantly worse rPFS, PFS2 and OS than non-HRR patients. Exploratory analyses suggested that for BRCA patients, there were no significant differences in outcomes associated with 1L treatment choice (ARSi or taxanes) or with the somatic/germline origin of the alterations. Conclusions: Worse outcomes were observed for mCRPC patients in the BRCA subgroup compared with non-BRCA subgroups, either HRR non-BRCA or non-HRR. Despite its heterogeneity, the HRR non-BRCA subgroup presented worse outcomes than the non-HRR subgroup. Screening early for HRR mutations, especially BRCA1/2, is crucial in improving mCRPC patient prognosis.

158 Background: ECHOS trial is a large real-world study, which is collecting data on mCSPC patients treated in the daily clinical practice in Italy from 2015. To date, > 1500 pts were included in the study, most of them treated with DOC, according to the availability of the active agents over the time in Italy. In the present analysis, we assessed the characteristics and outcomes of mCSPC pts progressing within 6 mos from the start of DOC. Methods: We retrospectively and prospectively reviewed the clinical records of a consecutive series of mCSPC pts treated with DOC in the daily clinical practice in 69 Italian Hospitals. The treatment mostly consisted of DOC at the standard dose of 75 mg/sqm every 3 wks for six courses. For each pt we recorded the pre and post-DOC clinical history, the baseline characteristics of the pts, the treatment details and clinical outcomes. For the purpose of the present study, we considered only pts who ended chemotherapy by September 2022. PR was defined as the onset of progressive disease within 6 mos from the DOC start. Results: Among 920 mCSPC pts treated with DOC, 122 (14.3%) were PR. Most of them (95.6%) presented a de novo (DN) disease, which showed mostly high volume (HV) features (82.3%). Compared to the pts without PR, those showing PR presented more frequently a visceral involvement (26.2% vs 18.2%; p = 0.038), had lower baseline levels of hemoglobin (12.8 g/dl vs 13.4 g/dl; p < 0.0001), and higher baseline levels of lactate dehydrogenase (266 U/L vs 220,5 U/L; p < 0.002). No other significant differences were observed in terms of baseline PSA and alkaline phosphatase levels, symptoms degree, disease volume and timing of mets presentation between PR e no-PR pts. The median number of life prolonging agents administered after DOC progression was 1 in pts with PR as well as in pts without PR. The median overall survival was 11.9 mos and 44.9 mos in PR and no-PR pts, respectively (p < 0.0001). Conclusions: Our data suggest that PR led a significant worsening of prognosis with a relevant shortening of life expectancy in pts who receive DOC for mCSPC.

Background: Serum biomarkers have been investigated as predictive risk factors for cancer-related cardiovascular (CV) risk, but their analysis is limited to their baseline level rather than their overtime change. Besides historically validated causal factors, inflammatory and oxidative stress (OS) related markers seem to be correlated to CV events but this association needs to be further explored. We conducted an observational study to determine the predictive role of the longitudinal changes of commonly used and OS-related biomarkers during the cancer treatment period. Methods: Patients undergoing anticancer therapies, either aged 75+ years old or younger with an increased CV risk according to European Society of Cardiology guidelines, were enrolled. We assessed the predictive value of biomarkers for the onset of CV events at baseline and during therapy using Cox model, Subpopulation Treatment-Effect Pattern Plot (STEPP) method and repeated measures analysis of longitudinal data. Results: From April 2018 to August 2021, 182 subjects were enrolled, of whom 168 were evaluable. Twenty-eight CV events were recorded after a median follow up of 9.2 months (Interquartile range, IQR: 5.1–14.7). Fibrinogen and troponin levels were independent risk factors for CV events. Specifically, patients with higher than the median levels of fibrinogen and troponin at baseline had higher risk compared with patients with values below the medians, hazard ratio (HR) = 3.95, 95% CI, 1.25–12.45 and HR = 2.48, 0.67–9.25, respectively. STEPP analysis applied to Cox model showed that cumulative event-free survival at 18 and 24 months worsened almost linearly as median values of fibrinogen increased. Repeated measure analysis showed an increase over time of D-Dimer (p-interaction event*time = 0.08), systolic (p = 0.07) and diastolic (p = 0.05) blood pressure and a decrease of left ventricular ejection fraction (p = 0.15) for subjects who experienced a CV event. Conclusions: Higher levels of fibrinogen and troponin at baseline and an increase over time of D-Dimer and blood pressure are associated to a higher risk of CV events in patients undergoing anticancer therapies. The role of OS in fibrinogen increase and the longitudinal monitoring of D-dimer and blood pressure levels should be further assessed.

Background: The treatment of heavily pretreated patients with metastatic renal cell carcinoma (mRCC) represents an unmet medical need and is still challenging. Objectives: The primary objective was to assess the effectiveness of the lenvatinib plus everolimus combination and the secondary objective was the toxicity profile of this combination. Design: We conducted a longitudinal retrospective study examining mRCC patients pre-treated with one or more lines of therapy among different cancer centers in Italy. Methods: The study included patients who received the combination of lenvatinib plus everolimus as either a second-line treatment or beyond. We assessed progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), response rate (RR), and toxicity profile. In addition, we explored the potential relationship between treatment effectiveness and clinical and laboratory parameters. Results: In all, 33 patients were assessed, the median age was 60 years, 57% had an Eastern Cooperative Oncology Group performance status of 1–2 and. 63% received ⩾ 3 prior lines of therapy. 62% were ‘intermediate risk’ according to the International Metastatic Renal Cell Carcinoma Database Consortium and 30% were ‘poor risk’. The RR was 42% (no complete response), 18% stable disease. Median OS was 11.2 months (95% CI 6.8–19.9), median PFS was 6.7 months (95% CI 0.6–30.8), and median TTF was 6.7 months (95% CI 4.8–16.6). A shorter OS was significantly associated with lymph node metastases ( p = 0.043, 95% CI), neutrophils/ lymphocytes ratio (NLR) ⩾ 3 ( p = 0.007), hemoglobin/red cell distribution width ratio cutoff value <0.7 was significant ( p = 0.03) while a shorter PFS was associated with lung ( p = 0.048) and brain metastases ( p = 0.023). The most frequent G1 toxicity was diarrhea (24%), G2 was fatigue (30%), and hypertension and skin toxicity (6%) for G3. Conclusion: Our findings suggest a clinically relevant effectiveness of lenvatinib plus everolimus combination with an acceptable toxicity profile for heavily pretreated patients with mRCC.

Metastatic hormone-sensitive prostate cancer benefits from upfront treatment intensification. To date, we do not have a validated prognostic model to guide treatment choice. In our study, docetaxel-treated patients with high Gleason score, high disease burden, pain or unfavorable laboratory parameters at baseline had worse outcomes. These results may be useful in tailoring treatment in this setting. Background: Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) dramatically changed. PEACE-1 and ARASENS trials established triplet therapy efficacy. Identifying prognostic factors supporting treatment choice is pivotal. Methods: TEAM is an observational, retrospective study to evaluate prognostic role of variables in mHSPC patients receiving upfront docetaxel in 11 Italian centers. Outcome measures were progression-free survival (PFS) and overall-survival (OS). Results: From September 2014 to December 2020, 147 patients were included. Median PFS and OS were 11.6 and 37.4 months. At univariate analysis, PFS-related variables were Gleason Score (GS) ( P = .001), opioid use ( P = .004), bone metastases number ( P < .001), baseline PSA ( P = .006), Hb ( P < .001), ALP ( P < .001) and LDH ( P = .002), time between ADT and docetaxel start ( P = .018), 3-month PSA ( P < .001) and ALP ( P < .001), and number of docetaxel cycles ( P < .001). OS-related variables were PSA at diagnosis ( P = .024), primary tumor treatment ( P = .022), baseline pain ( P = .015), opioid use ( P < .001), bone metastases number ( P < . 001), baseline Hb ( P < .001), ALP ( P < .001) and LDH ( P = .001), NLR ratio ( P = .039), 3 -month PSA ( P < .001) and ALP ( P < .001) and docetaxel cycles number ( P < .001). At multivariate analysis, independent prognostic variables were GS, opioid use, baseline LDH and time between ADT and docetaxel initiation for PFS, and baseline Hb and LDH for OS. Conclusion: Patients receiving upfront docetaxel with high GS, high disease burden, pain or opioid use, baseline unfavorable laboratory values had worse outcomes. Patients had greater docetaxel benefit when initiated early after ADT start. These parameters could be taken into account when selecting candidates for triplet therapy.

153 Background: ECHOS trial is a large real-world study which is collecting data on mCSPC patients treated in the daily clinical practice in Italy from 2015. To date, > 1500 pts were included in the study, most of them treated with DOC, according to the availability of the active agents over the time in Italy. In the present analysis, we assessed the outcomes of pts ≥75 yrs old who received DOC for mCSPC. Methods: We retrospectively and prospectively reviewed the clinical records of a consecutive series of mCSPC pts treated with DOC in the daily clinical practice in 69 Italian Hospitals. The treatment mostly consisted of DOC at the standard dose of 75 mg/sqm every 3 wks for six courses. For each pt we recorded the pre and post-DOC clinical history, the baseline characteristics of the pts, the treatment details and clinical outcomes. For the purpose of the present study, we considered only pts who ended chemotherapy by September 2022. Results: Among 920 mCSPC pts treated with DOC, 132 (14.4%) were ≥ 75 yrs old. Most of them (76%) presented de novo disease with high-volume features. Their baseline characteristics were similar to those of younger pts excepting for baseline hemoglobin levels which were significantly lower in older pts (median 12.6 vs 13.5; p = 0.001). Older pts received either a reduced dose (16.7%) or a modified schedule (8.4%) more frequently than younger one (p < 0.0001). Thirty-six pts experienced a grade 3-4 toxicity, which was mainly hematological (75% of the cases). The median progression-free survival (PFS) was 12.6 mos in older pts compared to 14.9 mos observed in younger ones (p 0.2). The median number of life prolonging agents administered after DOC progression was 1 in pts ≥75 yrs as well as in pts < 75 yrs. The median overall survival (OS) was 27.9 mos and 42.4 mos in older and younger pts, respectively (p < 0.0001). Conclusions: Our data suggest that DOC was efficacious and well-tolerated in mCSPC pts ≥75 yrs although the treatment was administered with either dose or schedule modifications in about 25% of the cases. No differences were observed in terms of PFS between pts ≥75 and ones < 75 yrs. Nevertheless, the median OS of older pts was significantly worse compared to that of younger ones.

Background:Tyrosine-kinase inhibitors (TKIs) and immunotherapy represent the backbone treatment for metastatic renal cell carcinoma (mRCC) patients. The aim of the present study was to describe mean corpuscular volume (MCV) and red cell distribution width (RDW) in mRCC patients treated with pazopanib or cabozantinib, and to explore their potential impact on oncological outcomes.Materials and methods:We conducted a multicenter retrospective observational study in mRCC patients treated with pazopanib or cabozantinib between January 2012 and December 2020 in nine Italian centers. Descriptive statistics, univariate, and multivariate analyses were performed.Objectives:The primary endpoints were the incidence and trend over time of anemia, macrocytosis (elevated MCV), and anisocytosis (elevated RDW). The secondary endpoints were the correlations of MCV and RDW with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).Results:A total of 301 patients were enrolled; mean Hb value was 12.5 g/dl, a mean increase of 1 g/dl was observed at day 15 and maintained at 3 months. Most patients had baseline macrocytosis (MCV levels > 87 fl), with a significant mean increase after 3 months of treatment. At univariate analysis patients with macrocytosis had better ORR, longer PFS, and OS. About one third of patients had baseline anisocytosis (RDW > 16%), with a significant mean increase after 3 months of treatment. At univariate analysis, patients with RDW values ⩽ 16% had higher ORR, longer PFS, and OS. At multivariate analysis, baseline macrocytosis was significantly associated with better PFS in patients treated with pazopanib and baseline anisocytosis with shorter OS in all patients.Conclusions:mRCC patients treated with pazopanib or cabozantinib may have baseline macrocytosis and anisocytosis. A significant increase of Hb, MCV, and RDW after TKIs start was observed. Baseline macrocytosis is positively correlated with PFS in patients treated with pazopanib and baseline anisocytosis affects survival of patients treated with TKIs.

Background: Obesity has been associated with improved response to immunotherapy in cancer patients. We investigated the role of body mass index (BMI) in patients from the ARON-1 study (NCT05287464) treated by dual immuno-oncology agents (IO + IO) or a combination of immuno-oncology drug and a tyrosine kinase inhibitors (TKI) as first -line therapy for metastatic renal cell carcinoma (mRCC). Patients and Methods: Medical records of patients with documented mRCC treated by immuno-oncology combinations were reviewed at 47 institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (OS), and overall clinical benefit (OCB), defined as the sum of the rate of partial/complete responses and stable disease. Univariate and multivariate analyses were used to explore the association of variables of interest with survival. Results: A total of 675 patients were included; BMI was > 25 kg/m(2) in 345 patients (51%) and was associated with improved OS (55.7 vs. 28.4 months, P < .001). The OCB of patients with BMI > 25 kg/m(2) versus those with BMI <= 25 kg/m(2) was significantly higher only in patients with nonclear cell histology (81% vs. 65%, P = .011), and patients with liver metastases (76% vs. 58%, P = .007), Neutrophil to lymphocyte ratio > 4 (77% vs 62%, P = .022) or treated by nivolumab plus ipilimumab (77% vs. 64%, P = .044). In the BMI <= 25 kg/m(2) subgroup, significant differences were found between patients with NLR > 4 versus <= 4 (62% vs. 82%, P = .002) and patients treated by IO + IO versus IO + TKIs combinations (64% vs. 83%, P = .002). Conclusion: Our study suggests that the prognostic significance and the association of BMI with treatment outcome varies across clinico-pathological mRCC subgroups.

167 Background: Although CHAARTED trial suggested a survival advantage in de novo (DN) high volume (HV) mCSPC pts, the use of DOC is still debated according to the timing of either metastatic onset [relapsed (REL) vs DN] or disease burden [low volume (LV) vs HV]. In this view, it could be of interest to describe the real-world use of DOC. From 2014, ECHOS multicenter study is collecting real world data from mCSPC pts in Italy, where DOC was the only reimbursed agent until recently. Here, we present study results after first data lock at the end of 2021. Methods: We reviewed the clinical records of the mCSPC pts treated with DOC in 34 Italian Institutions. For each pt we recorded pre and post-DOC clinical history, baseline characteristics, treatment details and clinical outcomes. Results: We identified 568 pts [median age 66.5 yrs (range 43-85)]. Most of them were classified as having a DN/HV disease (78%): the remaining had a REL/LV (2.5%), a REL/HV (8.1%), and a DN/LV disease (11.5%). After a median follow-up of 22 mos, 389 pts experienced disease progression and 227 died. The survival outcomes according to the metastases timing and disease volume is reported in the table. Conclusions: Our real-world experience shows that DOC is proposed not only in DN/HV pts, but also in the other pts regardless of metastases timing and disease volume. The prognosis of DN/HV pts treated with DOC appears to be worse than in CHAARTED trial. These findings need to be confirmed by further analyses made on larger number of pts enrolled in the ECHOS trial. [Table: see text]

5003 Background: Understanding of the association between HRR mutations and outcomes in mCRPC pts is limited. This analysis investigated the prevalence and outcomes of pts with/out HRR mutations (somatic and/or germline), stratified as BRCA, non-BRCA, or HRR non-BRCA, who initiated 1L mCRPC treatment with novel hormonal therapy (NHT) or taxane. Methods: Eligible pts from PROREPAIR-B (NCT03075735), PROSENZA (NCT02922218), PROSTAC (NCT02362620), and PROSABI (NCT02787837) studies underwent paired somatic/germline DNA analyses using a custom NGS panel that included ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2, RAD51B, and RAD54L. Those with pathogenic (likely) mutations in ≥1 allele of ≥1 gene were considered deficient (HRR). rPFS, PFS2, and OS were reported for BRCA, non-BRCA, and HRR non-BRCA subgroups; associations between mutations and outcomes were assessed using inverse probability weighted Cox models, which balanced the baseline (BL) characteristics between subgroups. Hazard ratios (HRs) with 95% confidence intervals (CIs) and p values are presented. Results: Of 729 pts, 223 (30.6%) were HRR, including 96 (13.2%) BRCA. 60.4% of pts were treated with NHT and 39.6% with taxane in 1L; 80.7% received at least second-line treatment. Median age at BL was 72.2 years, 63.5% had Gleason >7, 53.1% had ECOG ≥1, and 13.3% presented with visceral metastases. BL characteristics after adjustment were similar (standard mean difference: <0.1 in HRR and maximum 0.11 for all pts). BRCA pts had significantly worse rPFS, PFS2, and OS than non-BRCA pts; BRCA pts also had significantly worse PFS2 and OS than HRR non-BRCA pts. There were no significant differences between the outcomes of somatic and germline BRCA pts. Conclusions: BRCA pts, regardless of somatic/germline origin, had significantly worse rPFS, PFS2, and OS than the total non-BRCA population and significantly worse PFS2 and OS than non-BRCA pts in the HRR subgroup. It is crucial to screen early for HRR mutations, particularly in BRCA1/2, to begin timely, targeted mCRPC treatment and improve prognosis.[Table: see text]

CONTEXT:PARP inhibitors (PARPi) are established treatments for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) deficiency after androgen receptor signalling inhibitor (ARSI) failure. New PARPi + ARSI combinations have been tested in all comers, although their clinical relevance in HRR-proficient tumours remains uncertain. OBJECTIVE:To quantitatively synthesise evidence from randomised trials assessing the efficacy and safety of PARPi + ARSI combinations for first-line treatment of mCRPC. EVIDENCE ACQUISITION:We searched the PubMed, EMBASE, SCOPUS, and Cochrane Library databases up to February 28, 2023. Randomised controlled trials (RCTs) comparing PARPi + ARSI versus placebo + ARSI for first-line treatment of mCRPC were eligible. Two reviewers independently performed screening and data extraction and assessed the risk of bias, while a third reviewer evaluated the eligibility criteria. EVIDENCE SYNTHESIS:Overall, three phase 3 RCTs were included in the systematic review: PROPEL, MAGNITUDE, and TALAPRO-2. A total of 2601 patients with mCRPC were enrolled. Two of these trials (PROPEL and TALAPRO-2) assessed the radiographic progression-free survival benefit of PARPi + ARSI for first-line treatment of mCRPC, independent of HRR status. The pooled hazard ratio was 0.62 (95% confidence interval 0.53-0.72). The pooled hazard ratio for overall survival was 0.84 (95% confidence interval 0.72-0.98), indicating a 16% reduction in the risk of death among patients who received the combination. CONCLUSIONS:Results from this meta-analysis support the use of ARSI + PARPi combinations in biomarker-unselected mCRPC. However, such combinations might be less clinically relevant in HRR-proficient cancers, especially considering the change in treatment landscape for mCRPC. PATIENT SUMMARY:We looked at outcomes from trials testing combinations of two classes of drugs (PARP inhibitors and ARSI) in advanced prostate cancer. We found that these combinations seem to work regardless of gene mutations identified as biomarkers of response to PARP inhibitors when used on their own.

164 Background: ARSI [enzalutamide (ENZA) and abiraterone (ABI)] demonstrated to be efficacious as a first-line therapy for mCRPC, showing a median progression-free survival of 16 and 20 months (mos) in pivotal trials, respectively. Nevertheless, some pts of daily clinical practice show exceptionally prolonged disease control with very long duration of treatment. The present study aimed at identifying the characteristics of LTR pts who received one ARSI as a first-line for mCRPC. Methods: We retrospectively reviewed the clinical records of a consecutive series of 647 pts treated in the daily clinical practice with one ARSI as first-line mCRPC in four Italian high-volume Institutions. Pts who had previously received docetaxel in castration-sensitive setting were excluded. Pts received standard AA or ENZA doses (1,000 mg po daily plus prednisone 10 mg po daily or 160 mg po daily, respectively). ARSI were administered until progression and were followed according to each Institution policy. For each pt we recorded pre and post-ARSI clinical history, baseline characteristics, treatment details and clinical outcomes. Pts were considered as LTR in presence of an ARSI exposure ≥ 36 mos. LTR were compared to the progressed pts with an ARSI exposure < 36 mos. On-treatment pts with an ARSI exposure < 36 mos were not considered. Results: We identified 81 LTR pts (53 treated with ENZA and 28 treated with ABI). The median age was 76 yrs (range 56-89). The median treatment duration was 46.1 mos (range 36.4-88.6) and 52 pts were still on treatment. LTR were compared to no-LTR 415 pts (233 treated with ENZA and 182 treated with ABI). Compared to no-LTR, LTR pts showed longer PSA doubling time (PSADT) (PSADT) (p = 0.001) and time to mCRPC (p < 0.0001), lower levels of basal PSA (p = 0.01), and alkaline phosphatase (ALP) (p = 0.01), better ECOG PS (p = 0.01), lower Gleason score (p = 0.01), and less pain level (p = 0.04). ECOG PS, ALP, time to mCRPC and PSADT were all identified as independent predictors of time to treatment interruption in multivariate analysis. LTR showed an 89% decreased risk of death compared to no-LTR (HR = 0.11 IC95% 0.06-0.18). Conclusions: In our experience, several variables, which are usually considered as having a prognostic value, demonstrated to be able to predict the probability of prolonged disease control in mCRPC pts treated with first-line ARSI.

Emerging evidence highlights the potential prognostic relevance of circulating lipids in metastatic castration-resistant prostate cancer (mCRPC), with a proposed 3-lipid signature. This study aims to analyze the lipidomic profiles of individuals with mCRPC to identify lipid species that could serve as predictive indicators of prognosis and therapeutic response. Plasma samples were collected from mCRPC patients initiating first-line treatment (1 L) (n = 29) and those previously treated with at least two lines of therapy (> 2 L) (n = 19), including an androgen-receptor signaling inhibitor and a taxane. Employing an untargeted lipidomic approach, lipids were extracted from the plasma samples and subjected to analysis. A comprehensive identification and quantification of 789 plasma lipids was achieved. Notably, 75 species displayed significant dysregulation in > 2 L patients in comparison to the 1 L group. Among these, 63 species exhibited elevated levels, while 12 were reduced. Patients included in > 2 L cohort showed elevated levels of acylcarnitines (CAR), diacylglycerols (DG), phosphatidylethanolamines (PE), triacylglycerols (TG), and ceramides (Cer). Notably, some upregulated lipids, including CAR 14:0, CAR 24:1, Cer d18:1/16:0, Cer d18:1/18:0 (C18 Cer), Cer d18:2/18:0, Cer d18:1/24:1, and Cer d20:1/24:1, showed significant associations with overall survival (OS) in univariate models. Specifically, increased levels of C18 Cer remained significantly associated with poorer OS in the multivariate model, even after adjusting for treatment line and PSA levels (Hazard Ratio: 3.59 [95% Confidence Interval 1.51–8.52], p = 0.004). Employing quantitative mass spectrometry, our findings underscore the independent prognostic significance of C18 Cer in individuals with mCRPC. This discovery opens avenues for further studies within this field.

BACKGROUND:The advent of immune checkpoint inhibitors (ICIs) has revolutionized the metastatic renal cell carcinoma (mRCC) therapeutic landscape. Nevertheless, tyrosine-kinase inhibitors (TKIs) targeting the vascular endothelial growth factor (VEGF) axis still play a key role. The aim of the present study was to explore the prognostic performance of an integrated blood score, based on hemoglobin (Hb) concentration, mean corpuscular volume (MCV), and red cell distribution width (RDW), in mRCC patients treated with anti-VEGF TKIs. The primary endpoint was to correlate Hb, MCV, and RDW with progression-free survival (PFS) and overall survival (OS).MATERIALS AND METHODS:Our multicenter retrospective observational study involved mRCC patients treated with pazopanib or cabozantinib from January 2012 to December 2020 in nine Italian centers. Clinical records and laboratory data, including Hb levels, MCV, and RDW, were collected at baseline. Descriptive statistics and univariate and multivariate analyses were performed.RESULTS:We enrolled 301 mRCC patients of which 179 (59%) underwent pazopanib, and 122 (41%) cabozantinib. We considered baseline Hb ≥12 g/dL, MCV >87 fL, and RDW ≤16% as good prognostic factors; hence, developing a multiparametric score capable of delineating 4 different categories. The number of good prognostic factors was associated with significantly longer PFS and OS (p < 0.001 for both). Therefore, we developed a red blood cell-based score by stratifying cases into two groups (2-3 versus 0-1, good factors). The impact on PFS and OS was even more striking (median PFS (mPFS): 16.3 vs 7.9 months; median OS (mOS): 33.7 vs 14.1 months)), regardless of the TKI agent. When challenged with univariate and multivariate analysis, the blood score maintained its high prognostic significance in terms of OS (multivariate analysis HR for OS: 0.53, 95% CI 0.39-0.75; p < 0.001, respectively), while the impact on PFS resulted in borderline significance.CONCLUSIONS:Our analyses demonstrate the prognostic role of a multiparametric score based on easily exploitable blood parameters, such as Hb concentration, MCV, and RDW. The red blood cell-based score may underlie the upregulation of the HIF-1α pathway and VEGF axis, thereby identifying a selected population who is likely to benefit from TKI therapy.

Background Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. Methods We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. Results A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. Conclusions Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.