Management of urothelial cancer in patients with chronic kidney disease receiving platinum-based chemotherapy.

Despite recent advances in the management of urothelial cancer (UC), cisplatin-based combination chemotherapy regimens remain critical. However, their use can be complicated in patients with chronic kidney disease (CKD), which is not uncommon in UC patients. Based on the Galsky criteria for cisplatin ineligibility, most patients with CKD will be excluded from receiving cisplatin-based chemotherapy altogether. For patients with borderline kidney function, several strategies - such as the use of split-dose cisplatin, dose reductions, or extra hydration - may facilitate the use of cisplatin, but these need to be prospectively validated. This review highlights the critical need for a multidisciplinary team, including onco-nephrologists, to help manage renal complications and optimize delivery of cancer care in complex UC patients with CKD.

In patients with urothelial cancer, the presence of chronic kidney disease can significantly impact treatment options, eligibility for clinical trials, and overall patient outcomes. This review discusses key strategies and newer treatment options that can be used to optimize outcomes in patients who often can't receive standard treatments. Importantly, this article also highlights the critical importance and need for a multidisciplinary team of specialists, including kidney specialists with a focus on cancer patients, to help manage kidney function and deliver high-quality care to patients with urothelial cancer and chronic kidney disease.

The Survival Outcomes of the Metastatic Nonclear Cell Renal Cell Carcinoma in the Immunotherapy Era: Princess Margaret Cancer Centre Experience.

Immunotherapy (IO) with or without targeted therapy (TT) is the standard treatment for patients with metastatic clear cell renal cell carcinoma (RCC). The evidence supporting their use in metastatic nonclear cell renal cell carcinoma (nccRCC) subtypes is based on small prospective trials and retrospective analyses. Here, we report survival outcomes for patients with metastatic nccRCC treated with IO and/or TT at the Princess Margaret Cancer Centre, Toronto, ON, Canada. Demographics, disease characteristics, and survival outcomes were collected retrospectively. Overall (OS), progression-free survival (PFS), and objective response rates (ORR) were calculated. We identified 69 patients with metastatic nccRCC treated with IO and/or TT as the first-line treatment, and 36 (52.1%) patients as the second-line treatment. Median OS of the first line IO recipients (n = 12) and non-IO recipients (n = 57) was not reached (NR) and 17.2 months (95% confidence interval (95% CI): 7.3-27.0; P = 0.23), respectively. Median PFS of first-line IO recipients and non-IO recipients was NR and 4.7 months (95% CI: 3.7-5.6; P = 0.019), respectively. The ORR of IO recipients versus non-IO recipients was 50% versus 12.3% (P = 0.007). Median OS of the second-line IO recipients (n = 8) and non-IO recipients (n = 28) was NR and 6.3 months (95% CI: 3.2-9.3; P = 0.003), respectively. Median PFS of second-line IO recipients and non-IO recipients was 4.8 months (95% CI: 2.7-6.8) and 2.8 months (95% CI: 1.8-3.7; P = 0.014), respectively. ORR of IO recipients and non-IO recipients was 37.5% and 3.5%, respectively; P = 0.028. While the number of patients included in our retrospective review was small, our analysis suggested that patients with nccRCC have improved survival outcomes with IO treatment. Validation of prospective dataset is required before widespread clinical utilization.

Clinical variables associated with immune checkpoint inhibitor outcomes in patients with metastatic urothelial carcinoma: a multicentre retrospective cohort study.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are indicated for metastatic urothelial cancer (mUC), but predictive and prognostic factors are lacking. We investigated clinical variables associated with ICI outcomes. METHODS: We performed a multicentre retrospective cohort study of 135 patients who received ICI for mUC, 2016-2021, at three Canadian centres. Clinical characteristics, body mass index (BMI), metastatic sites, neutrophil-to-lymphocyte ratio (NLR), response and survival were abstracted from chart review. RESULTS: We identified 135 patients and 62% had received ICI as a second-line or later treatment for mUC. A BMI ≥25 was significantly correlated to a higher overall response rate (ORR) (45.4% vs 16.3%, p value=0.020). Patients with BMI ≥30 experienced longer median overall survival (OS) of 24.8 vs 14.4 for 25≤BMI<30 and 8.5 months for BMI <25 (p value=0.012). The ORR was lower in the presence of bone metastases (16% vs 41%, p value=0.006) and liver metastases (16% vs 39%, p value=0.013). Metastatic lymph nodes were correlated with higher ORR (40% vs 20%, p value=0.032). The median OS for bone metastases was 7.3 versus 18 months (p value <0.001). Patients with liver metastases had a median OS of 8.6 versus 15 months (p value=0.006). No difference for lymph nodes metastases (13.5 vs 12.7 months, p value=0.175) was found. NLR ≥4 had worse OS (8.2 vs 17.7 months, p value=0.0001). In multivariate analysis, BMI ≥30, bone metastases, NLR ≥4, performance status ≥2 and line of ICI ≥2 were independent factors for OS. CONCLUSIONS: Our data identified BMI and bone metastases as novel clinical biomarkers that were independently associated with ICI outcomes in mUC. External and prospective validation are warranted.

TOward a comPrehensive supportive Care intervention for Older men with metastatic Prostate cancer (TOPCOP3): A pilot randomized controlled trial and process evaluation.

INTRODUCTION: Current management of metastatic prostate cancer (mPC) includes androgen receptor axis-targeted therapy (ARATs), which is associated with substantial toxicity in older adults. Geriatric assessment and management and remote symptom monitoring have been shown to reduce toxicity and improve quality of life in patients undergoing chemotherapy, but their efficacy in patients being treated with ARATs has not been explored. The purpose of this study is to examine whether these interventions, alone or in combination, can improve treatment tolerability and quality of life (QOL) for older adults with metastatic prostate cancer on ARATs. MATERIALS AND METHODS: TOPCOP3 is a multi-centre, factorial pilot clinical trial coupled with an embedded process evaluation. The study includes four treatment arms: geriatric assessment and management (GA + M); remote symptom monitoring (RSM); geriatric assessment and management plus remote symptom monitoring; and usual care and will be followed for six months. The aim is to recruit 168 patients between two cancer centres in Toronto, Canada. Eligible participants will be randomized equally via REDCap. Participants in all arms will complete a comprehensive baseline assessment upon enrollment following the Geriatric Core dataset, as well as follow-up assessments at 1.5, 3, 4.5, and 6 months. The co-primary outcomes will be grade 3-5 toxicity and QOL. Toxicities will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. QOL will be measured by patient self-reporting using the EuroQol 5 dimensions of health questionnaire. Secondary outcomes include fatigue, insomnia, and depression. Finally, four process evaluation outcomes will also be observed, namely feasibility, fidelity, and acceptability, along with implementation barriers and facilitators. DISCUSSION: Data will be collected to observe the effects of GA + M and RSM on QOL and toxicities experienced by older adults receiving ARATs for metastatic prostate cancer. Data will also be collected to help the design and conduct of a definitive multicentre phase III randomized controlled trial. This study will extend supportive care interventions for older adults with cancer into new areas and inform the design of larger trials. TRIAL REGISTRATION: The trial is registered at clinicaltrials.gov (registration number: NCT05582772).

Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy.

BACKGROUND AND OBJECTIVE: In comparison to chemotherapy, enfortumab vedotin (EV) prolonged overall survival in patients with previously treated advanced urothelial carcinoma in EV-301. The objective of the present study was to assess patient experiences of EV versus chemotherapy using patient-reported outcome (PRO) analysis of health-related quality of life (HRQoL). METHODS: For patients in the phase 3 EV-301 trial randomized to EV or chemotherapy we assessed responses to the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, weekly for the first 12 wk, and then every 12 wk until discontinuation. We analyzed the QLQ-C30 change from baseline to week 12, the confirmed improvement rate, and the time to improvement or deterioration. KEY FINDINGS AND LIMITATIONS: Baseline PRO compliance rates were 91% for the EV arm (n = 301) and 89% for the chemotherapy arm (n = 307); the corresponding average rates from baseline to week 12 were 70% and 67%. Patients receiving EV versus chemotherapy had reduced pain (difference in change from baseline to week 12: -5.7, 95% confidence interval [CI] -10.8 to -0.7; p = 0.027) and worsening appetite loss (7.3, 95% CI 0.90-13.69; p = 0.026). Larger proportions of patients in the EV arm reported HRQoL improvement from baseline than in the chemotherapy arm; the odds of a confirmed improvement across ten QLQ-C30 function/symptom scales were 1.67 to 2.76 times higher for EV than for chemotherapy. Patients in the EV arm had a shorter time to first confirmed improvement in global health status (GHS)/QoL, fatigue, pain, and physical, role, emotional, and social functioning (all p < 0.05). EV delayed the time to first confirmed deterioration in GHS/QoL (p = 0.027), but worsening appetite loss occurred earlier (p = 0.009) in comparison to chemotherapy. CONCLUSIONS AND CLINICAL IMPLICATIONS: HRQoL with EV was maintained, and deterioration in HRQoL was delayed with EV in comparison to chemotherapy. Better results with EV were reported for some scales, with the greatest difference observed for pain. These findings reinforce the EV safety and efficacy outcomes and benefits observed in EV-301. PATIENT SUMMARY: Patients with previously treated advanced cancer of the urinary tract receiving the drug enfortumab vedotin maintained their HRQoL in comparison to patients treated with chemotherapy. The EV-301 trial is registered on ClinicalTrials.gov as NCT03474107 and on EudraCT as 2017-003344-21.

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.

The effect of cisplatin-based neoadjuvant chemotherapy on the renal function of patients undergoing radical cystectomy.

INTRODUCTION: Cisplatin-based neoadjuvant chemotherapy (NAC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy (RC). Cisplatin, however, can induce renal toxicity. Furthermore, RC is an independent risk factor for renal injury, with decreases in estimated glomerular filtration rate (eGFR) of up to 6 mL/min/1.73 m2 reported at one year postoperatively. Our objective was to evaluate the effect of cisplatin-based NAC and RC on the renal function of patients undergoing both. METHODS: We analyzed a multicenter database of patients with MIBC, all of whom received cisplatin-based NAC prior to RC. eGFR values were collected at time points T1 (before NAC), T2 (after NAC but before RC), and T3 (one year post-RC). eGFR and proportion of patients with eGFR <60 ml/min/1.73m2 (chronic kidney disease [CKD] stage ≥3) were compared between these time points. As all patients in this dataset had received NAC, we identified a retrospective cohort of patients from one institution who had undergone RC during the same time period without NAC for context. RESULTS: We identified 234 patients with available renal function data. From T1 to T3, there was a mean decline in eGFR of 17% (13 mL/min/1.73 m2) in the NAC cohort and an increase in proportion of patients with stage ≥3 CKD from 27% to 50%. The parallel cohort of patients who did not receive NAC was comprised of 236 patients. The mean baseline eGFR in this cohort was lower than in the NAC cohort (66 vs. 75 mL/min/1.73 m2). The mean eGFR decline in this non-NAC cohort from T1 to T3 was 6% (4 mL/min/1.73 m2), and the proportion of those with stage ≥3 CKD increased from 37% to 51%. CONCLUSIONS: Administration of NAC prior to RC was associated with a 17% decline in eGFR and a nearly doubled incidence of stage ≥3 CKD at one year after RC. Patients who underwent RC without NAC had a higher rate of stage ≥3 CKD at baseline but appeared to have less renal function loss at one year.

Identification of characteristics predictive of long-term survival with durvalumab or durvalumab plus tremelimumab in metastatic urothelial carcinoma.

BACKGROUND: This retrospective analysis of data from clinical trials in metastatic urothelial carcinoma (mUC) was conducted to determine baseline patient characteristics associated with long-term survival (LTS) following treatment with immune checkpoint inhibitors. METHODS: Data for this analysis were from patients with platinum-refractory mUC who received durvalumab or durvalumab plus tremelimumab in phase 1/2 studies. The primary outcome measure was LTS. Patients were categorised as overall survival (OS) ≥ 2 years (from first dose) or OS < 2 years. A univariable analysis assessed independent associations with LTS and multivariable logistic regression was employed including each variable with P ≤ 0.05 as covariates. RESULTS: Among 360 patients, 88 (24.4%) had OS ≥ 2 years and 272 (75.6%) had OS < 2 years. In univariable analysis, several baseline characteristics and laboratory measurements were associated with LTS including sex, ECOG PS, PD-L1 expression, prior surgery, time from initial diagnosis, lymph node-only involvement, visceral disease, haemoglobin level, absolute neutrophil count, neutrophil-lymphocyte ratio and lactate dehydrogenase level. In multivariable analysis, LTS was significantly associated with ECOG PS, PD-L1 expression, haemoglobin level and absolute neutrophil count. CONCLUSIONS: Several baseline clinical characteristics and laboratory measurements were associated with LTS for patients with platinum-refractory mUC treated with durvalumab or durvalumab plus tremelimumab.

Clinical trial reform in the post-COVID era.

The COVID-19 pandemic precipitated the acute and efficient rollout of telehealth and virtual health care around the world. This review article focuses on the adoption of virtual care in the management of oncology patients, and discusses how virtual care offers the potential for large-scale, positive impacts on access to clinical trials. Virtual care during and following the peak of the pandemic has been found to be both safe and efficacious for oncology patients. Features, such as wearable health technologies, remote monitoring, home visits, and investigations being done closer to home, represent just some of the strengths of the virtual assessment rollout that were successfully utilized. One of the primary criticisms of oncological clinical trials is that clinical trial participants are not always representative of the patient populations treated in routine practice. This is in part due to stringent inclusion criteria and more broadly pertains to a lack of access to clinical trials, many of which are geographic as most trials are conducted in an urban, academic, or 'centralized' center. This paper seeks to discuss the barriers to clinical trial participation and to propose that the virtual care transformation that occurred during the pandemic has equipped oncological clinicians and researchers with the tools to better address these obstacles. A review of the literature on the impact of the virtual care rollout during and after the peak of the COVID-19 pandemic both locally and abroad was conducted. It is proposed that improving patient access through the decentralization of clinical trials has the potential to enhance evidence-based, real-world data, and to produce generalizable trial results that ultimately improve patient outcomes.

Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis.

BACKGROUND: Previous randomised controlled trials comparing bladder preservation with radical cystectomy for muscle-invasive bladder cancer closed due to insufficient accrual. Given that no further trials are foreseen, we aimed to use propensity scores to compare trimodality therapy (maximal transurethral resection of bladder tumour followed by concurrent chemoradiation) with radical cystectomy. METHODS: This retrospective analysis included 722 patients with clinical stage T2-T4N0M0 muscle-invasive urothelial carcinoma of the bladder (440 underwent radical cystectomy, 282 received trimodality therapy) who would have been eligible for both approaches, treated at three university centres in the USA and Canada between Jan 1, 2005, and Dec 31, 2017. All patients had solitary tumours less than 7 cm, no or unilateral hydronephrosis, and no extensive or multifocal carcinoma in situ. The 440 cases of radical cystectomy represent 29% of all radical cystectomies performed during the study period at the contributing institutions. The primary endpoint was metastasis-free survival. Secondary endpoints included overall survival, cancer-specific survival, and disease-free survival. Differences in survival outcomes by treatment were analysed using propensity scores incorporated in propensity score matching (PSM) using logistic regression and 3:1 matching with replacement and inverse probability treatment weighting (IPTW). FINDINGS: In the PSM analysis, the 3:1 matched cohort comprised 1119 patients (837 radical cystectomy, 282 trimodality therapy). After matching, age (71·4 years [IQR 66·0-77·1] for radical cystectomy vs 71·6 years [64·0-78·9] for trimodality therapy), sex (213 [25%] vs 68 [24%] female; 624 [75%] vs 214 [76%] male), cT2 stage (755 [90%] vs 255 [90%]), presence of hydronephrosis (97 [12%] vs 27 [10%]), and receipt of neoadjuvant or adjuvant chemotherapy (492 [59%] vs 159 [56%]) were similar between groups. Median follow-up was 4·38 years (IQR 1·6-6·7) versus 4·88 years (2·8-7·7), respectively. 5-year metastasis-free survival was 74% (95% CI 70-78) for radical cystectomy and 75% (70-80) for trimodality therapy with IPTW and 74% (70-77) and 74% (68-79) with PSM. There was no difference in metastasis-free survival either with IPTW (subdistribution hazard ratio [SHR] 0·89 [95% CI 0·67-1·20]; p=0·40) or PSM (SHR 0·93 [0·71-1·24]; p=0·64). 5-year cancer-specific survival for radical cystectomy versus trimodality therapy was 81% (95% CI 77-85) versus 84% (79-89) with IPTW and 83% (80-86) versus 85% (80-89) with PSM. 5-year disease-free survival was 73% (95% CI 69-77) versus 74% (69-79) with IPTW and 76% (72-80) versus 76% (71-81) with PSM. There were no differences in cancer-specific survival (IPTW: SHR 0·72 [95% CI 0·50-1·04]; p=0·071; PSM: SHR 0·73 [0·52-1·02]; p=0·057) and disease-free survival (IPTW: SHR 0·87 [0·65-1·16]; p=0·35; PSM: SHR 0·88 [0·67-1·16]; p=0·37) between radical cystectomy and trimodality therapy. Overall survival favoured trimodality therapy (IPTW: 66% [95% CI 61-71] vs 73% [68-78]; hazard ratio [HR] 0·70 [95% CI 0·53-0·92]; p=0·010; PSM: 72% [69-75] vs 77% [72-81]; HR 0·75 [0·58-0·97]; p=0·0078). Outcomes for radical cystectomy and trimodality therapy were not statistically different among centres for cancer-specific survival and metastasis-free survival (p=0·22-0·90). Salvage cystectomy was done in 38 (13%) trimodality therapy patients. Pathological stage in the 440 radical cystectomy patients was pT2 in 124 (28%), pT3-4 in 194 (44%), and 114 (26%) node positive. The median number of nodes removed was 39, the soft tissue positive margin rate was 1% (n=5), and the perioperative mortality rate was 2·5% (n=11). INTERPRETATION: This multi-institutional study provides the best evidence to date showing similar oncological outcomes between radical cystectomy and trimodality therapy for select patients with muscle-invasive bladder cancer. These results support that trimodality therapy, in the setting of multidisciplinary shared decision making, should be offered to all suitable candidates with muscle-invasive bladder cancer and not only to patients with significant comorbidities for whom surgery is not an option. FUNDING: Sinai Health Foundation, Princess Margaret Cancer Foundation, Massachusetts General Hospital.

Epidemiology of Bladder Cancer in 2023: A Systematic Review of Risk Factors.

CONTEXT: Bladder cancer (BC) is common worldwide and poses a significant public health challenge. External risk factors and the wider exposome (totality of exposure from external and internal factors) contribute significantly to the development of BC. Therefore, establishing a clear understanding of these risk factors is the key to prevention. OBJECTIVE: To perform an up-to-date systematic review of BC's epidemiology and external risk factors. EVIDENCE ACQUISITION: Two reviewers (I.J. and S.O.) performed a systematic review using PubMed and Embase in January 2022 and updated it in September 2022. The search was restricted to 4 yr since our previous review in 2018. EVIDENCE SYNTHESIS: Our search identified 5177 articles and a total of 349 full-text manuscripts. GLOBOCAN data from 2020 revealed an incidence of 573 000 new BC cases and 213 000 deaths worldwide in 2020. The 5-yr prevalence worldwide in 2020 was 1 721 000. Tobacco smoking and occupational exposures (aromatic amines and polycyclic aromatic hydrocarbons) are the most substantial risk factors. In addition, correlative evidence exists for several risk factors, including specific dietary factors, imbalanced microbiome, gene-environment risk factor interactions, diesel exhaust emission exposure, and pelvic radiotherapy. CONCLUSIONS: We present a contemporary overview of the epidemiology of BC and the current evidence for BC risk factors. Smoking and specific occupational exposures are the most established risk factors. There is emerging evidence for specific dietary factors, imbalanced microbiome, gene-external risk factor interactions, diesel exhaust emission exposure, and pelvic radiotherapy. Further high-quality evidence is required to confirm initial findings and further understand cancer prevention. PATIENT SUMMARY: Bladder cancer is common, and the most substantial risk factors are smoking and workplace exposure to suspected carcinogens. On-going research to identify avoidable risk factors could reduce the number of people who get bladder cancer.

Triplet Therapy in Metastatic Castrate Sensitive Prostate Cancer (mCSPC)-A Potential New Standard of Care.

The treatment paradigm for metastatic castrate-sensitive prostate cancer (mCSPC) has evolved rapidly in the past decade with the approval of several life-prolonging therapies including docetaxel chemotherapy and multiple androgen receptor pathway inhibitors (ARPI) in combination with androgen deprivation therapy (ADT). Recently reported phase-three trials have demonstrated a survival benefit of upfront triplet therapy with ADT, docetaxel plus either abiraterone acetate or darolutamide when compared to ADT plus docetaxel alone. However, multiple questions including the incremental benefit of docetaxel to a combination of ADT and ARPI, the timing of ARPI, optimal patient selection for triplet therapy and clinical and genomic biomarkers still remain to be answered. Moreover, real-world data suggest suboptimal treatment intensification with many patients treated with ADT alone highlighting challenges in implementation. In this article, we review the phase-three data associated with triplet therapy in mCSPC. We also discuss the knowledge gaps that exist despite the completion of these studies and how ongoing studies are likely to change the paradigm in the near future. Finally, we provide a simple algorithm based on current data that clinicians can use in daily practice to select patients for appropriate treatment strategies.

Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After ≥2 Years of Follow-Up.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Initial results from the phase III JAVELIN Bladder 100 trial (ClinicalTrials.gov identifier: NCT02603432) showed that avelumab first-line (1L) maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free after 1L platinum-containing chemotherapy. Avelumab 1L maintenance treatment is now a standard of care for aUC. Here, we report updated data with ≥ 2 years of follow-up in all patients, including OS (primary end point), PFS, safety, and additional novel analyses. Patients were randomly assigned 1:1 to receive avelumab plus BSC (n = 350) or BSC alone (n = 350). At data cutoff (June 4, 2021), median follow-up was 38.0 months and 39.6 months, respectively; 67 patients (19.5%) had received ≥2 years of avelumab treatment. OS remained longer with avelumab plus BSC versus BSC alone in all patients (hazard ratio, 0.76 [95% CI, 0.63 to 0.91]; 2-sided P = .0036). Investigator-assessed PFS analyses also favored avelumab. Longer-term safety was consistent with previous analyses; no new safety signals were identified with longer treatment duration. In conclusion, longer-term follow-up continues to show clinically meaningful efficacy benefits with avelumab 1L maintenance plus BSC versus BSC alone in patients with aUC. An interactive visualization of data reported in this article is available.

Avelumab First-line Maintenance Therapy for Advanced Urothelial Carcinoma: Comprehensive Clinical Subgroup Analyses from the JAVELIN Bladder 100 Phase 3 Trial.

BACKGROUND: In the phase 3 JAVELIN Bladder 100 trial, avelumab first-line (1L) maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free following 1L platinum-based chemotherapy, leading to regulatory approval in various countries. OBJECTIVE: To analyze clinically relevant subgroups from JAVELIN Bladder 100. DESIGN, SETTING, AND PARTICIPANTS: Patients with unresectable locally advanced or metastatic UC without progression on 1L gemcitabine + cisplatin or carboplatin were randomized to receive avelumab + BSC (n = 350) or BSC alone (n = 350). Median follow-up was >19 mo in both arms (data cutoff October 21, 2019). This trial is registered on ClinicalTrials.gov as NCT02603432. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS (primary endpoint) and PFS were analyzed in protocol-specified and post hoc subgroups using the Kaplan-Meier method and Cox proportional hazards models. RESULTS AND LIMITATIONS: Hazard ratios (HRs) for OS with avelumab + BSC versus BSC alone were <1.0 across all subgroups examined, including patients treated with 1L cisplatin + gemcitabine (HR 0.69, 95% confidence interval [CI] 0.50-0.93) or carboplatin + gemcitabine (HR 0.64, 95% CI 0.46-0.90), patients with PD-L1+ tumors treated with carboplatin + gemcitabine (HR 0.67, 95% CI 0.39-1.14), and patients whose best response to chemotherapy was a complete response (HR 0.80, 95% CI 0.46-1.37), partial response (HR 0.62, 95% CI 0.46-0.84), or stable disease (HR 0.70, 95% CI 0.46-1.06). Observations were similar for PFS. Limitations include the smaller size and post hoc evaluation without multiplicity adjustment for some subgroups. CONCLUSIONS: Analyses of OS and PFS in clinically relevant subgroups were consistent with results for the overall population, further supporting avelumab 1L maintenance as standard-of-care treatment for patients with aUC who are progression-free following 1L platinum-based chemotherapy. PATIENT SUMMARY: In the JAVELIN Bladder 100 study, maintenance treatment with avelumab helped many different groups of people with advanced cancer of the urinary tract to live longer.

Rucaparib or Physician's Choice in Metastatic Prostate Cancer.

BACKGROUND: In a phase 2 study, rucaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), showed a high level of activity in patients who had metastatic, castration-resistant prostate cancer associated with a deleterious BRCA alteration. Data are needed to confirm and expand on the findings of the phase 2 study. METHODS: In this randomized, controlled, phase 3 trial, we enrolled patients who had metastatic, castration-resistant prostate cancer with a BRCA1, BRCA2, or ATM alteration and who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI). We randomly assigned the patients in a 2:1 ratio to receive oral rucaparib (600 mg twice daily) or a physician's choice control (docetaxel or a second-generation ARPI [abiraterone acetate or enzalutamide]). The primary outcome was the median duration of imaging-based progression-free survival according to independent review. RESULTS: Of the 4855 patients who had undergone prescreening or screening, 270 were assigned to receive rucaparib and 135 to receive a control medication (intention-to-treat population); in the two groups, 201 patients and 101 patients, respectively, had a BRCA alteration. At 62 months, the duration of imaging-based progression-free survival was significantly longer in the rucaparib group than in the control group, both in the BRCA subgroup (median, 11.2 months and 6.4 months, respectively; hazard ratio, 0.50; 95% confidence interval [CI], 0.36 to 0.69) and in the intention-to-treat group (median, 10.2 months and 6.4 months, respectively; hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001 for both comparisons). In an exploratory analysis in the ATM subgroup, the median duration of imaging-based progression-free survival was 8.1 months in the rucaparib group and 6.8 months in the control group (hazard ratio, 0.95; 95% CI, 0.59 to 1.52). The most frequent adverse events with rucaparib were fatigue and nausea. CONCLUSIONS: The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a BRCA alteration. (Funded by Clovis Oncology; TRITON3 ClinicalTrials.gov number, NCT02975934.).