Preliminary trial results showed that enzalutamide significantly improved metastasis-free survival among men who had nonmetastatic, castration-resistant prostate cancer and rapidly increasing ...prostate-specific antigen (PSA) levels while taking androgen-deprivation therapy. Results from the final analysis of overall survival have not yet been reported.
In this double-blind, phase 3 trial, men with nonmetastatic, castration-resistant prostate cancer (defined on the basis of conventional imaging and a PSA doubling time of ≤10 months) who were continuing to receive androgen-deprivation therapy were randomly assigned (in a 2:1 ratio) to receive enzalutamide at a dose of 160 mg or placebo once daily. Overall survival was assessed with a group sequential testing procedure and an O'Brien-Fleming-type alpha-spending function.
As of October 15, 2019, a total of 288 of 933 patients (31%) in the enzalutamide group and 178 of 468 (38%) in the placebo group had died. Median overall survival was 67.0 months (95% confidence interval CI, 64.0 to not reached) in the enzalutamide group and 56.3 months (95% CI, 54.4 to 63.0) in the placebo group (hazard ratio for death, 0.73; 95% CI, 0.61 to 0.89; P = 0.001). The exposure-adjusted rate of adverse events of grade 3 or higher was 17 per 100 patient-years in the enzalutamide group and 20 per 100 patient-years in the placebo group. Adverse events in the enzalutamide group were consistent with those previously reported for enzalutamide; the most frequently reported events were fatigue and musculoskeletal events.
Enzalutamide plus androgen-deprivation therapy resulted in longer median overall survival than placebo plus androgen-deprivation therapy among men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level. The risk of death associated with enzalutamide was 27% lower than with placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924.).
Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear.
In this ...phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated.
A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval CI, 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels.
Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).
Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This ...phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy.
We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life.
Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval CI, 0.90 to 1.22), meeting the predefined noninferiority margin (upper bound of the 95% confidence interval, <1.25). Overall survival was similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs. 55%), the hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P<0.05 for all 11 comparisons).
Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib. (Funded by GlaxoSmithKline Pharmaceuticals; COMPARZ ClinicalTrials.gov number, NCT00720941.).
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.
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).
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.
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.
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.
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•Treatment options for prostate cancer (PC) have greatly expanded in the last years.•Despite improvements in diagnosis and treatment options, PC remains one of the most frequent ...causes of mortality in men.•The cyclin-dependent kinases (CDK) pathway has a fundamental role for carcinogenesis.•CDK-inhibitors are novel agents representing a promising treatment approach in PC.•Several trials are evaluating the role of these agents in different stages of PC.
The rapidly expanding scenario of treatment options for patients affected by prostate cancer (PC) is leading to improved outcomes; however, PC still represents one of the most frequent causes of male mortality. Thus, while translational research is trying to unravel the molecular landscape underlying carcinogenesis, disease progression and treatment resistance, several clinical trials are evaluating novel options to further expand therapeutic options.
The cyclin-dependent kinases (CDK)-pathway represents a promising therapeutic target for different cancer types; due to the pivotal role of this pathway in the regulation of PC cell cycle, three CDK4/6-inhibitors (abemaciclib, palbociclib and ribociclib) are currently being investigated in several clinical trials.
In this paper, we review the current knowledge on CDK-pathway and the mechanism of action of CDK-inhibitors; we discuss the biological rationale for their use in PC and the state of the art of clinical trials focused on the demonstration of their potential role in early or advanced stage, in hormone-sensitive and castration-resistant state. Finally, the potential application of precision oncology for treatment selection in PC is discussed.
Statins are widely used in an ageing population, including subjects with solid malignancies. However, no conclusive evidence is currently available on their potential influence on patients' outcome. ...We aimed to assess whether statin exposure affects the survival of patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab.
Medical records of patients with documented mRCC treated with second- or third-line nivolumab were reviewed at ten institutions from Italy, Spain and the USA. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall clinical benefit. Univariate and multivariate analyses were used to explore the association of variables of interest with survival.
A total of 219 patients with mRCC receiving nivolumab between January 2016 and September 2021 were eligible for inclusion in this study; 59 (27%) were statin users. The median OS (34.4 versus 18.6 months, p = 0.017) and PFS (11.7 versus 4.6 months, p = 0.013) resulted apparently longer in statin users. Stratified by age, longer median OS and PFS were associated with statin exposure in both patients aged ≥70 y (median OS: 21.4 versus 10.1 months, p = 0.047; median PFS: 16.4 versus 4.6 months, p = 0.022) and <70 y (median OS: 34.4 versus 21.4 months, p = 0.043; median PFS: 10.3 versus 4.6 months, p = 0.042). Overall clinical benefit resulted higher in statin users than non-users (71% versus 54%, p = 0.030).
Our study suggests a prognostic impact of statin use in patients receiving nivolumab for mRCC.
•Statins are widely used in patients with solid malignancies.•We assessed the impact of statin exposure in patients with metastatic renal cell carcinoma treated by nivolumab.•Statin users showed longer median overall survival and progression-free survival.•Statin exposure was correlated with increased overall clinical benefit.•The synergy between statins and nivolumab should be carefully elucidated.
Background
Immune checkpoint inhibitors (ICIs) represent the standard of care as first- or second-line treatment in patients with renal cell carcinoma (RCC). Proton pump inhibitors (PPIs) are among ...the most prescribed drugs worldwide and are known to affect gut microbiota, which is gaining interest in its association with outcomes for patients on ICIs.
Objective
The aim of this study was to evaluate the impact of PPIs on outcomes in RCC patients receiving immunotherapy.
Patients and Methods
We retrospectively collected data from patients with metastatic RCC who received the combination of ipilimumab and nivolumab for first-line treatment (Cohort 1) or single-agent nivolumab for second-line or third-line treatment (Cohort 2) from five international centers with expertise in the treatment of RCC. Data about clinicopathological characteristics, PPI use, and outcome on ICIs were collected. Endpoints of the study were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Results
Two hundred and eighteen patients (71% male, median age 61 years) were included in the analysis, 62 in Cohort 1 (including 25 patients receiving PPIs) and 156 in Cohort 2 (including 88 patients receiving PPIs), and were followed up for a median of 42 months. In Cohort 1, no difference was observed in ORR (48% vs 57%;
p
= 0.203), PFS (12.2 vs 8.5 months;
p
= 0.928), or OS (not reached NR vs 27.3 months;
p
= 0.84). In Cohort 2, no difference was observed in ORR (32% vs 28%;
p
= 0.538), PFS (6.7 vs 9.0 months;
p
= 0.799), or OS (16.0 vs 26.0 months;
p
= 0.324).
Conclusions
In patients with RCC, concomitant PPI use did not seem to affect survival outcomes on ICIs, either as combination therapy or monotherapy.
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