BRCA Mutations in Prostate Cancer: Prognostic and Predictive Implications

Despite chemotherapy and novel androgen-receptor signalling inhibitors (ARSi) have been approved during the last decades, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with poor clinical outcomes. Several studies found that germline or acquired DNA damage repair (DDR) defects affect a high percentage of mCRPC patients. Among DDR defects, BRCA mutations show relevant clinical implications. BRCA mutations are associated with adverse clinical features in primary tumors and with poor outcomes in patients with mCRPC. In addition, BRCA mutations predict good response to poly-ADP ribose polymerase (PARP) inhibitors, such as olaparib, rucaparib, and niraparib. However, concerns still remain on the role of extensive mutational testing in prostate cancer patients, given the implications for patients and for their progeny. The present comprehensive review attempts to provide an overview of BRCA mutations in prostate cancer, focusing on their prognostic and predictive roles

Persistent neutrophil to lymphocyte ratio >3 during treatment with enzalutamide and clinical outcome in patients with castration-resistant prostate cancer

The baseline value of neutrophil to lymphocyte ratio (NLR) has been found to be prognostic in patients with metastatic castration resistant prostate cancer (CRPC). We evaluated the impact of baseline NLR and its change in patients receiving enzalutamide. We included consecutive metastatic CRPC patients treated with enzalutamide after docetaxel and studies the change of NLR (>3 vs ≤3) after week 4 and 12 weeks. Progression-free survival (PFS), overall survival (OS) and their 95% Confidence Intervals (95% CI) were estimated by the Kaplan-Meier method and compared with the log-rank test. The impact of NLR on PFS and OS was evaluated by Cox regression analyses and on prostate-specific antigen response rates (PSA RR; PSA decline >50%) were evaluated by binary logistic regression. Data collected on 193 patients from 9 centers were evaluated. Median age was 73.1 years (range, 42.8–90.7). The median baseline NLR was 3.2. The median PFS was 3.2 months (95% CI = 2.7–4.2) in patients with baseline NLR >3 and 7.4 months (95% CI = 5.5–9.7) in those with NLR ≤3, p < 0.0001. The median OS was 10.4 months (95% CI = 6.5–14.9) in patients with baseline NLR >3 and 16.9 months (95% CI = 11.2–20.9) in those with baseline NLR ≤3, p < 0.0001. In multivariate analysis, changes in NLR at 4 weeks were significant predictors of both PFS [hazard ratio (HR) 1.24, 95% confidence interval (95% CI) 1.07–1.42, p = 0.003, and OS (HR 1.29, 95% CI 1.10–1.51, p = 0.001. A persistent NLR >3 during treatment with enzalutamide seems to have both prognostic and predictive value in CRPC patients

The Role of Fast and Deep PSA Response in Castration-sensitive Prostate Cancer

Background: Outcomes of castration-sensitive prostate cancer (CSPC) have improved owing to new therapies and early treatment, previously reserved for castration-resistant disease (CRPC). Prostatic-specific antigen (PSA) remains the most used marker to follow-up patients under treatment, but only limited data are available about the prognostic role of its changes over time and the impact of response to subsequent therapies. This analysis aims to assess the prognostic role of the magnitude and velocity of PSA response in CSPC and describe how this may affect the outcome to subsequent treatment outcomes in CRPC. Patients and methods: A retrospective analysis was performed on patients with de novo CSPC referring to six oncology centers in Italy. Clinical and pathological features were recorded. PSA response (PSA50), defined as a decrease > 50% compared to baseline, PSA velocity (PSAv), defined as any decrease in PSA levels over time and the deep and fast PSA response (4mPSA50), defined as the PSA response reached within the threshold of 4 months from the beginning of androgen deprivation therapy (ADT) have been evaluated for their impact on survival. Survivals were estimated using the Kaplan-Meier method and compared across groups using the log-rank test. Cox proportional-hazard models, stratified according to baseline characteristics, were used to estimate hazard ratios for overall survival (OS). Results: A totals of 94.4% of patients had PSA50, which was correlated to longer OS compared to patients without PSA50 (56.0 vs. 14.8 months; p<0.001). The median PSAv was 6.9 (ng/dl)/month, which was predictive for longer OS: Each decrease of 1 (ng/dl)/month was able to improve OS by 0.2% (HR=0.998, 95%CI=0.997-1.000; p=0.008). A total of 47.9% of patients reached 4mPSA50, with a median OS and progression-free survival (PFS) to ADT-based therapy of 101.0 and 23.4 months compared to 41.9 and 11.0 months for those who did not (p<0.001), respectively. The independent prognostic role of 4mPSA50 was retained even when evaluated in multivariable analysis adjusted for other baseline characteristics and early docetaxel for CSPC. In CRPC, 4mPSA50 evaluated during CSPC retains its prognostic role even if it does not predict a different outcome between patients treated with abiraterone/enzalutamide or taxanes. Conclusion: Achieving a deep and fast PSA response correlates with a better outcome in patients with de novo mCSPC, also positively influencing the prognosis of the subsequent first-line therapy for CRPC disease

A Remote Monitoring System to Optimize the Home Management of Oral Anticancer Therapies (ONCO-TreC): Prospective Training-Validation Trial

Background: A platform designed to support the home management of oral anticancer treatments and provide a secure web-based patient–health care professional communication modality, ONCO-TreC, was tested in 3 cancer centers in Italy. Objective: The overall aims of the trial are to customize the platform; assess the system’s ability to facilitate the shared management of oral anticancer therapies by patients and health professionals; and evaluate system usability and acceptability by patients, caregivers, and health care professionals. Methods: Patients aged ≥18 years who were candidates for oral anticancer treatment as monotherapy with an Eastern Cooperative Oncology Group performance status score of 0 to 1 and a sufficient level of familiarity with mobile devices were eligible. ONCO-TreC consisted of a mobile app for patients and a web-based dashboard for health care professionals. Adherence to treatment (pill count) and toxicities reported by patients through the app were compared with those reported by physicians in medical records. Usability and acceptability were evaluated using questionnaires. Results: A total of 40 patients were enrolled, 38 (95%) of whom were evaluable for adherence to treatment. The ability of the system to measure adherence to treatment was high, with a concordance of 97.3% (95% CI 86.1%-99.9%) between the investigator and system pill count. Only 60% (3/5) of grade 3, 54% (13/24) of grade 2, and 19% (7/36) of grade 1 adverse events reported by physicians in the case report forms were also reported in the app directly by patients. In total, 94% (33/35) of patients had ≥1 app launch each week, and the median number of daily accesses per patient was 2. Approximately 71% (27/38) and 68% (26/38) of patients used the app for messages and vital sign entering, respectively, at least once during the study period. Conclusions: ONCO-TreC is an important tool for measuring and monitoring adherence to oral anticancer drugs. System usability and acceptability were very high, whereas its reliability in registering toxicity could be improved

Very Early PSA Response to Abiraterone in mCRPC Patients: A Novel Prognostic Factor Predicting Overall Survival

BACKGROUND Abiraterone Acetate (AA) is approved for the treatment of mCRPC after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated and for treatment of mCRPC progressed during or after docetaxel-based chemotherapy regimen. The aim of this study is to evaluate the role of early PSA decline for detection of therapy success or failure in mCRPC patients treated with AA in post chemotherapy setting.PATIENTS AND METHODS We retrospectively evaluated 87 patients with mCRPC treated with AA. Serum PSA levels were evaluated after 15, 90 days and then monthly. The PSA flare phenomenon was evaluated, according to a confirmation value at least one week apart. The primary endpoint was to demonstrate that an early PSA decline correlates with a longer progression free survival (PFS) and overall survival (OS). The secondary endpoind was to demonstrate a correlation between better outcome and demographic and clinical patient characteristics.RESULTS We have collected data of 87 patients between Sep 2011 and Sep 2014. Early PSA response (≥ 50% from baseline at 15 days) was found in 56% evaluated patients and confirmed in 29 patients after 90 days. The median progression free survival (PFS) was 5,5 months (4,6-6,5) and the median overall survival (OS) was 17,1 months (8,8-25,2). In early responders patients (PSA RR ≥ 50% at 15 days), we found a significant statistical advantage in terms of PFS at 1 year, HR 0.28, 95%CI 0.12-0.65, p=0.003, and OS, HR 0.21 95% CI 0.06-0.72, p=0.01. The results in PFS at 1 years and OS reached statistical significance also in the evaluation at 90 days.CONCLUSION A significant proportion (78.6%) of patients achieved a rapid response in terms of PSA decline. Early PSA RR (≥ 50% at 15 days after start of AA) can provide clinically meaningful information and can be considered a surrogate of longer PFS and OS

Risk of cardiovascular toxicity with combination of immune-checkpoint inhibitors and angiogenesis inhibitors: a meta-analysis

IntroductionCombinations of immune checkpoint inhibitors (ICIs) and angiogenesis inhibitors (AIs) have been investigated for the treatment of several tumor types. Both ICIs and AIs may lead to cardiovascular adverse events, and their combination may potentially increase the risk for cardiovascular toxicity. In the present meta-analysis, we aim to assess the cardiovascular toxicity of ICIs plus AIs vs. AIs alone. Secondary objectives are non-cardiovascular adverse events and efficacy.MethodsSystematic review was performed according to PRISMA statement. Phase II and III randomized clinical trials were identified by searching the MEDLINE/PubMed, Cochrane Library and ASCO Meeting abstracts, from inception to June 2022. The pooled risks for overall response rate (ORR), 1-year progression-free survival (PFS), adverse events (AEs), immune-related AEs, (irAEs), hypertension, and vascular events defined as stroke, myocardial infarction and pulmonary embolisms, were calculated.ResultsIn terms of cardiovascular toxicity, we found higher risk for severe hypertension among patients treated with ICIs plus AIs as compared with those receiving AIs (OR 1.24, 95% CI: 1.01–1.53), but no significant difference was found for any-grade hypertension, and for vascular events. There was also no difference in terms of overall AEs, whereas the incidence of irAEs was increased in the ICIs plus AIs arm, as expected. In terms of efficacy, ICIs plus AIs achieved better ORR (OR 2.25, 95% CI: 1.70–2.97) and PFS (HR 0.49, 95% CI: 0.39–0.63) as compared to AIs alone.ConclusionThe addition of ICIs to AIs significantly increased the risk of high-grade hypertension, but not that of acute vascular events

Use of the ONCO-TreC electronic diary compared with a standard paper diary to improve adherence to oral cancer therapy in patients with solid and haematological tumours: protocol for a randomised controlled trial

Introduction ONCO-TreC platform consists of a mobile application delivered to patients as electronic diary and a web-based dashboard managed by healthcare professionals. We aim to compare the effectiveness of ONCO-TreC electronic diary with a standard paper diary, in improving adherence to oral cancer therapy in patients with solid and haematological tumours. Methods and analysis This is an open label, superiority, randomised controlled trial conducted in two Italian oncology units. Patients will be randomised with a 1:1 ratio to electronic or paper diary. For both groups a counsellor will be responsible for drug and diary delivery. The evaluation period will end after six cycles of therapy. The primary aim is to compare the proportion of non-adherent patients in the two arms. Adherence will be measured through pill count; anyone who takes less than 90% of the total prescribed drug dose will be considered non-adherent. Assuming a percentage of non-adherent patients to oral therapy of 40% in arm B, and a 60% reduction in this percentage in arm A, a sample of 124 patients will provide 80% power to identify an absolute difference greater than 24 percentage points using a bilateral Fisher’s exact test with a significance level of 0.05. Considering a dropout rate of 10%, approximately 136 patients will have to be enrolled. The primary analysis will be performed on the intention-to-treat population. Secondary aims are to describe the reasons for non-adherence, the level of satisfaction of patients and healthcare professionals with the paper and electronic diary, and the impact of non-adherence in terms of healthcare costs. Ethics and dissemination Ethical approval was obtained from Romagna Ethics Committee (CEROM), study ID 2108, prot. n. IRST 100.28 of 10/04/2020. Informed consent will be obtained from all study participants. Findings will be disseminated through peer-reviewed journals, conferences and event presentations

Persistent neutrophil to lymphocyte ratio >3 during treatment with enzalutamide and clinical outcome in patients with castration-resistant prostate cancer

The baseline value of neutrophil to lymphocyte ratio (NLR) has been found to be prognostic in patients with metastatic castration resistant prostate cancer (CRPC). We evaluated the impact of baseline NLR and its change in patients receiving enzalutamide. We included consecutive metastatic CRPC patients treated with enzalutamide after docetaxel and studies the change of NLR (>3 vs ?3) after week 4 and 12 weeks. Progression-free survival (PFS), overall survival (OS) and their 95% Confidence Intervals (95% CI) were estimated by the Kaplan-Meier method and compared with the log-rank test. The impact of NLR on PFS and OS was evaluated by Cox regression analyses and on prostate-specific antigen response rates (PSA RR; PSA decline >50%) were evaluated by binary logistic regression. Data collected on 193 patients from 9 centers were evaluated. Median age was 73.1 years (range, 42.8-90.7). The median baseline NLR was 3.2. The median PFS was 3.2 months (95% CI = 2.7-4.2) in patients with baseline NLR >3 and 7.4 months (95% CI = 5.5-9.7) in those with NLR ?3, p < 0.0001. The median OS was 10.4 months (95% CI = 6.5-14.9) in patients with baseline NLR >3 and 16.9 months (95% CI = 11.2-20.9) in those with baseline NLR ?3, p < 0.0001. In multivariate analysis, changes in NLR at 4 weeks were significant predictors of both PFS [hazard ratio (HR) 1.24, 95% confidence interval (95% CI) 1.07-1.42, p = 0.003, and OS (HR 1.29, 95% CI 1.10-1.51, p = 0.001. A persistent NLR >3 during treatment with enzalutamide seems to have both prognostic and predictive value in CRPC patients

Phase II Randomized Study of Vandetanib Plus Gemcitabine or Gemcitabine Plus Placebo as First-Line Treatment of Advanced Non–Small-Cell Lung Cancer in Elderly Patients

Introduction:The aim of the present study was to evaluate the efficacy and tolerability of vandetanib plus gemcitabine (V/G) compared with gemcitabine alone in elderly patients with untreated advanced non–small-cell lung cancer.Methods:This was a phase II, randomized, double-blind study. A total of 124 elderly patients (mean age, 75 yr; age range, 70–84 yr; 73% men) received V/G (n = 61) or placebo plus gemcitabine (n = 63). Progression-free survival (PFS) was the primary endpoint. Secondary endpoints were overall survival, objective response rate, duration of response, disease control rate, time to deterioration of performance status, and safety outcomes.Results:PFS was significantly prolonged with V/G (median, 183 days; 95% confidence interval, 116–214) compared with placebo plus gemcitabine (median, 169 days; 95% confidence interval, 95–194; p = 0.047). No statistically significant differences between arms were observed in all secondary endpoints, including overall survival. The addition of vandetanib to gemcitabine was well tolerated. The rate of patients with ≥1 treatment-related adverse event was comparable in the two arms, pyrexia, dyspnea, and neutropenia being the most common adverse events.Conclusions:V/G combination was associated with a statistically significant prolongation of PFS compared with gemcitabine alone in untreated elderly patients with advanced non–small-cell lung cancer, with an acceptable safety profile