The Rapidly Evolving Landscape of First-Line Targeted Therapy in Metastatic Urothelial Cancer: A Systematic Review.

BACKGROUND: Metastatic urothelial carcinoma (mUC) historically is treated with first-line platinum-based combination chemotherapy, preferably cisplatin plus gemcitabine whenever possible. In recent years, multiple classes of targeted therapy have demonstrated benefit, with some receiving approval in mUC. This review will summarize phase III efficacy and safety data for targeted agents, principally immune checkpoint inhibitors (ICIs), as either first-line or first-line switch-maintenance therapy for mUC and interpret these findings in the context of the current treatment landscape. MATERIALS AND METHODS: Published and presented phase III data on targeted therapy for the first-line or first-line switch-maintenance treatment of mUC were identified using the key search terms "targeted therapy" AND "urothelial carcinoma" AND "advanced" OR respective aliases according to the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Of the six eligible phase III targeted therapy trials, two assessing ICIs met their primary endpoints in platinum-eligible patients. First-line ICI plus chemotherapy combinations have not improved overall survival (OS), although final OS results of the IMVigor 130 trial are pending. Switch-maintenance using an ICI in patients achieving at least stable disease following platinum-based chemotherapy statistically significantly improved OS (21.4 vs. 14.3 months, hazard ratio, 0.69; 95% confidence interval, 0.56-0.86; p = .001). Current sequencing options for mUC include first-line platinum-based chemotherapy with a switch to ICI either immediately or upon disease progression. CONCLUSION: Recent targeted therapy trials have expanded ICI sequencing options for mUC. The treatment landscape is likely to evolve rapidly, with results from multiple phase III trials expected in the next 5 years. IMPLICATIONS FOR PRACTICE: Multiple classes of targeted agents are approved for use in metastatic urothelial carcinoma (mUC). Six phase III trials have recently provided insight on the benefit of these agents in the first-line setting. In platinum-eligible patients, immune checkpoint inhibitors (ICIs) combined with first-line platinum-based chemotherapy failed to demonstrate improved survival, although ICI monotherapy as switch-maintenance significantly improved overall survival in patients with mUC who had achieved at least stable disease following first-line platinum-based chemotherapy. In patients ineligible for any chemotherapy, pembrolizumab, atezolizumab, or pembrolizumab in combination with enfortumab vedotin may be options.

Description of a Multi-faceted COVID-19 Pandemic Physician Workforce Plan at a Multi-site Academic Health System.

BACKGROUND: The evolving COVID-19 pandemic has and continues to present a threat to health system capacity. Rapidly expanding an existing acute care physician workforce is critical to pandemic response planning in large urban academic health systems. INTERVENTION: The Medical Emergency-Pandemic Operations Command (MEOC)-a multi-specialty team of physicians, operational leaders, and support staff within an academic Department of Medicine in Calgary, Canada-partnered with its provincial health system to rapidly develop a comprehensive, scalable pandemic physician workforce plan for non-ventilated inpatients with COVID-19 across multiple hospitals. The MEOC Pandemic Plan comprised seven components, each with unique structure and processes. METHODS: In this manuscript, we describe MEOC's Pandemic Plan that was designed and implemented from March to May 2020 and re-escalated in October 2020. We report on the plan's structure and process, early implementation outcomes, and unforeseen challenges. Data sources included MEOC documents, health system, public health, and physician engagement implementation data. KEY RESULTS: From March 5 to October 26, 2020, 427 patients were admitted to COVID-19 units in Calgary hospitals. In the initial implementation period (March-May 2020), MEOC communications reached over 2500 physicians, leading to 1446 physicians volunteering to provide care on COVID-19 units. Of these, 234 physicians signed up for hospital shifts, and 227 physicians received in-person personal protective equipment simulation training. Ninety-three physicians were deployed on COVID-19 units at four large acute care hospitals. The resurgence of cases in September 2020 has prompted re-escalation including re-activation of COVID-19 units. CONCLUSIONS: MEOC leveraged an academic health system partnership to rapidly design, implement, and refine a comprehensive, scalable COVID-19 acute care physician workforce plan whose components are readily applicable across jurisdictions or healthcare crises. This description may guide other institutions responding to COVID-19 and future health emergencies.

Retreatment of men with metastatic castrate-resistant prostate cancer with abiraterone.

BACKGROUND: Abiraterone acetate (AA), oral CYP17 inhibitor, is an active agent in the treatment of metastatic castrate-resistant prostate cancer (mCRPC). METHODS: We (R.L.A and N.A) retrospectively evaluated outcome in 12 men who were re-treated with AA following prior treatment with AA at the Princess Margaret Cancer Centre. RESULTS: All men were heavily pre-treated for mCRPC with a median of four prior lines of therapy, one of which was AA (given either pre- or post-chemotherapy). Eleven out of 12 (92%) men stopped their first treatment course of AA due to progression and one stopped for financial reasons. Seven men had a PSA decrease ≥50% following their first AA treatment, of which three (46%) had a PSA decrease ≥50% to AA re-treatment. The responses to AA re-treatment were generally short-lived with a median biochemical progression-free survival of 2.3 months and median treatment duration of 3.2 months. No PSA responses to AA re-treatment were seen in five men who did not have an initial PSA response to AA. CONCLUSIONS: Our data suggest that AA re-challenge may have limited benefit in select men with mCRPC, and warrants further formal research.

High-dose chemotherapy with autologous stem-cell transplantation for relapsed metastatic germ cell tumors The Alberta experience.

INTRODUCTION: High-dose chemotherapy with autologous stem-cell transplantation (HDC-ASCT) is standard therapy for metastatic germ cell tumors (mGCTs) in patients whose disease progresses during or after conventional chemotherapy. We conducted a retrospective review of HDC-ASCT in relapsed mGCT patients in the province of Alberta, Canada, over the past two decades. METHODS: Patients with mGCTs who received HDC-ASCT at two provincial cancer referral centers from 2000-2018 were identified from institutional databases. Baseline clinical and treatment characteristics were collected, as well as overall survival (OS ) and disease-free survival (DFS). Relevant prognostic variables were analyzed. RESULTS: Forty-three patients were identified. The median age was 28 years (range 19-56). A majority (95%) had non-seminoma histology and testis/retroperitoneal primary (84%). Twenty patients (47%) had poor-risk disease, as per The International Germ Cell Consensus Classification (IGCCC), at start of first-line chemotherapy. HDC-ASCT was used as second-line therapy in 65% of patients, and 58% of ASCT patients received tandem transplants. Median followup after ASCT was 22 months (range 2-181). At last followup, 42% of patients were alive without disease, including 3/7 (43%) of patients with primary mediastinal disease. Two-year and five-year DFS/OS ratios were 44%/65% and 38%/45%, respectively. Median OS and DFS for all patients were 30.0 months (13.3-46.6) and 8.0 months (0.9-15.1), respectively. CONCLUSIONS: We found that HDC-ASCT is an effective salvage therapy in mGCT, consistent with existing literature. Patients appeared to benefit regardless of primary site. Although limited by small sample size, we found a numerical difference in DFS and OS between second- and third-line HDC-ASCT and single vs. tandem ASCT.

Benefit of Neoadjuvant Cisplatin-based Chemotherapy for Invasive Bladder Cancer Patients Treated with Radiation-based Therapy in a Real-world Setting: An Inverse Probability Treatment Weighted Analysis.

BACKGROUND: Neoadjuvant chemotherapy (NAC) improves survival for patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy. Studies on the potential benefit of NAC before radiation-based therapy (RT) are conflicting. OBJECTIVE: To evaluate the effect of NAC on patients with MIBC treated with curative-intent RT in a real-world setting. DESIGN, SETTING, AND PARTICIPANTS: The study cohort consisted of 785 patients with MIBC (cT2-4aN0-2M0) who underwent RT at academic centers across Canada. Patients were classified into two treatment groups based on the administration of NAC before RT (NAC vs no NAC). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The inverse probability of treatment weighting (IPTW) with absolute standardized differences (ASDs) was used to balance covariates across treatment groups. The impact of NAC on complete response, overall, and cancer-specific survival (CSS) after RT in the weighted cohort was analyzed. RESULTS AND LIMITATIONS: After applying the exclusion criteria, 586 patients were included; 102 (17%) received NAC before RT. Patients in the NAC subgroup were younger (mean age 65 vs 77 yr; ASD 1.20); more likely to have Eastern Cooperative Oncology Group performance status 0-1 (87% vs 78%; ASD 0.28), lymphovascular invasion (32% vs 20%; ASD 0.27), higher cT stage (cT3-4 in 29% vs 20%; ASD 0.21), and higher cN stage (cN1-2 in 32% vs 4%; ASD 0.81); and more commonly treated with concurrent chemotherapy (79% vs 67%; ASD 0.28). After IPTW, NAC versus no NAC cohorts were well balanced (ASD <0.20) for all included covariates. NAC was significantly associated with improved CSS (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.14-0.56; p < 0.001) and overall survival (HR 0.56; 95% CI 0.38-0.84; p = 0.005). This study was limited by potential occult imbalances across treatment groups. CONCLUSIONS: If tolerated, NAC might be associated with improved survival and should be considered for eligible patients with MIBC planning to undergo bladder preservation with RT. Prospective trials are warranted. PATIENT SUMMARY: In this study, we showed that neoadjuvant chemotherapy might be associated with improved survival in patients with muscle-invasive bladder cancer who elect for curative-intent radiation-based therapy.

Improving adherence and health outcomes in testicular cancer survivors using a mobile health-based intervention: A mixed-methods pilot study.

Objective: Testicular cancer (TC) is one of the most common cancers among young men, with survival rates exceeding 97% due to effective treatments. Post-treatment follow-up care is important for long-term survival and monitoring psychosocial symptoms, yet TC survivors (TCS) show poor adherence to post-treatment care. Mobile-health-based interventions show high acceptability in men with cancer. This study will examine the feasibility of using the Zamplo health app to improve adherence to post-treatment care and support psychosocial outcomes in TCS. Methods: This mixed-methods, longitudinal, single-arm pilot study will recruit N = 30 patients with a diagnosis of TC who finished treatment within ≤ 6 months and are currently aged ≥18 years old. Adherence to follow-up appointments (e.g. blood work, scans) will be assessed (primary outcome), and measures for fatigue, depression, anxiety, sexual satisfaction and function, social roles satisfaction, general mental and physical health and body image (secondary outcomes) will be completed at four-time points: baseline, 3, 6 and 12 months. One-on-one semi-structured interviews will be conducted post-intervention (month 12). Results: Improvements in post-treatment follow-up appointment adherence and psychosocial outcomes will be analyzed using descriptive statistics, paired samples t-tests to determine changes across time points 1 through 4, and correlation analysis. Qualitative data will be analyzed using thematic analysis. Conclusion: Findings will inform future, larger trials that incorporate evaluation of sustainability and economic implications to improve adherence to TC follow-up guidelines. Findings will be disseminated via infographics, social media, publications and presentations conducted in partnership with TC support organizations and at conferences.

Evaluation of Trends in Treatment of Metastatic Hormone Sensitive Prostate Cancer (mHSPC) Across Canada During the COVID-19 Pandemic.

BACKGROUND: In metastatic hormone sensitive prostate cancer (mHSPC), treatment intensification with either docetaxel or an androgen-receptor-axis targeted therapy (ARAT), added to androgen deprivation therapy (ADT) is the new standard of care. To better understand patterns of treatment intensification in Canada and specifically how it has been influenced by the COVID-19 pandemic, we conducted a national survey of genitourinary medical oncologists from across Canada. METHODS: Using SurveyMonkey, we conducted an online survey of 119 medical oncologists in Canada from January 15 to January 27, 2021. The survey consisted of 16 questions, including demographics, and asked specifically about their approach to managing mHSPC before and during the pandemic. RESULTS: Overall there were 50/119 (42%) respondents. Most were male (65%), from Ontario (35%), practicing in academic centers (71%), with 45% reporting their practices focused primarily on genitourinary malignancies and one other tumor site. The majority were in practice 1 to 5 years (34%). Overall 65% indicated their practice patterns had changed since the pandemic, with 51% offering more ARATs and less docetaxel chemotherapy. In low volume mHSPC, the use of ARATs increased from 73% to 79%, while the use of docetaxel remained unaltered at 2%. In high volume disease, the use of ARATs increased from 63% to 84%, while the use of docetaxel decreased from 37% to 14%. Use of granulocyte colony stimulating factor (G-CSF) with docetaxel chemotherapy increased by 35%. Post-pandemic, 45% reported they intend to maintain these changes. Only 18% reported they had prostate cancer patients test positive for COVID-19, and all patients recovered. CONCLUSION: Management of patients with mHSPC in Canada has changed during the pandemic, with increased uptake of ARATs and reduced use of docetaxel, a trend expected to continue beyond the pandemic. How this trend will impact uptake of triplet therapy (ADT + ARAT + Docetaxel), downstream treatment choices and overall outcomes remains to be seen.

Large, Nested Variant of Urothelial Carcinoma Is Enriched with Activating Mutations in Fibroblast Growth Factor Receptor-3 among Other Targetable Mutations.

The large, nested variant of urothelial carcinoma (LNVUC) is characterized by bland histomorphology mimicking that of benign von Brunn nests. In the current study, we aimed to investigate the Fibroblast Growth Factor Receptor-3 (FGFR-3) activation and missense mutation in 38 cases, including 6 cases diagnosed with LNVUC and 32 with metastatic invasive urothelial carcinoma (UC). Initially, six formalin-fixed paraffin-embedded (FFPE) tissue samples of the LNVUC were subjected to whole-exome sequencing (WES), and then we performed targeted sequencing on 32 cases of metastatic invasive UC of various morphological subtypes, which were interrogated for the FGFR3. Our results revealed 3/6 (50%) LNVUC cases evaluated by WES in our study showed an activating mutation in FGFR-3, 33% showed an activating mutation in PIK3CA, and 17% showed activating mutation in GNAS or MRE11. Additionally, 33% of cases showed a truncating mutation in CDKN1B. All LNVUC in our study that harbored the FGFR-3 mutation showed additional activating or truncating mutations in other genes. Overall, 6/32 (18.75%) cases of random metastatic invasive UC showed missense mutations of the FGFR-3 gene. The LNVUC variant showed the higher incidence of FGFR-3 mutations compared to other types of mutations. Additionally, all LNVUC cases show additional activating or truncating mutations in other genes, thus being amenable to novel targeted therapy.

Radiation-based Therapy for Muscle-invasive Bladder Cancer: Contemporary Outcomes Across Tertiary Centers.

BACKGROUND: Radiation therapy (RT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). OBJECTIVE: To analyze predictors of complete response (CR) and survival after RT for MIBC. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter retrospective study of 864 patients with nonmetastatic MIBC who underwent curative-intent RT from 2002 to 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Regression models were used to explore prognostic factors associated with CR, cancer-specific survival (CSS), and overall survival (OS). RESULTS AND LIMITATIONS: The median patient age was 77 yr and median follow-up was 34 mo. Disease stage was cT2 in 675 patients (78%) and cN0 in 766 (89%). Neoadjuvant chemotherapy (NAC) was given to 147 patients (17%) and concurrent chemotherapy to 542 (63%). A CR was experienced by 592 patients (78%). cT3-4 stage (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.29-0.63; p < 0.001) and hydronephrosis (OR 0.50, 95% CI 034-0.74; p = 0.001) were significantly associated with lower CR. The 5-yr survival rates were 63% for CSS and 49% for OS. Higher cT stage (HR 1.93, 95% CI 1.46-2.56; p < 0.001), carcinoma in situ (HR 2.10, 95% CI 1.25-3.53; p = 0.005), hydronephrosis (HR 2.36, 95% CI 1.79-3.10; p < 0.001), NAC use (HR 0.66, 95% CI 0.46-0.95; p = 0.025), and whole-pelvis RT (HR 0.66, 95% CI 0.51-0.86; p = 0.002) were independently associated with CSS; advanced age (HR 1.03, 95% CI 1.01-1.05; p = 0.001), worse performance status (HR 1.73, 95% CI 1.34-2.22; p < 0.001), hydronephrosis (HR 1.50, 95% CI 1.17-1.91; p = 0.001), NAC use (HR 0.69, 95% CI 0.49-0.97; p = 0.033), whole-pelvis RT (HR 0.64, 95% CI 0.51-0.80; p < 0.001), and being surgically unfit (HR 1.42, 95% CI 1.12-1.80; p = 0.004) were associated with OS. The study is limited by the heterogeneity of different treatment protocols. CONCLUSIONS: RT for MIBC yields a CR in most patients who elect for curative-intent bladder preservation. The benefit of NAC and whole-pelvis RT require prospective trial validation. PATIENT SUMMARY: We investigated outcomes for patients with muscle-invasive bladder cancer treated with curative-intent radiation therapy as an alternative to surgical removal of the bladder. The benefit of chemotherapy before radiotherapy and whole-pelvis radiation (bladder plus the pelvis lymph nodes) needs further study.

Real-World Cabazitaxel Use and Outcomes in Metastatic Castrate-Resistant Prostate Cancer: The Impact of Response to First ARPI.

BACKGROUND: For post-docetaxel treatment of metastatic castrate-resistant prostate cancer (mCRPC), cabazitaxel has demonstrated superior third line PFS and OS compared to androgen receptor pathway inhibitors (ARPIs) in patients who progress within 12 months on first ARPI. The impact of first ARPI response, in particular responses beyond 12 months, on cabazitaxel outcomes in real-world populations is uncertain, as are other factors impacting cabazitaxel use. MATERIALS AND METHODS: mCRPC patients in Alberta, Canada who received docetaxel from October 1, 2012 to December 31, 2017 were included. We reviewed mCRPC therapies, correlating cabazitaxel use with patient characteristics and TROPIC trial inclusion/exclusion criteria. OS and PFS were evaluated in patients who received cabazitaxel, stratified by time to progression on first ARPI ≤ 12 months (poor ARPI responders, PAR) or >12 months (strong ARPI responders, SAR), using the Kaplan-Meier method. RESULTS: PAR patients had inferior OS compared to SAR patients (12.3 vs. 24.8 months, P < .001). OS was longer in PAR patients receiving cabazitaxel compared to those not treated with cabazitaxel (16.9 vs. 10.3 months, P = .015), but this benefit was not seen in the SAR group (17.1 vs. 32 months, P = .084). Cabazitaxel use was associated with reduced PFS first line post-docetaxel in SAR (3.5 vs. 14.7 months, P < .001) but not PAR patients. Of 592 patients, 170 (29%) received cabazitaxel post-docetaxel, compared to 280 (47%) and 250 (42%) for abiraterone and enzalutamide. 238 patients (40%) did not have a discussion of cabazitaxel documented. Cabazitaxel use was increased in patients who fit TROPIC trial criteria (P < .001). CONCLUSIONS: In a real-world mCRPC cohort, cabazitaxel use was associated with longer OS among PAR patients, but crucially not among strong ARPI responders. Cabazitaxel was used less frequently and later than ARPIs post-docetaxel. These data help support first ARPI progression time as a consideration in treatment sequencing.

Understanding Treatment Patterns and Outcomes among Patients with De Novo Unresectable Locally Advanced or Metastatic Urothelial Cancer: A Population-Level Retrospective Analysis from Alberta, Canada.

Despite a high disease burden, real-world data on treatment patterns in patients with unresectable locally advanced or metastatic urothelial carcinoma (la/mUC) in Canada are limited. This retrospective, longitudinal cohort study describes treatment patterns and survival in a population of patients with de novo unresectable la/mUC from Alberta, Canada, diagnosed between 1 January 2015 and 31 December 2019, followed until mid-2020. The outcomes of interest were systemic therapy treatment patterns and overall survival (OS). Of 206 patients, most (65.0%, n = 134) did not receive any systemic therapies. Of 72 patients (35.0%) who received first-line systemic therapy, the median duration of treatment was 2.8 months (IQR 3.3). Thirty-five patients (48.6% of those who received first-line therapy) received subsequent second-line therapy, for a median of 3.0 months (IQR 3.3). In all patients (n = 206), the median OS from diagnosis was 5.3 months (95% CI, 4.5-7.0). In patients who received treatment, the median OS from the initiation of first-line and second-line systemic therapy was 9.1 (6.4-11.6) and 4.6 months (3.9-19.2), respectively. The majority of patients did not receive first-line systemic therapy, and, in those who did, survival outcomes were poor. This study highlights the significant unmet need for safe and efficacious therapies for patients with la/mUC in Canada.

The prognostic impact of bone metastasis in patients with metastatic urothelial carcinoma treated with first-line platinum-based chemotherapy.

Background: In metastatic urothelial cancer (mUC), bone metastasis (BM) are associated with significant morbidity and mortality, yet their role as an independent prognostic variable remains unclear. We aimed to determine the impact of BM on overall survival (OS) in patients with mUC treated with first-line platinum-based chemotherapy (PBC). Methods: mUC patients receiving PBC at the Princess Margaret Cancer Center, Tom Baker Cancer Center, or Cross Cancer Institute from January 2005 to January 2018 were identified retrospectively using central pharmacy database records. Patient disease, treatment, and response characteristics were collected. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method. Variables reaching significance (p < 0.05) in univariable analysis (UVA) of survival (OS) were included in multivariable analysis (MVA) (Cox). Results: Overall, 376 patients with a median follow-up of 16.8 (range: 2.2-218.3) months were included. Median age was 67 (range: 28-91) years, 76% were male, 63% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1, and 41% had BM. All patients received first-line PBC. Patients with BM had inferior median PFS (4.9 months (95% CI 3.6-6.2) versus 6.5 months (95% CI 5.4-7.6), p = 0.03) and median OS (8.8 months (95% CI 7.8-9.7) versus 10.8 months (95% CI 9.1-12.5), p = 0.002). In UVA, ECOG PS 2-3 (p < 0.001), presence of BM (p = 0.002), and WBC count ⩾ 11,000 cells/mm3 (p = 0.001) were associated with inferior survival. Prior cystectomy (p < 0.001) and lack of progression (stable disease, partial or complete response) on treatment was associated with improved OS (p < 0.001). These variables maintained significance in MVA. Conclusion: In this retrospective study, mUC patients with BM had worse OS suggesting that BM may be an independent negative prognostic factor and including BM as a stratification factor in future mUC clinical trial designs may be warranted. A greater focus must be placed on novel therapeutic strategies to better manage BM to reduce both morbidity and mortality.

Stage migration of testicular germ cell tumours in Alberta, Canada, during the COVID-19 pandemic: a retrospective cohort study.

BACKGROUND: An absence of screening recommendations and the rapid progression of testicular germ cell tumours (TGCTs) offer a perspective on the potential impact of the COVID-19 pandemic on cancer presentations. We evaluated the presenting cancer stages of TGCTs in a real-world population before and during the pandemic to assess stage migration. METHODS: We performed a retrospective review of all new patients with TGCT diagnoses in Alberta, Canada, from Dec. 31, 2018, to Apr. 30, 2021, using the Alberta Cancer Registry. Because potential changes in staging should not occur instantaneously, we used a 6-month lag time from Apr. 1, 2020, for seminomas, and a 3-month lag time for nonseminomas, to compare initial cancer stages at presentation before and during the pandemic. We evaluated monthly rates of presentation by stage and histology. Exploratory outcomes included the largest tumour dimension, tumour markers and, for advanced disease, risk category and treatment setting. RESULTS: Of 335 patients with TGCTs, 231 were diagnosed before the pandemic and 104 during the pandemic (using a lag time). In total, 18 (7.8%) patients diagnosed before the pandemic presented with stage III disease, compared to 16 (15.4%) diagnosed during the pandemic (relative risk 1.97, 95% confidence interval [CI] 1.05-3.72). We observed no significant differences for secondary outcomes. Without a lag time, the rate ratio for a stage II presentation decreased significantly during the pandemic (0.40, 95% CI 0.21-0.72). INTERPRETATION: We observed signs of TGCT stage migration during the COVID-19 pandemic, driven by a decline in stage II disease and a potential rise in stage III disease. Management of TGCTs should remain a priority, even during a global pandemic.

Defining cisplatin eligibility in patients with muscle-invasive bladder cancer.

The current treatment paradigm for muscle-invasive bladder cancer (MIBC) consists of cisplatin-based neoadjuvant chemotherapy followed by local definitive therapy, or local definitive therapy alone for cisplatin-ineligible patients. Given that MIBC has a high propensity for distant relapse and is a chemotherapy-sensitive disease, under-utilization of chemotherapy is associated with suboptimal cure rates. Cisplatin eligibility criteria are defined for patients with metastatic bladder cancer by the Galsky criteria, which include creatinine clearance ≥60 ml/min. However, consensus is still lacking regarding cisplatin eligibility criteria in the neoadjuvant, curative MIBC setting, which continues to represent a substantial barrier to the standardization of patient care and clinical trial design. Jiang and colleagues accordingly suggest an algorithm for assessing cisplatin eligibility in patients with MIBC. Instead of relying on an absolute renal function threshold, their algorithm emphasizes a multidisciplinary and patient-centred approach. They also propose mitigation strategies to minimize the risk of cisplatin-induced nephrotoxicity in selected patients with impaired renal function. This new framework is aimed at reducing the inappropriate exclusion of some patients from cisplatin-based neoadjuvant chemotherapy (which leads to under-treatment) and harmonizing clinical trial design, which could lead to improved overall outcomes in patients with MIBC.

Association of Concomitant Bone Resorption Inhibitors With Overall Survival Among Patients With Metastatic Castration-Resistant Prostate Cancer and Bone Metastases Receiving Abiraterone Acetate With Prednisone as First-Line Therapy.

Importance: Bone resorption inhibitors (BRIs) are recommended by international guidelines to prevent skeletal-related events (SREs) among patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Abiraterone acetate with prednisone is currently the most common first-line therapy for the treatment of patients with mCRPC; however, the clinical impact of the addition of BRIs to abiraterone acetate with prednisone in this disease setting is unknown. Objective: To evaluate the association of the use of concomitant BRIs with overall survival (OS) and time to first SRE among patients with mCRPC and bone metastases receiving abiraterone acetate with prednisone as first-line therapy. Design, Setting, and Participants: This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019. Exposures: Patients were classified by receipt vs nonreceipt of concomitant BRIs and subclassified by volume of disease (high volume or low volume, using definitions from the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] E3805 study) at the initiation of abiraterone acetate with prednisone therapy. Main Outcomes and Measures: The primary end point was OS. The secondary end point was time to first SRE. The Kaplan-Meier method and Cox proportional hazards models were used. Results: Of the 745 men (median age, 77.6 years [interquartile range, 68.1-83.6 years]; 699 White individuals [93.8%]) included in the analysis, 529 men (71.0%) received abiraterone acetate with prednisone alone (abiraterone acetate cohort), and 216 men (29.0%) received abiraterone acetate with prednisone plus BRIs (BRI cohort). A total of 420 men (56.4%) had high-volume disease, and 276 men (37.0%) had low-volume disease. The median follow-up was 23.5 months (95% CI, 19.8-24.9 months). Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months; hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; P < .001). The OS benefit in the BRI cohort was greater for patients with high-volume vs low-volume disease (33.6 vs 19.7 months; HR, 0.51; 95% CI, 0.38-0.68; P < .001). The BRI cohort also had a significantly shorter time to first SRE compared with the abiraterone acetate cohort (32.4 vs 42.7 months; HR, 1.27; 95% CI, 1.00-1.60; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; 95% CI, 1.57-3.35; P < .001). In the multivariable analysis, concomitant BRIs use was independently associated with longer OS (HR, 0.64; 95% CI, 0.52-0.79; P < .001). Conclusions and Relevance: In this study, the addition of BRIs to abiraterone acetate with prednisone as first-line therapy for the treatment of patients with mCRPC and bone metastases was associated with longer OS, particularly in patients with high-volume disease. These results suggest that the use of BRIs in combination with abiraterone acetate with prednisone as first-line therapy for the treatment of mCRPC with bone metastases could be beneficial.

Optimizing management of advanced urothelial carcinoma: A review of emerging therapies and biomarker-driven patient selection.

INTRODUCTION: Advanced urothelial carcinoma has been challenging to treat due to limited treatment options, poor response rates, and poor long-term survival. New treatment options hold the promise of improved outcomes for these patients. METHODS: A multidisciplinary working group drafted a management algorithm for advanced urothelial carcinoma using "consensus development conference" methodology. A targeted literature search identified new and emerging treatments for inclusion in the management algorithm. Published clinical data were considered during the algorithm development process, as well as the risks and benefits of the treatment options. Biomarkers to guide patient selection in clinical trials for new treatments were incorporated into the algorithm. RESULTS: The advanced urothelial carcinoma management algorithm includes newly approved first-line anti-programmed death receptor-1 (PD1)/ programmed death-ligand 1 (PD-L1) therapies, a newly approved anti-fibroblast growth factor receptors (FGFR) therapy, and an emerging anti-Nectin 4 therapy, which have had encouraging results in phase 2 trials for second-line and third-line therapy, respectively. This algorithm also incorporates suggestions for biomarker testing of PD-L1 expression and FGFR gene alterations. CONCLUSIONS: Newly approved and emerging therapies are starting to cover an unmet need for more treatment options, better response rates, and improved overall survival in advanced urothelial carcinoma. The management algorithm provides guidance on how to incorporate these new options, and their associated biomarkers, into clinical practice.

Efficacy and Safety of nab-Paclitaxel vs Paclitaxel on Survival in Patients With Platinum-Refractory Metastatic Urothelial Cancer: The Canadian Cancer Trials Group BL.12 Randomized Clinical Trial.

IMPORTANCE: Treatment options for platinum-refractory metastatic urothelial cancer (mUC) are limited, and outcomes remain poor. Nab-paclitaxel is an albumin-bound formulation of paclitaxel showing promising activity and tolerability in a prior single-arm trial. OBJECTIVES: To evaluate the efficacy and safety of nab-paclitaxel vs paclitaxel in platinum-refractory mUC. DESIGN, SETTING, AND PARTICIPANTS: In this investigator-initiated, open-label, phase 2 randomized clinical trial conducted across Canada and Australia from January 2014 to April 2017, eligible patients had histologically confirmed, radiologically evident mUC of the urinary tract. Mixed histologic findings, except small cell, were permitted provided UC was the predominant histologic finding. All patients had received platinum-based chemotherapy either in the metastatic setting or were within 12 months of perioperative chemotherapy. Patients with prior taxane chemotherapy were not included. Patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 2 and adequate organ function. INTERVENTIONS: Patients were randomized to nab-paclitaxel, 260 mg/m2, or paclitaxel, 175 mg/m2, every 3 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS). RESULTS: Among 199 patients, median age was 67 (range, 24-88) years; 144 (72%) were men; 167 (84%) were ECOG PS 0-1; 59 (30%) had liver metastases; and 110 (55%) were within 6 months of prior platinum-based chemotherapy. At a median follow-up of 16.4 months, there was no significant difference between nab-paclitaxel vs paclitaxel for median PFS (3.4 months vs 3.0 months; hazard ratio [HR], 0.92; 90% CI, 0.68-1.23; 1-sided P = .31). Median overall survival was 7.5 months for nab-paclitaxel vs 8.8 months for paclitaxel (HR, 0.95; 90% CI, 0.70-1.30; 1-sided P = .40); and objective response rate (ORR) was 22% for nab-paclitaxel vs 25% for paclitaxel (P = .97). Grade 3/4 adverse events were more frequent with nab-paclitaxel (64/97 [66%]) compared with paclitaxel (45/97 [46%]), P = .009; but peripheral sensory neuropathy was similar (all grades, 72/97 [74%] vs 64/97 [66%]; grade 3/4, 7/97 [7%] vs 3/97 [3%]; P = .27). There were no apparent differences in scores for health-related quality of life. CONCLUSIONS AND RELEVANCE: In this open-label, phase 2 randomized clinical trial of patients with platinum-refractory mUC, nab-paclitaxel had similar efficacy to paclitaxel; but worse toxic effects. The ORR with either taxane, however, was higher than previously reported and similar to those reported for the immune checkpoint inhibitors, suggesting that the taxanes remain a reasonable option in this setting. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02033993.

Validation of a neuroendocrine-like classifier confirms poor outcomes in patients with bladder cancer treated with cisplatin-based neoadjuvant chemotherapy.

PURPOSE: Neuroendocrine (NE)-like carcinoma is a newly recognized molecular subtype of conventional urothelial carcinoma of the bladder with transcriptomic profiles and clinical outcomes highly similar to histological NE carcinoma. The identification of NE-like tumors is challenging, as these tumors often appear histologically like urothelial carcinoma and can be missed by routine morphological criteria. We previously developed a single-sample classifier to identify NE-like tumors, which we aimed to validate in an independent cohort. MATERIALS AND METHODS: A single-sample genomic classifier was performed on transurethral specimens from a retrospective multicenter cohort of 234 patients who underwent cisplatin-based neoadjuvant chemotherapy and subsequent radical cystectomy. Outcomes were compared for NE-like vs. non-NE-like. RESULTS: We identified 10 patients with urothelial tumors of the NE-like subtype, all of which had robust gene expression of neuronal markers, but did not express markers associated with basal or luminal tumors. The cancer-specific mortality rates were significantly higher compared to non-NE-like tumors (P < 0.001), with 5 of the 10 patients dying within 12 months from surgery. CONCLUSIONS: The single-sample classifier was able to identify urothelial carcinomas with NE-like subtype. These NE-like tumors have demonstrated transcriptomic profiles and clinical behavior similar to histological NE tumors across multiple patient cohorts. We propose that NE-like tumors should be managed similarly to histological NE tumors, and that standard treatments for small cell lung cancer as well as novel strategies may be evaluated in these patients.