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Novel immune checkpoint inhibitors hold promise for non-muscle-invasive bladder cancer. Cooperation between urologists and other multidisciplinary bladder cancer specialists can surmount the challenges involved in using these agents in bladder-sparing approaches. This strategy could deliver a new era of comprehensive evaluation and multimodal treatment for this patient population.

Lay abstract Patients with metastatic castration-resistant prostate cancer are often first treated with novel hormonal therapy (NHT) using abiraterone or enzalutamide. To aid decisions about what treatment to use next, we reviewed information about patients who were treated with an alternative NHT (226 patients) or the nuclear medicine radium-223 (120 patients) after the first NHT. Most patients given radium-223 had cancer that had spread to their bones only, whereas many patients given an alternative NHT had cancer in their bones and other parts of their body. Around one in four patients given radium-223 and one in five given an alternative NHT had symptoms related to their bone metastases after starting treatment. Five in every ten patients given radium-223 received further therapy, including chemotherapy in 50% of these patients, while four in every ten patients given an alternative NHT received further therapy, including chemotherapy in 75%. On average, patients lived for almost a year after starting radium-223 or an alternative NHT.

Management of metastatic prostate cancer has undergone a revolution over the past decade with the introduction of several novel agents and repurposing of others. Several clinical trials reported improved outcomes with the intensification of androgen deprivation therapy by the addition of docetaxel chemotherapy or novel hormonal agents (abiraterone, enzalutamide, or apalutamide) in the metastatic castration-sensitive state. Relugolix has been recently approved as the first oral gonadotropin-releasing hormone receptor antagonist agent with a superior cardiovascular side-effect profile, and serum testosterone suppression compared with a gonadotropin-releasing hormone agonist, leuprolide. Poly-ADP ribose polymerase inhibitors (olaparib and rucaparib) have demonstrated significant clinical benefit for patients harboring deleterious mutations in genes belonging to the homologous recombination repair pathway and have received Food and Drug Administration approval. Recently, lutetium-177-prostate-specific membrane antigen-617 with standard of care treatment has shown to improve overall survival in men with advanced-stage prostate-specific membrane antigen–positive metastatic castration-resistant prostate cancer. These recent approvals, successes, and the ongoing investigation of multiple novel agents are expected to continue to dramatically improve survival outcomes of men with metastatic prostate cancer in the coming years.

Purpose: We performed an exploratory analysis of prostate cancer-related pain and fatigue on health-related quality of life in patients with metastatic castration-sensitive prostate cancer receiving apalutamide (240 mg/day) or placebo, with continuous androgen deprivation therapy (ADT), in the phase 3, randomized, double-blind, placebo controlled TITAN trial (NCT02489318). Materials and Methods: Patient-reported outcomes for pain and fatigue were evaluated using the Brief Pain Inventory-Short Form and Brief Fatigue Inventory. Time to deterioration (TTD) was estimated by Kaplan-Meier method; hazard ratios and 95% confidence intervals were calculated using Cox proportional hazards model. General estimating equations for logistic regression estimated treatment-related differences in the likelihood of worsening pain or fatigue. Results: Compliance for completing the Brief Pain Inventory-Short Form and Brief Fatigue Inventory was high (96% to 97%) in the first year. Median followup times were similar between treatments (19 to 22 months). Median pain TTD was longer with apalutamide than placebo for pain at its least in the last 24 hours (28.7 vs 21.8 months, respectively; p=0.0146), pain interfered with mood (not estimable vs 22.4 months; p=0.0017), pain interfered with walking ability (28.7 vs 20.2 months; p=0.0027), pain interfered with relations (not estimable vs 23.0 months; p=0.0139) and pain interfered with sleep (28.7 vs 20.9 months; p=0.0167). Likelihood for fatigue and worsening fatigue were similar between groups. Conclusions: Patients with metastatic castration-sensitive prostate cancer receiving apalutamide plus ADT vs placebo plus ADT reported consistently favorable TTD of pain. No difference for change in fatigue was observed with apalutamide vs placebo. Janssen Research Development; Janssen Global Services, LLC The authors would like to thank the patients who participated in this study and their families, as well as the investigators, study coordinators, study teams and nurses. The TITAN study was funded by Janssen Research & Development. Editorial assistance was provided by Patricia McChesney, PhD, of Parexel, with funding from Janssen Global Services, LLC.

Background In oncology trials, treatment switching from the comparator to the experimental regimen is often allowed but may lead to underestimating overall survival (OS) of an experimental therapy. Objective This study evaluates the impact of treatment switching from control to olaparib on OS using the final survival data from the PROfound study and compares validated adjustment methods to estimate the magnitude of OS benefit with olaparib. Patients and methods The primary population from PROfound (Cohort A) was included, alongside two populations approved for treatment with olaparib by the European Medicines Agency and US Food and Drug Administration: BRCAm and Cohort A+B (excluding the PPP2R2A gene). Five methods were explored to adjust for switching: excluding or censoring patients in the control arm who receive subsequent olaparib, Rank Preserving Structural Failure Time Model (RPSFTM), Inverse Probability of Censoring Weights, and Two-Stage Estimation. Results The RPSFTM was considered the most appropriate approach for PROfound as the results were robust to sensitivity analysis testing of the common treatment effect assumption. For Cohort A, the final OS hazard ratio reduced from 0.69 (95% CI 0.5–0.97) to between 0.42 (0.18–0.90) and 0.52 (0.31–1.00) for olaparib versus control, depending on the RPSFTM selected. Median OS reduced from 14.7 months to between 11.73 and 12.63 months for control. Conclusions The magnitude of the statistically significant (P

OBJECTIVES: To compare clinical outcomes with programmed-death ligand-1 immune checkpoint inhibitors (ICIs) in patients with advanced urothelial carcinoma (aUC) who have vs have not undergone radical surgery (RS) or radiation therapy (RT) prior to developing metastatic disease. PATIENTS AND METHODS: We performed a retrospective cohort study collecting clinicopathological, treatment and outcomes data for patients with aUC receiving ICIs across 25 institutions. We compared outcomes (observed response rate [ORR], progression-free survival [PFS], overall survival [OS]) between patients with vs without prior RS, and by type of prior locoregional treatment (RS vs RT vs no locoregional treatment). Patients with de novo advanced disease were excluded. Analysis was stratified by treatment line (first-line and second-line or greater [second-plus line]). Logistic regression was used to compare ORR, while Kaplan–Meier analysis and Cox regression were used for PFS and OS. Multivariable models were adjusted for known prognostic factors. RESULTS: We included 562 patients (first-line: 342 and second-plus line: 220). There was no difference in outcomes based on prior locoregional treatment among those treated with first-line ICIs. In the second-plus-line setting, prior RS was associated with higher ORR (adjusted odds ratio 2.61, 95% confidence interval [CI]1.19–5.74]), longer OS (adjusted hazard ratio [aHR] 0.61, 95% CI 0.42–0.88) and PFS (aHR 0.63, 95% CI 0.45–0.89) vs no prior RS. This association remained significant when type of prior locoregional treatment (RS and RT) was modelled separately. CONCLUSION: Prior RS before developing advanced disease was associated with better outcomes in patients with aUC treated with ICIs in the second-plus-line but not in the first-line setting. While further validation is needed, our findings could have implications for prognostic estimates in clinical discussions and benchmarking for clinical trials. Limitations include the study’s retrospective nature, lack of randomization, and possible selection and confounding biases.

Background Non-clear cell renal cell carcinoma (nccRCC) accounts for ≤20% of RCC cases. Lenvatinib (a multitargeted tyrosine kinase inhibitor) in combination with everolimus (an mTOR inhibitor) is approved for the treatment of advanced RCC after one prior antiangiogenic therapy. Objective To determine the safety and efficacy of lenvatinib plus everolimus as a first-line treatment for patients with advanced nccRCC. Design, setting, and participants This open-label, single-arm, multicenter, phase 2 study enrolled patients with unresectable advanced or metastatic nccRCC and no prior anticancer therapy for advanced disease. Intervention Lenvatinib (18 mg) plus everolimus (5 mg) orally once daily. Outcome measurements and statistical analysis The primary endpoint was the objective response rate (ORR) as assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety assessments. The 95% confidence intervals (CIs) for ORRs were calculated using the two-sided Clopper-Pearson method. Median PFS and median OS were estimated using the Kaplan-Meier product-limit method and their 95% CIs were estimated via a generalized Brookmeyer and Crowley method. Results and limitations The study (start date: February 20, 2017) enrolled 31 patients with nccRCC (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2). At the data cutoff date (July 17, 2019), the best overall response was a partial response (eight patients: papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) for an overall ORR of 26% (95% CI 12–45). Median PFS was 9.2 mo (95% CI 5.5–not estimable), and median OS was 15.6 mo (95% CI 9.2–not estimable). The most common treatment-emergent adverse events were fatigue (71%), diarrhea (58%), decreased appetite (55%), nausea (55%), and vomiting (52%). Limitations include the small sample size and single-arm design. Conclusions Lenvatinib plus everolimus showed promising anticancer activity in patients with advanced nccRCC with an ORR of 26% and is worthy of further study. The safety profile was consistent with the established profile of the study-drug combination. Patient summary We examined the combination of lenvatinib plus everolimus as the first therapy for 31 patients who had advanced nccRCC. We found that this treatment seemed effective, because most patients had a decrease in tumor size and manageable treatment-related side effects. Clinical registration This trial is registered at ClinicalTrials.Gov as NCT02915783.

Objectives: The objectives of the study were to explore the factors influencing serum IgG response against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) among healthcare workers (HCWs) of a tertiary healthcare facility in India. Material and Methods: It was a monocentric, observational study during the month of September 2020. In the study, a cross-sectional quantitative serological assessment of IgG response against SARS-CoV-2 among HCWs of All India Institute of Medical Sciences (AIIMS), Patna, Bihar, was done using a chemiluminescent immunoassay (CLIA) platform named “ADVIA Centaur COV2G.” Statistical Package for the Social Sciences (SPSS) (version 22.0) was used for data analysis. Results: Among the study subjects, 761 (82.8%) had detectable serum IgG traces against SARS-CoV-2 with median (interquartile range [IQR]) of 0.03 (0.01–0.08). Those who were male by gender (spearman rho correlation co-efficient [ρ] = 0.08; P ≤ 0.05), technician (ρ= 0.07; P ≤ 0.05), attendant (ρ= 0.19; P ≤ 0.01), and sanitary staff (ρ= 0.13; P ≤ 0.01) by occupation, posted in laboratories (ρ= 0.09; P ≤ 0.01), had prior SARS-CoV-2 infection (ρ= 0.26; P ≤ 0.01), used to take steam inhalation (ρ= 0.10; P ≤ 0.01), preferred non-vegetarian diet (ρ= 0.10; P ≤ 0.01), consumed azithromycin (ρ= 0.13; P ≤ 0.01), zinc (ρ= 0.08; P ≤ 0.05) had significantly higher whereas doctors (ρ= −0.10; P ≤ 0.01), and nurses (ρ= −0.16; P ≤ 0.01) had significantly lower serum IgG response against SARS-CoV-2 compared to others. Conclusion: Gender, occupation, place of posting, prior SARS-CoV-2 infection, use of steam inhalation, diet preference, consumption of azithromycin, and zinc emerged as significant attributes of serum IgG response against SARS-CoV-2 among the study subjects.

Background Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature. Methods This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival. Results Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST. Conclusions AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.

Purpose: Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, blocks proliferation in a RB and cyclin D–dependent manner in preclinical prostate cancer models. We hypothesized that cotargeting androgen receptor and cell cycle with palbociclib would improve outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Patients and Methods: A total of 60 patients with RB-intact mHSPC were randomized (1:2) to Arm 1: androgen deprivation (AD) or Arm 2: AD + palbociclib. Primary endpoint was PSA response rate (RR) after 28 weeks of therapy. Secondary endpoints included safety, PSA, and clinical progression-free survival (PFS), as well as PSA and radiographic RR. Tumors underwent exome sequencing when available. Circulating tumor cells (CTC) were enumerated at various timepoints. Results: A total of 72 patients with mHSPC underwent metastatic disease biopsy and 64 had adequate tissue for RB assessment. A total of 62 of 64 (97%) retained RB expression. A total of 60 patients initiated therapy (Arm 1: 20; Arm 2: 40). Neutropenia was the most common grade 3/4 adverse event in Arm 2. Eighty percent of patients (Arm 1: 16/20, Arm 2: 32/40; P = 0.87) met primary PSA endpoint ≤4 ng/mL at 28 weeks. PSA undetectable rate at 28 weeks was 50% and 43% in Arms 1 and 2, respectively (P = 0.5). Radiographic RR was 89% in both arms. Twelve-month biochemical PFS was 69% and 74% in Arms 1 and 2, respectively (P = 0.72). TP53 and PIK3 pathway mutations, 8q gains, and pretreatment CTCs were associated with reduced PSA PFS. Conclusions: Palbociclib did not impact outcome in RB-intact mHSPC. Pretreatment CTC, TP53 and PIK3 pathway mutations, and 8q gain were associated with poor outcome.

Emerging efficacy data have led to the emergency use authorization or approval of COVID-19 vaccines in several countries worldwide. Most trials of COVID-19 vaccines excluded patients with active malignancies, and thus data on the safety, tolerability and efficacy of the vaccines in patients with cancer are currently limited. Given the risk posed by the COVID-19 pandemic, decisions regarding the use of vaccines against COVID-19 in patients participating in trials of investigational anticancer therapies need to be addressed promptly. Patients should not have to choose between enrolling on oncology clinical trials and receiving a COVID-19 vaccine. Clinical trial sponsors, investigators and treating physicians need operational guidance on COVID-19 vaccination for patients with cancer who are currently enrolled or might seek to enrol in clinical trials. Considering the high morbidity and mortality from COVID-19 in patients with cancer, the benefits of vaccination are likely to far outweigh the risks of vaccine-related adverse events. Herein, we provide operational COVID-19 vaccine guidance for patients participating in oncology clinical trials. In our perspective, continued quality oncological care requires that patients with cancer, including those involved in trials, be prioritized for COVID-19 vaccination, which should not affect trial eligibility., Patients with cancer have a high risk of morbidity and mortality from COVID-19. The rapid development of COVID-19 vaccines has provided new hope of mitigating the disease. Herein, the COVID19 and Cancer Clinical Trials Working Group calls for prioritization of patients with cancer, importantly including those participating in oncology clinical trials, for COVID-19 vaccination. The authors also provide operational COVID-19 vaccine guidance for patients participating in oncology clinical trials.

Objectives: To compare clinical outcomes between patients with locally advanced (unresectable) or metastatic urothelial carcinoma (aUC) in the upper and lower urinary tract receiving immune checkpoint inhibitors (ICIs). Patients and methods: We performed a retrospective cohort study collecting clinicopathological, treatment, and outcome data for patients with aUC receiving ICIs from 2013 to 2020 across 24 institutions. We compared the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) between patients with upper and lower tract UC (UTUC, LTUC). Uni- and multivariable logistic and Cox regression were used to assess the effect of UTUC on ORR, OS, and PFS. Subgroup analyses were performed stratified based on histology (pure, mixed) and line of treatment (first line, subsequent line). Results: Out of a total of 746 eligible patients, 707, 717, and 738 were included in the ORR, OS, and PFS analyses, respectively. Our results did not contradict the hypothesis that patients with UTUC and LTUC had similar ORRs (24% vs 28% ; adjusted odds ratio [aOR] 0.73, 95% confidence interval [CI] 0.43-1.24), OS (median 9.8 vs 9.6 months ; adjusted hazard ratio [aHR] 0.93, 95% CI 0.73- 1.19), and PFS (median 4.3 vs 4.1 months ; aHR 1.01, 95% CI 0.81-1.27). Patients with mixed- histology UTUC had a significantly lower ORR and shorter PFS vs mixed-histology LTUC (aOR 0.20, 95% CI 0.05-0.91 and aHR 1.66, 95% CI 1.06-2.59), respectively). Conclusion: Overall, patients with UTUC and LTUC receiving ICIs have comparable treatment response and outcomes. Subgroup analyses based on histology showed that those with mixed- histology UTUC had a lower ORR and shorter PFS compared to mixed-histology LTUC. Further studies and evaluation of molecular biomarkers can help refine patient selection for immunotherapy.

Background Genomic biomarkers that predict response to anti‐PD1 therapy in prostate cancer are needed. Frameshift mutations are predicted to generate more neoantigens than missense mutations; therefore, we hypothesized that the number or proportion of tumor frameshift mutations would correlate with response to anti‐PD1 therapy in prostate cancer. Methods To enrich for response to anti‐PD1 therapy, we assembled a multicenter cohort of 65 men with mismatch repair‐deficient (dMMR) prostate cancer. Patient characteristics and outcomes were determined by retrospective chart review. Clinical somatic DNA sequencing was used to determine tumor mutational burden (TMB), frameshift mutation burden, and frameshift mutation proportion (FSP), which were correlated to outcomes on anti‐PD1 treatment. We subsequently used data from a clinical trial of pembrolizumab in patients with nonprostatic dMMR cancers of various histologies as a biomarker validation cohort. Results Nineteen of 65 patients with dMMR metastatic castration‐resistant prostate cancer were treated with anti‐PD1 therapy. The PSA50 response rate was 65%, and the median progression‐free survival (PFS) was 24 (95% confidence interval 16–54) weeks. Tumor FSP, more than overall TMB, correlated most strongly with prolonged PFS and overall survival (OS) on anti‐PD1 treatment and with density of CD8+ tumor‐infiltrating lymphocytes. High FSP similarly identified patients with longer PFS as well as OS on anti‐PD1 therapy in a validation cohort. Conclusion Tumor FSP correlated with prolonged efficacy of anti‐PD1 treatment among patients with dMMR cancers and may represent a new biomarker of immune checkpoint inhibitor sensitivity. Implications for Practice Given the modest efficacy of immune checkpoint inhibition (ICI) in unselected patients with advanced prostate cancer, biomarkers of ICI sensitivity are needed. To facilitate biomarker discovery, a cohort of patients with DNA mismatch repair‐deficient (dMMR) prostate cancer was assembled, as these patients are enriched for responses to ICI. A high response rate to anti‐PD1 therapy in these patients was observed; however, these responses were not durable in most patients. Notably, tumor frameshift mutation proportion (FSP) was identified as a novel biomarker that was associated with prolonged response to anti‐PD1 therapy in this cohort. This finding was validated in a separate cohort of patients with nonprostatic dMMR cancers of various primary histologies. This works suggests that FSP predicts response to anti‐PD1 therapy in dMMR cancers, which should be validated prospectively in larger independent cohorts., Biomarkers of immune checkpoint inhibition sensitivity are needed. This article reports on genomic biomarkers that may predict response to anti‐PD1 therapy in prostate cancer.

Recently, mutations in speckle-type pox virus and zinc finger protein (SPOP) gene (mutant SPOP [mtSPOP]) have been associated with improved outcomes to abiraterone in the castration-resistant setting. We hypothesized that mtSPOP would be associated with improved outcomes to systemic therapy in men with de novo metastatic castration-sensitive prostate cancer (d-mCSPC). Retrospective data of newly diagnosed d-mCSPC patients were collected from four institutions. Eligibility criteria included standard androgen deprivation therapy without intensification, and SPOP mutational status (mtSPOP or wild-type SPOP [wtSPOP]) determination by targeted next-generation sequencing from tumor biopsies. A total of 121 men (25 mtSPOP [21%] and 96 wtSPOP [79%]) were included. After adjusting for covariates, mtSPOP was significantly associated with better median progression-free survival (35 vs 13 mo; adjusted hazard ratio [HR] 0.47; p = 0.016) and overall survival (97 vs 69 mo; adjusted HR 0.32; p = 0.027), with similar HR and p value on the univariate analysis. These findings, upon external validation, may assist with counseling and prognostication in the clinic, and inform the design of future clinical trials in this setting. Patient summary : Presence of tumor mutation in speckle-type pox virus and zinc finger protein (SPOP) gene was associated with improved survival outcomes in men with de novo metastatic castration-sensitive prostate cancer receiving standard androgen deprivation therapy.

LAY SUMMARY Despite longer survival with immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1), metastatic urothelial carcinoma remains lethal. There is an unmet need to further improve the efficacy of these agents. In their phase 2 trial, Zhang et al. evaluated the combination of pembrolizumab (a PD-1 inhibitor) plus acalabrutinib (a novel agent inhibiting an enzyme considered relevant to immunotherapy resistance) based on strong rationale but did not demonstrate clinical benefit compared with pembrolizumab alone. Future trials that examine such promising rational combinations may be able to evaluate selected patients based on validated biomarkers to optimize benefit in an endless pursuit of personalizing therapies.

Summary Background Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. Methods In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. Findings Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57–76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53–2·21), male sex (1·63, 1·07–2·48), smoking status (former smoker vs never smoked: 1·60, 1·03–2·47), number of comorbidities (two vs none: 4·50, 1·33–15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11–7·18), active cancer (progressing vs remission: 5·20, 2·77–9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79–4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07–0·84) or the US-Midwest (0·50, 0·28–0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. Interpretation Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. Funding American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

Purpose: Radium-223 is approved for metastatic castration-resistant prostate cancer (mCRPC) based on improved overall survival, and delay in skeletal related events. However, it is not associated with PSA or radiographic response, which poses a challenge in real-time assessment of its efficacy. Surrogate markers of treatment outcomes may facilitate tailoring treatment duration with radium-223, by limiting the duration of therapy with radium-223 in these patients. Here, we sought to investigate the utility of bone metabolic markers (BMMs) as surrogate markers of response to radium-223 in mCRPC. Patients and Methods: A prospective phase II trial of radium-223 plus enzalutamide (RE) versus enzalutamide alone was designed to assess surrogacy of BMMs with respect to response to radium-223. Enzalutamide was used as a comparator in lieu of placebo due to the progressive disease. Co-primary endpoints were relative change in serum BMM N-telopeptide (NTP) levels from baseline to 6 months between the two arms and safety and feasibility of the combination. Results: Thirty-nine men were randomized to RE (n = 27) or enzalutamide (n = 12). Combination was safe and feasible. Primary endpoint was met. A statistically significant relative change to NTP ratios between arms (0.64, 95% confidence interval, 0.51–0.81; P = 0.00048) favored RE versus enzalutamide. Overall, BMMs decreased with the RE therapy compared with enzalutamide. Improved PSA response rate in RE versus enzalutamide (P = 0.024), correlated with decline in BMMs. Conclusions: BMMs declined significantly with combination therapy, and were associated with improved outcomes. Upon external validation, BMMs may emerge as surrogate markers to monitor treatment with radium-223 in real-time.

PURPOSE This guideline provides recommendations for available tissue-based prostate cancer biomarkers geared toward patient selection for active surveillance, identification of clinically significant disease, choice of postprostatectomy adjuvant versus salvage radiotherapy, and to address emerging questions such as the relative value of tissue biomarkers compared with magnetic resonance imaging. METHODS An ASCO multidisciplinary Expert Panel, with representatives from the European Association of Urology, American Urological Association, and the College of American Pathologists, conducted a systematic literature review of localized prostate cancer biomarker studies between January 2013 and January 2019. Numerous tissue-based molecular biomarkers were evaluated for their prognostic capabilities and potential for improving management decisions. Here, the Panel makes recommendations regarding the clinical use and indications of these biomarkers. RESULTS Of 555 studies identified, 77 were selected for inclusion plus 32 additional references selected by the Expert Panel. Few biomarkers had rigorous testing involving multiple cohorts and only 5 of these tests are commercially available currently: Onco type Dx Prostate, Prolaris, Decipher, Decipher PORTOS, and ProMark. With various degrees of value and validation, multiple biomarkers have been shown to refine risk stratification and can be considered for select men to improve management decisions. There is a paucity of prospective studies assessing short- and long-term outcomes of patients when these markers are integrated into clinical decision making. RECOMMENDATIONS Tissue-based molecular biomarkers (evaluating the sample with the highest volume of the highest Gleason pattern) may improve risk stratification when added to standard clinical parameters, but the Expert Panel endorses their use only in situations in which the assay results, when considered as a whole with routine clinical factors, are likely to affect a clinical decision. These assays are not recommended for routine use as they have not been prospectively tested or shown to improve long-term outcomes—for example, quality of life, need for treatment, or survival. Additional information is available at www.asco.org/genitourinary-cancer-guidelines .

Cabozantinib is an oral, tyrosine-kinase inhibitor with potent activity against VEGFR2 and MET, along with multiple other tyrosine kinases involved in cancer development and progression. Herein, we will focus on preclinical and clinical studies leading to the approval of cabozantinib in advanced renal cell carcinoma and hepatocellular carcinoma. Covered studies include NCT01100619, CABOSUN, METEOR, NCT00940225 and the CELESTIAL trial. Finally, we review future directions of cabozantinib development by highlighting some ongoing clinical trials.

Prostate cancer is the most common cancer in men and is estimated to be responsible for more than 31,600 deaths in 2019, in the United States [1]. Despite the decline in the incidence of localized ...

Background: Cixutumumab, a monoclonal antibody targeting insulin-like growth factor I receptor, did not improve undetectable PSA rate at 28 weeks when combined with androgen deprivation in the randomized phase II SWOG S0925 trial for patients with new metastatic hormone-sensitive prostate cancer. We now present mature survival analyses, along with pre-specified secondary and exploratory endpoints. Methods: We randomized 210 patients to androgen deprivation with or without cixutumumab, 105 per treatment arm. We used Kaplan-Meier curves to analyze overall survival, radiographic progression-free survival, and castration resistance-free survival by treatment arm, disease volume, and risk group. We explored differences in survival by treatment arm via covariate-adjusted Cox proportional hazards models adjusted for disease volume and risk. Results: No difference was seen between treatment arms in overall survival (HR 1.01 [0.70-1.45]; p=0.97), radiographic progression-free survival (HR 1.17 [0.85-1.60]; p=0.35), or castration resistance-free survival (HR 1.02 [0.75-1.41]; p=0.88). At baseline, 105/198 (53.0%) patients had high risk features and 119/210 (56.7%) had high volume disease; 16.7% of patients had discordant classifications of high or low category for risk and volume. Adjusting for risk or volume yielded no differences in overall survival between arms. Inferior survival was observed in high risk (HR 1.89 [1.29-2.80]; p=0.001) and high volume (HR 2.75 [1.84-4.10]; p0.2 to ≤4.0 ng/mL (HR 3.72 [1.99-6.95]; p4.0 ng/mL (HR 7.13 [4.24-11.9]; p

BACKGROUND: In a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving previously untreated patients with advanced renal-cell carcinoma compared avelumab plus axitinib with the standard-of-care sunitinib. METHODS: We randomly assigned patients in a 1:1 ratio to receive avelumab (10 mg per kilogram of body weight) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were progression-free survival and overall survival among patients with programmed death ligand 1 (PD-L1)–positive tumors. A key secondary end point was progression-free survival in the overall population; other end points included objective response and safety. RESULTS: A total of 886 patients were assigned to receive avelumab plus axitinib (442 patients) or sunitinib (444 patients). Among the 560 patients with PD-L1–positive tumors (63.2%), the median progression-free survival was 13.8 months with avelumab plus axitinib, as compared with 7.2 months with sunitinib (hazard ratio for disease progression or death, 0.61; 95% confidence interval [CI], 0.47 to 0.79; P

BackgroundXL092 is a novel oral multi-targeted inhibitor of receptor tyrosine kinases. In preclinical studies, oral dosing with XL092 resulted in pharmacodynamic inhibition of MET, TAM kinases (AXL, MER), and VEGFR2 phosphorylation and was associated with significant anti-tumor activity in xenograft tumor models. Drugs targeting TAM kinases may promote an immune-permissive environment, which may enhance response to immune checkpoint inhibitors (ICIs). The combination of XL092 and anti–PD-1 ICI exhibited greater anti-tumor activity in a syngeneic tumor model than either agent alone.[1] Preliminary XL092 pharmacokinetic data indicate a median terminal half-life of 21 hours, suitable for daily dosing.MethodsThis multi-center, phase 1, open-label study aims to enroll approximately 800 patients total in dose-escalation and cohort-expansion stages (NCT03845166). The dose-escalation stage will enroll patients with inoperable locally advanced or metastatic solid tumors in a 3+3 design (monotherapy cohorts) or rolling 6 design (combination cohorts). Patients will receive escalating doses of XL092 alone or in combination with ICIs (atezolizumab 1200mg Q3W or avelumab 800mg Q2W). Following identification of the maximum tolerated dose (MTD) and/or recommended dose (RD) of XL092 monotherapy, the expansion stage will enroll XL092 monotherapy cohorts in 3 tumor-specific indications (renal cell carcinoma [RCC], metastatic castration-resistant prostate carcinoma [mCRPC], and hormone-receptor positive breast carcinoma [HR+ BC]) using a Simon’s optimal 2-stage design. Once the MTDs/RDs are identified for XL092 in combination with each ICI, the expansion stage will also enroll patients in tumor-specific cohorts for XL092+atezolizumab (RCC, mCRPC, HR+ BC, and colorectal carcinoma) and XL092+avelumab (urothelial carcinoma) using Simon’s optimal 2-stage design or a Precision-Based design. A limited number of patients will be enrolled in dedicated biomarker cohorts, with tumor and blood samples collected, to evaluate the pharmacodynamic effects of XL092 alone and in combination with ICIs. Key eligibility criteria include unresectable or metastatic solid tumors; measurable disease per RECIST 1.1 (expansion cohorts only); available tumor tissue (archival or fresh biopsy); and ECOG 0-1. The primary objective of the dose-escalation stage is to determine MTDs/RDs of XL092 when administered alone or in combination with ICIs, and the primary objective of the expansion stage is to evaluate objective response rate and progression-free survival rate by investigator per RECIST 1.1 of XL092 as monotherapy or in combination with ICIs. Secondary objectives include evaluation of the safety of XL092 alone and in combination with ICIs and evaluation of plasma pharmacokinetics of XL092 and its potential metabolites. The study is open for enrollment.AcknowledgementsMedical writing support provided by Griselda Zuccarino-Catania, PhD (Exelixis, Inc.)Trial RegistrationNCT03845166ReferencesHsu J, Chong C, Goon L, et al. XL092, a Multi-targeted Inhibitor of MET, VEGFR2, AXL and MER with an Optimized Pharmacokinetic Profile. European Journal of Cancer [abstract 33] 2020;138 Suppl 2:S16.Ethics ApprovalStudy approved by institutional Review Boards at each investigational site.

Background: Length of hospital stay (LOS) for a disease is a vital estimate for healthcare logistics planning. The study aimed to illustrate the effect of factors elicited on arrival on LOS of the COVID-19 patients. Materials and Methods: It was a retrospective, record based, unmatched, case control study using hospital records of 334 COVID-19 patients admitted in an East Indian tertiary healthcare facility during May to October 2020. Discharge from the hospital (cases/survivors) was considered as an event while death (control/non-survivors) as right censoring in the case-control survival analysis using cox proportional hazard model. Results: Overall, we found the median LOS for the survivors to be 8 days [interquartile range (IQR): 7-10 days] while the same for the non-survivors was 6 days [IQR: 2-11 days]. In the multivariable cox-proportional hazard model; travel distance (>16 km) [adjusted hazard ratio (aHR): 0.69, 95% CI: (0.50-0.95)], mode of transport to the hospital (ambulance) [aHR: 0.62, 95% CI: (0.45-0.85)], breathlessness (yes) [aHR: 0.56, 95% CI: (0.40-0.77)], number of co-morbidities (1-2) [aHR: 0.66, 95% CI: (0.47-0.93)] (≥3) [aHR: 0.16, 95% CI: (0.04-0.65)], COPD/asthma (yes) [ [aHR: 0.11, 95% CI: (0.01-0.79)], DBP (Conclusion: Factors elicited on arrival were found to be significantly associated with LOS. A scoring system inculcating these factors may be developed to predict LOS of the COVID-19 patients.

Background: Both novel hormonal therapies and docetaxel are approved for treatment of metastatic prostate cancer (mPC, in castration sensitive or refractory settings). Present knowledge gaps include lack of real-world data on treatment patterns in patients with newly diagnosed mPC, and comparative effectiveness of novel hormonal therapies (NHT) versus docetaxel after treatment with a prior NHT. Methods: Herein we extracted patient-level data from a large real-world database of patients with mPC in United States. Utilization of NHT or docetaxel for mPC and comparative effectiveness of an alternate NHT versus docetaxel after one prior NHT was evaluated. Comparative effectiveness was examined via Cox proportional hazards model with propensity score matching weights. Each patient’s propensity for treatment was modeled via random forest based on 22 factors potentially driving treatment selection. Results: The majority of patients (54%) received only androgen deprivation therapy for mPC. In patients treated with an NHT, alternate NHT was the most common next therapy and was associated with improved median overall survival over docetaxel (abiraterone followed by docetaxel vs. enzalutamide (8.7 vs. 15.6 months, adjusted hazards ratio, aHR 1.32, p = 0.009, and enzalutamide followed by docetaxel vs. abiraterone (9.7 vs. 13.2 months aHR 1.40, p = 0.009). Limitations of the study include retrospective design.

INTRODUCTION AND OBJECTIVE:The final analysis of TITAN confirmed improvement in long-term outcomes in metastatic castration-sensitive prostate cancer (mCSPC) with apalutamide (APA) + androgen depri...

INTRODUCTION AND OBJECTIVE:The phase 3 TITAN and SPARTAN studies demonstrated improved outcomes with the addition of apalutamide (APA) to androgen deprivation therapy (ADT); outcomes included prolo...

PURPOSE: Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in patients with sRCC. PATIENTS AND METHODS: Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histological classification per local pathology report. Patients were randomized 1:1 to receive NIVO (3 mg/kg) plus IPI (1 mg/kg) Q3W (four doses) then NIVO 3 mg/kg Q2W, or SUN 50 mg orally QD (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and IMDC intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics. RESULTS: Of 1096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months’ minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS (95% CI) favored NIVO+IPI (NR [25.2-NE]; n=74) versus SUN (14.2 months [9.3–22.9]; n=65) (HR 0.45 [95% CI, 0.3–0.7; P=0.0004]); PFS benefits with NIVO+IPI were similarly observed (median 26.5 vs 5.1 months; HR 0.54 [95% CI, 0.33–0.86; P=0.0093]). Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with SUN, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged. CONCLUSIONS: NIVO+IPI showed unprecedented long-term survival, response and complete response benefits versus SUN in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population.

Background: There has been a growing interest in ivermectin ever since it was reported to have an in-vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This trial was conducted to test the efficacy of ivermectin in mild and moderate coronavirus disease 19 (COVID-19). Methods: A double blind, parallel, randomised, placebo-controlled trial conducted among adult COVID-19 patients with mild to moderate disease severity on admission in a COVID dedicated tertiary healthcare of eastern India. Enrolment was done between 1st August and 31st October 2020. On day 1 and 2 post enrolment, patients in the intervention arm received ivermectin 12 mg while the patients in the non-interventional arm received placebo tablets. Results: About one-fourth (23.6%) of the patients in the intervention arm and one-third (31.6%) in the placebo arm were tested reverse transcriptase polymerase chain reaction (RTPCR) negative for SARS-CoV-2 on 6th day. Although this difference was found to be statistically insignificant [rate ratio (RR): 0.8; 95% confidence interval (CI): 0.4-1.4; p=0.348]. All patients in the ivermectin group were successfully discharged. In comparison the same for the placebo group was observed to be 93%. This difference was found to be statistically significant (RR: 1.1; 95% CI; 1.0-1.2; p=0.045). Conclusions: Inclusion of ivermectin in treatment regimen of mild to moderate COVID-19 patients could not be said with certainty based on our study results as it had shown only marginal benefit in successful discharge from the hospital with no other observed benefits.

Lessons Learned Background Endoglin is an angiogenic receptor expressed on proliferating tumor vessels and renal cell carcinoma (RCC) stem cells that is implicated as a mechanism of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors. This study evaluated an antiendoglin monoclonal antibody (carotuximab, TRC105) combined with axitinib in patients with advanced or metastatic clear cell renal cell carcinoma (mccRCC) who had progressed following one or more prior VEGF inhibitors. Methods TRAXAR was a multicenter, international randomized 1:1 (stratified by ECOG, 0 vs. 1), phase II study of carotuximab combined with axitinib versus axitinib alone in mccRCC patients who had progressed following one or more prior VEGF inhibitors. The primary endpoint was progression-free survival (PFS) assessed by independent central review (ICR) per RECIST 1.1 Results A total of 150 patients were randomized. The combination therapy resulted in shorter median PFS by RECIST 1.1 than axitinib monotherapy (6.7 vs. 11.4 months). The combination was tolerated similarly to axitinib monotherapy, and there were no treatment related deaths. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels. Conclusion The combination of carotuximab with axitinib did not demonstrate additional efficacy over single agent axitinib in patients with mccRCC who progressed following one or more prior VEGF inhibitor treatment.

Context No head-to-head clinical trials compare contemporary first-line therapies for metastatic renal cell carcinoma (mRCC). A network meta-analysis provides an approach for quantitative analysis. Objective To indirectly compare the efficacy and safety of first-line treatments for mRCC in the intention-to-treat (ITT) population and by clinical risk group. Evidence acquisition An updated systematic review from database inception to February 17, 2019 identified all parallel-group randomized controlled trials assessing first-line therapy for mRCC. “Clinically relevant” studies were selected for a network meta-analysis. Progression-free survival (PFS) was the primary outcome. Overall survival (OS), overall response rate (ORR), and grade 3 and 4 adverse events (AEs) were secondary outcomes. Evidence synthesis We identified 12 relevant trials: 12 reported outcomes for PFS, nine for OS, 10 for ORR, and nine for AEs. In the ITT population, cabozantinib (surface under the cumulative ranking curves [SUCRA] 84%), avelumab plus axitinib (SUCRA 68%), and pembrolizumab plus axitinib (SUCRA 82%) were superior to the other agents for PFS; pembrolizumab plus axitinib appeared superior for OS (SUCRA 95%); and atezolizumab demonstrated the lowest likelihood of AEs (SUCRA 100%). Findings were similar in the intermediate/poor-risk subgroup. Based on the limited data available, avelumab plus axitinib may be preferred in patients with favorable-risk disease. Conclusions The optimal first-line treatment for mRCC appears to differ by efficacy endpoint, toxicity, and clinical risk group. Direct comparative studies remain important in guiding treatment choice. Patient summary Head-to-head comparisons do not exist for the newest treatments of metastatic renal cell carcinoma (mRCC). In an indirect comparison, we found that pembrolizumab plus axitinib and cabozantinib are good options for most patients with mRCC.

Summary Background Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma. Methods We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment. Findings Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19–36) of 112 patients. At a median follow-up of 11 months (IQR 6–18), median time to treatment failure was 6·7 months (95% CI 5·5–8·6), median progression-free survival was 7·0 months (5·7–9·0), and median overall survival was 12·0 months (9·2–17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status. Interpretation While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options. Funding None.

There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently unavailable. A recent translational study suggested that SLCO2B1 genotype could predict response to abiraterone acetate for men with advanced prostate cancer. Here, we investigate whether germline variants in SLCO2B1 are predictive of response to first-line abiraterone acetate in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line abiraterone acetate in men with mCRPC. We performed a prespecified multivariate Cox regression analysis to assess the independent predictive value of rs12422149 and rs1789693 on PFS on abiraterone acetate. Of 401 men with advanced prostate cancer genotyped, 323 were homozygous wild-type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line abiraterone acetate for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared with the homozygous wild-type group (8.9 months vs. 6.3 months; HR, 0.46; 95% confidence interval, 0.23–0.94; P = 0.03). No significant difference in median PFS was seen by rs1789693 genotype. In this first clinical validation of translational data reported by Mostaghel and colleagues, germline variant alleles in rs12422149 of SLCO2B1 are common and predict improved response to first-line abiraterone acetate in men with mCRPC.

Given the underrepresentation of older patients in registration trials for metastatic renal cell carcinoma (mRCC), data to support the use of any particular systemic therapy over others, based on age, is limited. This is further complicated by clinical trials not commonly reporting adverse events by age. Thus, recommendations on treatment of older patients with mRCC are generally extrapolated from data on younger patients enrolled in these trials, which may not be ideal as many older patients are frail, have age-related organ dysfunction, or have multiple medical co-morbidities. In the last decade, the treatment landscape for mRCC has drastically changed with the approval of more than ten targeted therapies, as well as immune checkpoint inhibitors. Thus, treatment selection and sequencing of treatments can be especially challenging for clinicians. We begin this review by analyzing the available efficacy and toxicity data of these treatments in younger and older patients. We also discuss a network meta-analysis that compares the efficacy of these agents in older patients with mRCC. Utilizing this data, we suggest that nivolumab plus ipilimumab and cabozantinib may be favored for first-line treatment of specific populations of older patients. For salvage treatment, we suggest that cabozantinib may be the preferred agent for older patients.

More than half of patients diagnosed with renal cell carcinoma (RCC) are age 65 or older. However, older patients are often unable to meet eligibility criteria for clinical trial enrollment due to multiple factors, such as comorbidities and polypharmacy, which leads to under-representation of this population in clinical trials. Given this, efficacy data from the registration trials may not apply to older patients. Our objective was to evaluate the efficacy of first-line and salvage-line treatment in older patients, and compare efficacy between older and younger patients with metastatic RCC (mRCC).Pivotal phase three clinical trials for first-line and salvage-line treatments were included if they reported overall survival (OS) or progression-free survival (PFS) results stratified by age (/≥65 years). The meta-analysis of OS and PFS stratified by age/≥65 years was conducted in the context of Bayesian hierarchical log-linear models with both within and between study variance components.In the first-line setting, data suggests that Nivolumab plus Ipilimumab is the most efficacious treatment for older patients (PFS hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.23-1.45, probability best 39.7%). In the salvage-line setting, Cabozantinib is likely the most efficacious therapy for older patients (PFS HR 0.15, 95% CI 0.08-0.28, probability best 77.2%). Evidence suggests that the majority of first-line treatments have worse efficacy in older patients compared to younger patients.For older patients, first-line Nivolumab plus Ipilimumab and salvage-line Cabozantinib may offer the best survival outcomes. Most first-line drugs for mRCC have inferior performance in older patients compared to their younger counterparts.

BACKGROUND: No standard of care exists for patients with high-risk biochemical recurrence (BCR) after prostatectomy. OBJECTIVE: To evaluate whether addition of docetaxel to androgen deprivation therapy (ADT) improved progression-free survival (PFS) in high-risk BCR patients. DESIGN, SETTING, AND PARTICIPANTS: TAX3503 was a multicenter phase 3 trial that randomized patients with high-risk BCR to ADT for 18 mo ± docetaxel (75 mg/m(2) q3w for ten cycles). Eligibility included prostate-specific antigen (PSA) ≥1.0 ng/ml after prostatectomy alone or after postoperative radiation therapy, PSA doubling time ≤9 mo, and absence of metastases on computed tomography and bone scintigraphy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was PFS following testosterone recovery to noncastrate levels (testosterone >50 ng/dl). Secondary endpoints included time to testosterone recovery, overall survival (OS), quality of life, and safety. RESULTS AND LIMITATIONS: Between September 2007 and May 2011, 413 patients were assigned to ADT ± docetaxel. In 2012, following completion of accrual and treatment, the sponsor withdrew support of the study, and in 2013, a registry was created to secure the primary endpoint. The final analysis included data from the original trial and registry. At a median follow-up of 33.6 mo, 260 patients demonstrated testosterone recovery, which occurred similarly between groups. ADT plus docetaxel trended toward a nonclinically meaningful improvement in PFS (median 26.2 vs 24.7 mo) for the testosterone-recovered population (218 events, hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.61–1.04) and in OS for the intention-to-treat population (medians not reached, HR 0.51, 95% CI 0.23–1.10). Grade ≥3 adverse events occurred more frequently in the ADT plus docetaxel group (48.0% vs 10.8%). CONCLUSIONS: TAX3503 did not demonstrate a meaningful benefit of adding docetaxel to ADT in patients with high-risk BCR. Testosterone recovery was unaffected by addition of docetaxel to ADT.

BackgroundDisulfiram and metals inactivate key oncoproteins resulting in anti-neoplastic activity. The goal of this study was to determine the maximum tolerated dose of copper when administered with disulfiram in patients with advanced solid tumors and liver involvement.MethodsDisulfiram 250 mg was administered daily in 28-day cycles. Four doses of copper gluconate were tested (2, 4, 6, and 8 mg of elemental copper) in a standard 3 + 3 dose escalation design. Patients were evaluated for dose limiting toxicities and response. ProteinS-glutathionylation was evaluated as a pharmacodynamic marker.ResultsTwenty-one patients were enrolled and 16 patients were evaluable for dose limiting toxicities. Among the 21 patients, there was a median of 4 lines of prior chemotherapy. Five Grade 3 toxicities were observed (anorexia, elevated aspartate aminotransferase or AST, elevated alkaline phosphatase, fever, and fatigue). Response data was available for 15 patients. Four patients had stable disease with the longest duration of disease control being 116 days. The median duration of treatment for evaluable patients was 55 days (range 28–124). Reasons for discontinuation included functional decline, disease progression, and disease-associated death. IncreasedS-glutathionylation of serum proteins was observed with treatment.ConclusionDisulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase inS-glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function.Trial registrationNCT00742911, first posted 28/08/2008.

IMPORTANCE: Management of high-risk non–muscle-invasive bladder cancer (NMIBC) represents a clinical challenge due to high failure rates despite prior bacillus Calmette-Guérin (BCG) therapy. OBJECTIVE: To describe real-world patient characteristics, long-term outcomes, and the economic burden in a population with high-risk NMIBC treated with BCG therapy. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study identified 412 patients with high-risk NMIBC from 63 139 patients diagnosed with bladder cancer who received at least 1 dose of BCG within Department of Veterans Affairs (VA) centers across the US from January 1, 2000, to December 31, 2015. Adequate induction BCG therapy was defined as at least 5 installations, and adequate maintenance BCG therapy was defined as at least 7 installations. Data were analyzed from January 2, 2020, to January 20, 2021. EXPOSURES: Intravesical BCG therapy, including adequate induction BCG therapy, was defined as at least 5 intravesical instillations of BCG within 70 days from BCG therapy start date. Adequate maintenance BCG therapy was defined as at least 7 installations of BCG within 274 days of the start (the first instillation) of adequate induction BCG therapy (ie, adequate induction BCG plus some form of additional BCG). MAIN OUTCOMES AND MEASURES: The Kaplan-Meier method was used to estimate outcomes, including event-free survival. All-cause expenditures were summarized as medians with corresponding interquartile ranges (IQRs) and adjusted to 2019 USD. RESULTS: Of the 412 patients who met inclusion criteria, 335 (81%) were male and 77 (19%) were female, with a median age of 67 (IQR, 61-74) years. Follow-up was 2694 person-years. A total of 392 patients (95%) received adequate induction BCG therapy, and 152 (37%) received adequate BCG therapy. For all patients with high-risk NMIBC, the 10-year progression-free survival rate and disease-specific death rate were 78% and 92%, respectively. Patients with carcinoma in situ (Cis) had worse disease-free survival than those without Cis (hazard ratio [HR], 1.85; 95% CI, 1.34-2.56). Total median costs at 1 year were $29 459 (IQR, $14 991-$52 060); at 2 years, $55 267 (IQR, $28 667-$99 846); and at 5 years, $117 361 (IQR, $59 680-$211 298). Patients with progressive disease had significantly higher median 5-year costs ($232 729 [IQR, $151 321-$341 195] vs $94 879 [IQR, $52 498-$172 631]; P

Lessons Learned Background Previously, we showed the combination of radium-223 and enzalutamide to be safe and associated with improved efficacy based on a concomitant decline in serum bone metabolism markers compared with enzalutamide alone in a phase II trial of men with metastatic castration-resistant prostate cancer (mCRPC) [1]. Methods Secondary endpoints were not included in our initial report, and we include them herein, after a median follow-up of 22 months. These objectives included long-term safety, prostate-specific antigen (PSA)–progression-free survival (PFS), and radiographic progression-free survival; PSA-PFS2 (time from start of protocol therapy to PSA progression on subsequent therapy); time to next therapy (TTNT); and overall survival (OS). Survival analysis and log-rank tests were performed using the R statistical package v.4.0.2 (https://www.r-project.org). Statistical significance was defined as p Results Of 47 patients (median age, 68 years), 35 received the combination and 12 enzalutamide alone. After a median follow-up of 22 months, final safety results did not show any increase in fractures or other adverse events in the combination arm. PSA-PFS2 was significantly improved, and other efficacy parameters were numerically improved in the combination over the enzalutamide arm. Conclusion The combination of enzalutamide and radium-223 was found to be safe and associated with promising efficacy in men with mCRPC. These hypothesis-generating results portend well for the ongoing phase III PEACE III trial in this setting.

Considering recently published studies, this commentary addresses racial inequality in cancer care for patients with prostate cancer.

PURPOSE Prostate cancer (PCa) becomes resistant to androgen ablation through adaptive upregulation of the androgen receptor in response to the low-testosterone microenvironment. Bipolar androgen therapy (BAT), defined as rapid cycling between high and low serum testosterone, disrupts this adaptive regulation in castration-resistant PCa (CRPC). METHODS The TRANSFORMER (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance) study is a randomized study comparing monthly BAT (n = 94) with enzalutamide (n = 101). The primary end point was clinical or radiographic progression-free survival (PFS); crossover was permitted at progression. Secondary end points included overall survival (OS), prostate-specific antigen (PSA) and objective response rates, PFS from randomization through crossover (PFS2), safety, and quality of life (QoL). RESULTS The PFS was 5.7 months for both arms (hazard ratio [HR], 1.14; 95% CI, 0.83 to 1.55; P = .42). For BAT, 50% decline in PSA (PSA50) was 28.2% of patients versus 25.3% for enzalutamide. At crossover, PSA50 response occurred in 77.8% of patients crossing to enzalutamide and 23.4% to BAT. The PSA-PFS for enzalutamide increased from 3.8 months after abiraterone to 10.9 months after BAT. The PFS2 for BAT→enzalutamide was 28.2 versus 19.6 months for enzalutamide→BAT (HR, 0.44; 95% CI, 0.22 to 0.88; P = .02). OS was 32.9 months for BAT versus 29.0 months for enzalutamide (HR, 0.95; 95% CI, 0.66 to 1.39; P = .80). OS was 37.1 months for patients crossing from BAT to enzalutamide versus 30.2 months for the opposite sequence (HR, 0.68; 95% CI, 0.36 to 1.28; P = .225). BAT adverse events were primarily grade 1-2. Patient-reported QoL consistently favored BAT. CONCLUSION This randomized trial establishes meaningful clinical activity and safety of BAT and supports additional study to determine its optimal clinical integration. BAT can sensitize CRPC to subsequent antiandrogen therapy. Further study is required to confirm whether sequential therapy with BAT and enzalutamide can improve survival in men with CRPC.