Impact on clinical practice of the implementation of guidelines for the toxicity management of targeted therapies in kidney cancer. The protect-2 study.

BACKGROUND: The impact of such recommendations after their implementation of guidelines has not usually been evaluated. Herein, we assessed the impact and compliance with the Spanish Oncology Genitourinary Group (SOGUG) Guidelines for toxicity management of targeted therapies in metastatic renal cell carcinoma (mRCC) in daily clinical practice. METHODS: Data on 407 mRCC patients who initiated first-line targeted therapy during the year before and the year after publication and implementation of the SOGUG guideline program were available from 34 Spanish Hospitals. Adherence to SOGUG Guidelines was assessed in every cycle. RESULTS: Adverse event (AE) management was consistent with the Guidelines as a whole for 28.7% out of 966 post-implementation cycles compared with 23.1% out of 892 pre-implementation cycles (p = 0.006). Analysis of adherence by AE in non-compliant cycles showed significant changes in appropriate management of hypertension (33% pre-implementation vs. 44.5% post-implementation cycles; p < 0.0001), diarrhea (74.0% vs. 80.5%; p = 0.011) and dyslipemia (25.0% vs. 44.6%; p < 0.001). CONCLUSIONS: Slight but significant improvements in AE management were detected following the implementation of SOGUG recommendations. However, room for improvement in the management of AEs due to targeted agents still remains and could be the focus for further programs in this direction.

Avelumab First-line Maintenance for Advanced Urothelial Carcinoma: Analysis from JAVELIN Bladder 100 by Duration of First-line Chemotherapy and Interval Before Maintenance.

BACKGROUND: In the JAVELIN Bladder 100 phase 3 trial, avelumab first-line maintenance + best supportive care (BSC) prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (advanced UC) without progression after first-line platinum-based chemotherapy. OBJECTIVE: To report post hoc analyses of subgroups defined by the duration of first-line chemotherapy and interval before maintenance. DESIGN, SETTING, AND PARTICIPANTS: Patients with advanced UC without progression after four to six cycles of platinum-based chemotherapy and a 4-10-wk interval after chemotherapy (n = 700) were randomized to receive avelumab + BSC or BSC alone. Subgroups were defined by duration (quartile [Q]) and estimated number of cycles of chemotherapy, and interval between chemotherapy and maintenance. The median follow-up was >19 mo in both arms. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS (primary endpoint), PFS, and safety were assessed. RESULTS AND LIMITATIONS: Hazard ratios (95% confidence interval) for OS with avelumab + BSC versus BSC alone were as follows: by chemotherapy duration-Q3: 0.63 (0.39-1.00); by number of cycles-four cycles: 0.69 (0.48-1.00), five cycles: 0.98 (0.57-1.71), and six cycles: 0.66 (0.47-0.92); and by interval-4-<6 wk: 0.75 (0.54-1.04), 6-<8 wk: 0.67 (0.43-1.06), and 8-10 wk: 0.69 (0.47-1.02). Results were similar for PFS. Safety was similar across subgroups. All analyses were exploratory. CONCLUSIONS: Post hoc analyses of OS and PFS in subgroups defined by first-line chemotherapy duration and interval before maintenance were generally consistent with the results in the overall population, with similar safety findings. Prospective trials are warranted to confirm these findings. PATIENT SUMMARY: Avelumab maintenance treatment helped patients with advanced urothelial cancer without disease progression after at least four cycles of prior chemotherapy, and who started maintenance treatment at least 4 wk after chemotherapy, to live longer.

First-line Avelumab plus Chemotherapy in Patients with Advanced Solid Tumors: Results from the Phase Ib/II JAVELIN Chemotherapy Medley Study.

PURPOSE: Chemotherapy can potentially enhance the activity of immune checkpoint inhibitors by promoting immune priming. The phase Ib/II JAVELIN Chemotherapy Medley trial (NCT03317496) evaluated first-line avelumab + concurrent chemotherapy in patients with advanced urothelial carcinoma or non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Avelumab 800 or 1,200 mg was administered continuously every 3 weeks with standard doses of cisplatin + gemcitabine in patients with urothelial carcinoma, or carboplatin + pemetrexed in patients with nonsquamous NSCLC. Dual primary endpoints were dose-limiting toxicity (DLT; phase Ib) and confirmed objective response (phase Ib/II). RESULTS: In phase Ib, urothelial carcinoma and NSCLC cohorts received avelumab 800 mg (n = 13 and n = 6, respectively) or 1,200 mg (n = 6 each) + chemotherapy. In evaluable patients with urothelial carcinoma treated with avelumab 800 or 1,200 mg + chemotherapy, DLT occurred in 1/12 (8.3%) and 1/6 (16.7%), respectively; no DLT occurred in the NSCLC cohort. In phase II, 35 additional patients with urothelial carcinoma received avelumab 1,200 mg + chemotherapy. Across all treated patients, safety profiles were similar irrespective of avelumab dose. Objective response rates (95% confidence internal) with avelumab 800 or 1,200 mg + chemotherapy, respectively, across phase Ib/II, were 53.8% (25.1-80.8) and 39.0% (24.2-55.5) in urothelial carcinoma, and 50.0% (11.8-88.2) and 33.3% (4.3-77.7) in NSCLC. CONCLUSIONS: Preliminary efficacy and safety findings with avelumab + chemotherapy in urothelial carcinoma and NSCLC were consistent with previous studies of similar combination regimens. Conclusions about clinical activity are limited by small patient numbers. SIGNIFICANCE: This phase Ib/II trial evaluated avelumab (immune checkpoint inhibitor) administered concurrently with standard first-line chemotherapy in patients with advanced urothelial carcinoma or advanced nonsquamous NSCLC without actionable mutations. Efficacy and safety appeared consistent with previous studies of similar combinations, although patient numbers were small.

Real-world prostate-specific antigen reduction and survival outcomes of metastatic hormone-sensitive prostate cancer patients treated with apalutamide: An observational, retrospective, and multicentre study.

Background: Metastatic hormone-sensitive prostate cancer (mHSPC) treatment has changed drastically during the last years with the emergence of androgen receptor-targeted agents (ARTAs). ARTA combined with androgen deprivation therapy has demonstrated better oncological and survival outcomes in these patients. However, the optimal choice among different ARTAs remains uncertain due to their analogous efficacy. Objectives: The objective of this study was to describe prostate-specific antigen (PSA) response and oncological outcomes of patients with mHSPC treated with apalutamide. Material and methods: Medical records from three different hospitals in Spain were used to conduct this study. Patients diagnosed with mHSPC and under apalutamide treatment were included between March 2021 and January 2023. Data regarding PSA response, overall survival (OS), and radiographic progression-free survival (rPFS) were collected and stratified by metastasis volume, timing, and stating. Results: 193 patients were included; 34.2% of patients were de novo mHSPC, and the majority was classified as m1b. The 18-month OS and rPFS were 92.5% and 88.9%, respectively. Patients with PSA levels ≤0.2 ng/ml showcased an 18-month OS rate of 98.7%, contrasting with 65.3% for those with PSA >0.2 ng/ml. Similar trends emerged for rPFS (97.4% and 53.7%, respectively). When differentiating between low-volume and high-volume metastasis, the OS rate stood at 98.4% and 80.7%, respectively, while the rPFS rates were 93% and 81.6%, respectively. No significant differences were found between groups stratified by metastasis timing. Conclusion: This real-world study on patients with mHSPC treated with apalutamide plus androgen deprivation therapy revealed robust oncological outcomes, aligning with the emerging evidence. The study's hallmark finding highlights the significance of rapid and deep PSA response as a predictor of improved oncological and survival outcomes.

Prostate-specific Antigen at 3 Months as a Predictor of Radiologic Progression-free Survival in Metastatic Hormone-sensitive Prostate Cancer Treated with Apalutamide: Analysis of 633 Patients in a Real-world Database.

Background and objective: The depth of the prostate-specific antigen (PSA) decline after androgen receptor pathway inhibitor (ARPI) treatment combined with androgen deprivation therapy for patients with metastatic hormone-sensitive prostate cancer (mHSPC) may affect prognosis. The primary objective in our study was the correlation between the PSA response at 3 mo and radiologic progression-free survival (rPFS) at 24 mo. Three groups were defined according to the PSA decline: complete response (PSA ≤0.02 ng/ml), partial response (PSA >0.02 and ≤0.2 ng/ml), and incomplete response (PSA >0.2 ng/ml). Secondary objectives were correlation between the PSA response at 3 mo and overall survival, and the development of a model predicting complete PSA response. Methods: We conducted a retrospective multicenter study of patients with mHSPC treated with apalutamide from May 2018 to September 2023 registered in the Real-World Evidence APA registry across 20 centers. Key findings and limitations: We included 633 patients with mHSPC. The median age at diagnosis was 68 yr (interquartile range [IQR] 63-75) and median PSA was 16 ng/ml (IQR 7.5-64). Some 63% of the short had low-volume disease, 51% had de novo disease, 48% had recurrent disease. At 3 mo, 27% had a complete response, 42% a partial response, and 31% an incomplete response, with corresponding rRFS rates at 24 mo of 92%, 86%, and 63%. According to the predictive model, a complete PSA response at 3 mo was associated with the use of next-generation imaging and PSA <50 ng/ml at diagnosis. Study limitations include heterogeneity among the groups and variations in data quality and assessment methods. Conclusions and clinical implications: Patients with a complete PSA response after 3 mo of apalutamide treatment face a very low risk of progression within 2 yr. Conversely, nearly 50% of patients with an incomplete PSA response will experience disease progression. Patient summary: For patients with metastatic prostate cancer that is still responsive to hormone therapy, a complete response after treatment with a drug called apalutamide is associated with a very low risk of progression within 2 years. However, nearly half of patients with an incomplete response to apalutamide will experience progression of their cancer.

Patient-reported Outcomes from JAVELIN Bladder 100: Avelumab First-line Maintenance Plus Best Supportive Care Versus Best Supportive Care Alone for Advanced Urothelial Carcinoma.

BACKGROUND: In JAVELIN Bladder 100, avelumab first-line maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS; primary endpoint) versus BSC alone in patients with advanced urothelial carcinoma (aUC) without disease progression with first-line platinum-containing chemotherapy. OBJECTIVE: To evaluate patient-reported outcomes (PROs) with avelumab plus BSC versus BSC alone. DESIGN, SETTING, AND PARTICIPANTS: A randomized phase 3 trial (NCT02603432) was conducted in 700 patients with locally advanced or metastatic urothelial carcinoma that had not progressed with first-line gemcitabine plus cisplatin or carboplatin. PROs were a secondary endpoint. INTERVENTION: Avelumab plus BSC (n = 350) or BSC alone (n = 350). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Bladder Symptom Index-18 (FBlSI-18) and EuroQol five-level EQ-5D (EQ-5D-5L) assessments were analyzed using descriptive statistics and mixed-effect models. Time to deterioration (TTD; prespecified definition: a ≥3-point decrease from baseline in the FBlSI-18 disease-related symptoms-physical subscale for two consecutive assessments) was evaluated via Kaplan-Meier analyses. RESULTS AND LIMITATIONS: Completion rates for scheduled on-treatment PRO assessments were >90% (overall and average per assessment). Results from descriptive analyses and mixed-effect or repeated-measures models of FBlSI-18 and EQ-5D-5L were similar between arms. TTD was also similar, both in the prespecified analysis (hazard ratio 1.26 [95% confidence interval: 0.90, 1.77]) and in the post hoc analyses including off-treatment assessments and different event definitions. Limitations included the open-label design and limited numbers of evaluable patients at later time points. CONCLUSIONS: Addition of avelumab first-line maintenance to BSC in patients with aUC that had not progressed with first-line platinum-containing chemotherapy prolonged OS, with a relatively minimal effect on quality of life. PATIENT SUMMARY: In this trial of people with advanced urothelial carcinoma who had benefited from first-line chemotherapy (ie, had stable disease or reduced tumor size), treatment with avelumab maintenance plus best supportive care (BSC) versus BSC alone improved survival significantly, without compromising quality of life, as reported by the patients themselves.