Single-Hit and Multi-hit PIK3CA Short Variant Genomic Alterations in Clinically Advanced Prostate Cancer: A Genomic Landscape Study.

BACKGROUND: Tumors harboring two or more PIK3CA short variant (SV) ("multi-hit") mutations have been linked to improved outcomes with anti-PIK3CA-targeted therapies in breast cancer. The landscape and clinical implications of multi-hit PIK3CA alterations in clinically advanced prostate cancer (CAPC) remains elusive. OBJECTIVE: To evaluate the genomic landscape of single-hit and multi-hit PIK3CA genomic alterations in CAPC. PATIENTS AND METHODS: The Foundation Medicine FoundationCore database was used to identify 19,978 CAPC tumors that underwent hybrid capture-based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA) and determine tumor mutational burden (TMB), microsatellite instability (MSI), genomic ancestry, single-base substitution mutational signatures, and homologous recombination deficiency signature (HRDsig). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). RESULTS: 18,741 (93.8%) tumors were PIK3CA wild type (WT), 1155 (5.8%) featured single PIK3CA SV, and 82 (0.4%) featured multi-hit PIK3CA SVs. Single-hit (6.6 versus 3.8; p < 0.0001) and multi-hit (12.8 versus 3.8; p < 0.0001) featured more driver GA per tumor than PIK3CA WT CAPC, as well as higher prevalence of MMR mutational signature, MSI high status, and TMB levels versus PIK3CA WT (p < 0.0001). Other differences in GA included higher frequencies of GA in BRCA2 in multi-hit versus WT (18.3% versus 8.5%; p = 0.0191), ATM in multi-hit versus WT (13.4% versus 5.6%; p = 0.02) and PTEN in single-hit versus WT (40.2% versus 30.1%; p < 0.0001). Homologous recombination deficiency signatures were higher in PIK3CA WT versus single-hit (11.2% versus 7.6%; p = 0.0002). There were no significant differences in PD-L1 expression among the three groups. CONCLUSIONS: Identification of multi-hit PIK3CA GA in CAPC highlights a potentially unique phenotype that may be associated with response to anti-PIK3CA targeted therapy and checkpoint inhibition, supporting relevant clinical trial designs.

Efficacy and safety of pembrolizumab in patients with advanced urothelial carcinoma deemed potentially ineligible for platinum-containing chemotherapy: Post hoc analysis of KEYNOTE-052 and LEAP-011.

BACKGROUND: First-line pembrolizumab monotherapy is a standard of care for platinum-ineligible patients with advanced urothelial carcinoma (UC). No global standardized definition of platinum ineligibility exists. This study aimed to evaluate the efficacy and safety of pembrolizumab monotherapy in patients with UC who met various criteria for platinum ineligibility. METHODS: Patients from KEYNOTE-052 and LEAP-011 deemed potentially platinum ineligible were pooled for this post hoc exploratory analysis as follows: group 1: Eastern Cooperative Oncology Group performance status (ECOG PS) 2; group 2: ECOG PS 2 and age ≥80 years, renal dysfunction, or visceral disease; and group 3: any two other factors regardless of ECOG PS. Patients received pembrolizumab 200 mg intravenously every 3 weeks. End points included objective response rate (ORR), progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1, by blinded independent central review, overall survival (OS), and safety. RESULTS: A total of 612 patients treated with pembrolizumab from KEYNOTE-052 (n = 370) and LEAP-011 (n = 242) were included; the median (range) follow-up was 56.3 months (51.2-65.3 months) and 12.8 months (0.2-25.1 months), respectively. For group 1, ORR was 26.2%, median PFS was 2.7 months, and median OS was 10.1 months. For group 2, ORR ranged from 23.5% to 33.3%, median PFS ranged from 2.1 to 4.4 months, and median OS ranged from 9.1 to 10.1 months. For group 3, ORR ranged from 25.7% to 27.9%, median PFS ranged from 2.1 to 2.8 months, and median OS ranged from 9.0 to 10.6 months. Treatment-related adverse event rates were consistent across groups. CONCLUSIONS: Frontline pembrolizumab has consistent antitumor activity and safety in patients with advanced UC categorized as potentially ineligible for platinum-based chemotherapy, regardless of the variable definitions of platinum ineligibility used.

Association of Tumor Mutational Burden and Microsatellite Instability With Response and Outcomes in Patients With Urothelial Carcinoma Treated With Immune Checkpoint Inhibitor.

BACKGROUND: Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB) are associated with immune checkpoint inhibitor (ICI) efficacy. We examined the association between TMB and MSI status with survival in patients with urothelial carcinoma (UC) treated with ICI. METHODS: Patients from 15 institutions were treated with ICI monotherapy. Primary endpoint was overall survival and secondary endpoints included observed response rate (ORR), and progression-free (PFS) calculated from ICI initiation. TMB was analyzed as dichotomous (≥10 vs. <10 mut/Mb) and continuous variable. RESULTS: We identified 411 patients: 203 were treated with ICI 1L/upfront; 104 with 2 + L. For the 1L/upfront: median [m] OS was numerically longer in patients with TMB ≥10 versus TMB <10: mOS 35 versus 26 months (HR = 0.6) and with MSI-H and MSI-S (mOS NR vs. 22 months), though neither association was statistically significant. A statistically significant association was found between TMB (continuous variable) and OS (HR = 0.96, P = .01). For 2 + L: mOS was numerically longer in patients with TMB ≥10 versus TMB <10: (20 vs. 12 months; HR = 0.9); mOS was 12 and 17 months for patients with MSI-H and MSI-S, respectively. Eighty-nine patients received maintenance avelumab (mAV): mOS was longer in patients with TMB ≥10 versus TMB <10: 61 versus 17 months; (HR = 0.2, P = .02) and with MSI-H and MSI-S (NR vs. 24 months). CONCLUSIONS: Although not reaching statistical significance in several subsets, patients with high TMB and MSI-H had numerically longer OS with ICI, especially with mAV. Further validation is needed.

Small Cell Bladder Cancer: Treatment Patterns for Local Disease and Associated Outcomes. A Retrospective Cohort Study.

BACKGROUND: Small cell bladder cancer (SCBC) is a rare histologic subtype with relative paucity of data regarding treatment response and outcomes. We reviewed 2 databases to compare outcomes in patients with localized SCBC treated with cystectomy versus concurrent chemoradiotherapy (CCRT). We hypothesized that survival would be similar with these therapy approaches. METHODS: We retrospectively reviewed our institutional and SEER-Medicare databases to identify patients with SCBC. Overall survival (OS) was determined from the date of diagnosis to last follow-up/death. For those with nonmetastatic disease, a multivariate Cox analysis was used to compare locoregional therapy with neoadjuvant chemotherapy (NAC) + cystectomy versus CCRT. RESULTS: We identified 53 patients in our institutional database and 1166 patients in SEER-Medicare with localized SCBC. Median OS (mOS) with NAC + cystectomy was 46 months (95% CI, 21-72) and 45 months (95% CI, 0-104) in the institutional and SEER-Medicare databases, respectively, whereas mOS with CCRT was 26 months (95% CI, 5-47) and 23 months (95% CI, 18-28) in the 2 series, respectively. In multivariate analysis, NAC followed by cystectomy was associated with an approximately 30% reduction in mortality compared to CCRT in both institutional and national databases but did not reach statistical significance (Institution HR 0.71, 95% CI, 0.22-2.4, P = .58; SEER HR 0.73, 95% CI, 0.49-1.08; P = .11). CONCLUSIONS: SCBC is very aggressive with limited survival observed in our institutional and SEER-Medicare datasets regardless of locoregional therapy used. There is an unmet need to define the optimal locoregional therapy for nonmetastatic stage and identify novel therapeutic targets.

Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma.

BACKGROUND: Muscle-invasive urothelial carcinoma is an aggressive disease with high rates of relapse. Whether pembrolizumab as adjuvant therapy would be effective in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery is unknown. METHODS: In this phase 3 trial, we randomly assigned patients, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks for 1 year or to undergo observation. Randomization was stratified according to pathological stage, centrally tested programmed death ligand 1 (PD-L1) status, and previous neoadjuvant chemotherapy. The coprimary end points were disease-free survival and overall survival in the intention-to-treat population. We considered the trial to be successful if either disease-free survival or overall survival was significantly longer with pembrolizumab than with observation. RESULTS: A total of 702 patients underwent randomization; 354 were assigned to receive pembrolizumab, and 348 were assigned to observation. As of July 5, 2024, the median duration of follow-up for disease-free survival was 44.8 months. The median disease-free survival was 29.6 months (95% confidence interval [CI], 20.0 to 40.7) with pembrolizumab and 14.2 months (95% CI, 11.0 to 20.2) with observation (hazard ratio for disease progression or death, 0.73; 95% CI, 0.59 to 0.90; two-sided P = 0.003). Grade 3 or higher adverse events (regardless of attribution) occurred in 50.7% of the patients in the pembrolizumab group and in 31.6% of the patients in the observation group. CONCLUSIONS: Among patients with high-risk muscle-invasive urothelial carcinoma after radical surgery, disease-free survival was significantly longer with adjuvant pembrolizumab than with observation. (Funded by the National Cancer Institute of the National Institutes of Health and others; Alliance A031501 AMBASSADOR ClinicalTrials.gov number, NCT03244384.).

TROPHY-U-01 Cohort 2: A Phase II Study of Sacituzumab Govitecan in Cisplatin-Ineligible Patients With Metastatic Urothelial Cancer Progressing After Previous Checkpoint Inhibitor Therapy.

PURPOSE: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate with an SN-38 payload, approved for patients with locally advanced (LA) or metastatic urothelial cancer (mUC) who progressed after platinum (PT)-based chemotherapy and a checkpoint inhibitor (CPI). Here, we report results from Cohort 2 of TROPHY-U-01 trial, evaluating the efficacy and safety of SG in patients with mUC. METHODS: TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973) is a multicohort, open-label phase II study. Cohort 2 includes patients with LA or mUC who have had progression or recurrence after a CPI and were cisplatin-ineligible at study initiation. Patients received SG 10 mg/kg on days 1 and 8 of 21-day cycles. The primary end point was objective response rate (ORR) per central review; secondary end points were clinical benefit rate (CBR), duration of response (DOR), and progression-free survival (PFS) per central review and safety. RESULTS: Cohort 2 included 38 patients (61% male; median age 72.5 years; 66% visceral metastases [29% liver]; 50% received previous PT-based chemotherapy as previous [neo]adjuvant therapy]). At a median follow-up of 9.3 months, ORR was 32% (95% CI, 17.5 to 48.7), CBR 42% (95% CI, 26.3 to 59.2), median DOR 5.6 months (95% CI, 2.8 to 13.3), median PFS 5.6 months (95% CI, 4.1 to 8.3), and median overall survival 13.5 months (95% CI, 7.6 to 15.6). Grade ≥3 treatment-emergent adverse events occurred in 87% of patients, most commonly neutropenia (34%), anemia (24%), leukopenia (19%), fatigue (18%), and diarrhea (16%). CONCLUSION: SG monotherapy demonstrated a relatively high ORR with rapid responses; this was feasible with a manageable toxicity profile in cisplatin-ineligible patients who had progression after CPI therapy. Limitations include a moderate sample size and lack of random assignment. These results warrant further evaluation of SG alone and in combinations in patients with LA/mUC.

Urachal and Nonurachal Adenocarcinomas of the Urinary Bladder: A Comprehensive Genomic Profiling Study.

PURPOSE: Although both urachal (U) and nonurachal (NU) bladder adenocarcinomas (adenoCas) share several histologic similarities, they differ in location and sometimes in therapeutic options. We analyzed the differences in genomic alterations (GAs) between these tumor entities, with the aim of identifying potential therapeutic targets for clinical trials. MATERIALS AND METHODS: Overall, 133 U and 328 NU adenoCas were analyzed. Hybrid capture-based comprehensive genomic profiling (CGP) was performed to evaluate all classes of GA. Germline status of GA was predicted using a validated somatic-germline computational method. CGP was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc). RESULTS: The most frequent GA in both U and NU cohorts included TP53 (86.5% v 81.1%) and KRAS (34.6% v 27.7%). GAs characteristic of colorectal adenoCa, such as SMAD4 (P = .069) and GNAS (P = .071), were more common in U versus NU. Conversely, TERT (P < .01) and RB1 (P = .071) were more prevalent in NU adenoCa. Notably, both U and NU adenoCas exhibited possibly targetable GA in PIK3CA (7.5% v 7.9%) and ERBB2 (6.8% v 7.6%). Biomarkers associated with potential benefit from anti-PD-1/L1 were infrequent. Median tumor mutational burden was 2.6 and 3.5 mutations per megabase for U and NU, respectively, and PD-L1 expression >1% was rare. Genomic ancestry and genomic signature distribution were similar in both tumor types. GAs were most commonly of somatic nature. Limitations include lack of clinical data, tumor heterogeneity, and retrospective nature. CONCLUSION: U and NU adenoCAs revealed differences in GA, with PIK3CA and ERBB2 being identified as putative therapeutic targets. Biomarkers of response to anti-PD-(L)1 were uncommon. Results highlight the potential of CGP to personalize treatment options of bladder adenoCa and inform clinical trial designs.

Sacituzumab Govitecan Demonstrates Efficacy across Tumor Trop-2 Expression Levels in Patients with Advanced Urothelial Cancer.

PURPOSE: Human trophoblast cell surface antigen 2 (Trop-2) is a protein highly expressed in urothelial cancer (UC). Sacituzumab govitecan (SG) is a Trop-2-directed antibody drug conjugate with a hydrolysable linker and a potent SN-38 payload. This study explored Trop-2 expression in tumors treated with SG in cohorts 1 to 3 (C1-3) from the TROPHY-U-01 study and evaluated whether efficacy was associated with Trop-2 expression. PATIENTS AND METHODS: TROPHY-U-01 (NCT03547973) is an open-label phase II study that assessed the efficacy and safety of SG (alone or in combinations) in patients with unresectable locally advanced or metastatic UC (mUC). Archival tumor samples collected at enrollment for C1-3 were analyzed for Trop-2 membrane expression by considering histological scores (H-scores; scale 0-300) and the percentage of membrane positive tumor cells at low magnification (4×). The association of Trop-2 with clinical endpoints [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] was evaluated. RESULTS: In C1-3, tissue was collected from 158 (82%) of 192 treated patients, and 146 (76%) had evaluable Trop-2 data. Trop-2 was highly expressed in tumor samples. The median [interquartile range (IQR)] Trop-2 H-score was 215 (180-246), and the median (IQR) percentage of membrane positive tumor cells was 91% (80-98). Trop-2 expression at any level was observed in 98% of patients. Furthermore, ORR, PFS, and OS benefits were observed across all Trop-2 expression levels. CONCLUSIONS: Trop-2 protein is highly expressed in UC, as confirmed by examining tumors from patients enrolled in the TROPHY-U-01 trial. The results indicate that SG demonstrates efficacy in mUC across Trop-2 expression levels.

Pembrolizumab plus either epacadostat or placebo for cisplatin-ineligible urothelial carcinoma: results from the ECHO-307/KEYNOTE-672 study.

BACKGROUND: Indoleamine 2,3- dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been correlated with shorter disease-specific survival in patients with urothelial carcinoma (UC). IDO1 may counteract the antitumor effects of immune checkpoint inhibitors. Epacadostat is a potent and highly selective inhibitor of IDO1. In the phase I/II ECHO-202/KEYNOTE-037 study, epacadostat plus pembrolizumab resulted in a preliminary objective response rate (ORR) of 35% in a cohort of patients with advanced UC. METHODS: ECHO-307/KEYNOTE-672 was a double-blinded, randomized, phase III study. Eligible adults had confirmed locally advanced/unresectable or metastatic UC of the urinary tract and were ineligible to receive cisplatin-based chemotherapy. Participants were randomly assigned (1:1) to receive epacadostat (100 mg twice daily) plus pembrolizumab (200 mg every 3 weeks) or placebo plus pembrolizumab for up to 35 pembrolizumab infusions. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors (version 1.1). RESULTS: A total of 93 patients were randomized (epacadostat plus pembrolizumab, n = 44; placebo plus pembrolizumab, n = 49). Enrollment was stopped early due to emerging data from the phase III ECHO-301/KEYNOTE-252 study. The median duration of follow-up was 64 days in both arms. Based on all available data at cutoff, ORR (unconfirmed) was 31.8% (95% CI, 22.46-55.24%) for epacadostat plus pembrolizumab and 24.5% (95% CI, 15.33-43.67%) for placebo plus pembrolizumab. Circulating kynurenine levels numerically increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and decreased in the epacadostat-plus-pembrolizumab arm. Epacadostat-plus-pembrolizumab combination treatment was well tolerated with a safety profile similar to the placebo arm. Treatment discontinuations due to treatment-related adverse events were more frequent with epacadostat (11.6% vs. 4.1%). CONCLUSIONS: Treatment with epacadostat plus pembrolizumab resulted in a similar ORR and safety profile as placebo plus pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced/unresectable or metastatic UC. At a dose of 100 mg twice daily, epacadostat did not appear to completely normalize circulating kynurenine levels when administered with pembrolizumab. Larger studies with longer follow-up and possibly testing higher doses of epacadostat, potentially in different therapy settings, may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03361865, retrospectively registered December 5, 2017.

Urine Biopsy as Dynamic Biomarker to Enhance Clinical Staging of Bladder Cancer in Radical Cystectomy Candidates.

PURPOSE: There is significant interest in identifying complete responders to neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) to potentially avoid removal of a pathologically benign bladder. However, clinical restaging after NAC is highly inaccurate. The objective of this study was to develop a next-generation sequencing-based molecular assay using urine to enhance clinical staging of patients with bladder cancer. METHODS: Urine samples from 20 and 44 patients with bladder cancer undergoing RC were prospectively collected for retrospective analysis for molecular correlate analysis from two clinical trials, respectively. The first cohort was used to benchmark the assay, and the second was used to determine the performance characteristics of the test as it correlates to responder status as measured by pathologic examination. RESULTS: First, to benchmark the assay, known mutations identified in the tissue (MT) of patients from the Accelerated Methotrexate, Vinblastine, Doxorubicin, Cisplatin trial (ClinicalTrials.gov identifier: NCT01611662, n = 16) and a cohort from University of California-San Francisco (n = 4) were cross referenced against mutation profiles from urine (MU). We then determined the correlation between MU persistence and residual disease in pre-RC urine samples from a second prospective clinical trial (The pT0 trial; ClinicalTrials.gov identifier: NCT02968732). Residual MU status correlated strongly with residual disease status (pT0 trial; n = 44; P = .0092) when MU from urine supernatant and urine pellet were assessed separately and analyzed in tandem. The sensitivity, specificity, PPV, and NPV were 91%, 50%, 86%, and 63% respectively, with an overall accuracy of 82% for this second cohort. CONCLUSION: MU are representative of MT and thus can be used to enhance clinical staging of urothelial carcinoma. Urine biopsy may be used as a reliable tool that can be further developed to identify complete response to NAC in anticipation of safe RC avoidance.

The spectrum of cutaneous toxicities related to novel genitourinary cancer therapies.

CONTEXT: Genitourinary cancers (GUCs) encompass malignancies affecting the urinary and reproductive systems, including renal cell carcinoma (RCC), urothelial carcinoma (UC), and prostate cancer (PC). With the rapidly evolving therapeutic domain of these cancers, cutaneous adverse events (AEs) remain among the most observed toxicities. OBJECTIVE: To explore the dermatologic AEs linked to novel GUC treatments, their underlying pathophysiology, clinical presentations, and risk factors. EVIDENCE ACQUISITION: A narrative review of the literature from PubMed and Embase databases was conducted. The search strategy included dermatologic/cutaneous adverse events, risk factors, and pathophysiology in conjunction with the following classes of therapies; immune checkpoint inhibitors (ICIs), antiangiogenic therapies, enfortumab vedotin (EV), erdafitinib, and androgen receptor antagonists (ARAs). EVIDENCE SYNTHESIS: Maculopapular rash, pruritus, and alopecia are present among the five classes of therapies. ICIs demonstrate the highest incidence of severe drug AEs including Steven Johnson syndrome/toxic epidermal necrolysis. Unique cutaneous AEs present with specific therapies including hand-foot skin reaction and subungual splinter hemorrhage with antiangiogenic drugs, stomatitis/mucositis and onycholysis with erdafitinib. Incidence and type of cutaneous AE also differed within therapies in the same class as seen with apalutamide displaying the highest risk of cutaneous AEs within ARAs. Risk factors for development of cutaneous AEs can be general to therapies, or specific, and include age, immune status, BMI, and gender. CONCLUSIONS: Dermatologic AEs may impact patients' quality of life and increase the tendency to dose reduce, hold or discontinue life-saving therapies, underscoring the need for vigilant monitoring, early recognition, and collaborative management between medical oncologists, pharmacists, dermatologists and other specialists.

Patterns of chemotherapy use with primary radiotherapy for localized bladder cancer in patients 65 or older.

Introduction: Bladder preservation with concurrent chemoradiotherapy after maximum transurethral resection of bladder tumor is an alternative to radical cystectomy in select patients with muscle invasive bladder cancer (MIBC). Concurrent administration of radio-sensitizing chemotherapy and radiation therapy (RT) has been shown to have superior disease control compared with RT alone and can often be administered with modest added toxicity. We sought to describe national patterns of chemotherapy use. Methods: The linked surveillance, epidemiology, and end results (SEER)-Medicare database was used to identify patients with cT2-4, N0/X, M0/X BC who received radiation between 2004 and 2018. Data on demographics, clinicopathologic factors, therapy and outcomes were extracted. Concurrent utilization of chemotherapy with RT was also identified (CRT). Multivariate logistic regression (MVA) models were used to explore factors associated with receipt of chemotherapy and overall survival (OS). Results: 2190 patients met inclusion criteria. Of these, 850 (38.8%) received no chemotherapy. Among those receiving chemotherapy, the most frequent regimens were single agent carboplatin, cisplatin, or gemcitabine. Factors that were independently associated with decreased likelihood of chemotherapy use were increasing age (OR 0.93, CI 0.92 - 0.95), Hispanic race (compared with White, OR 0.62, CI 0.39 - 0.99), cT3 or T4 (compared with cT2, OR 0.70, CI 0.55 - 0.90), and lower National Cancer Institute comorbidity index (OR 0.60, CI 0.51 - 0.70) (p < 0.05). Variables independently associated with increased likelihood of receipt of chemotherapy were married status (OR 1.28, CI 1.06 - 1.54), higher socioeconomic status (OR 1.31, CI 1.06 - 1.64), and later year of diagnosis (OR 1.09, CI 1.06 - 1.12). Receipt of concurrent chemotherapy with RT was associated with superior OS compared with RT alone. Conclusion: Over a third of patients >/65 years old receiving curative-intent RT for MIBC do not receive concurrent chemotherapy. Considering the improvement in oncologic outcomes with CRT over RT alone and more options, such as low dose gemcitabine which can be administered with modest toxicity, efforts are needed to identify barriers to utilization and increase the use of radio-sensitizing chemotherapy.

Optimizing the Use of Next-Generation Sequencing Assays in Patients With Urothelial Carcinoma: Recommendations by the 2023 San Raffaele Retreat Panel.

BACKGROUND: The application of precision medicine in clinical practice implies a thorough evaluation of actionable genomic alterations to streamline therapeutic decision making. Comprehensive genomic profiling of tumor via next-generation sequencing (NGS) represents a great opportunity but also several challenges. During the 2023 San Raffaele Retreat, we aimed to provide expert recommendations for the optimal use of NGS in urothelial carcinoma (UC). MATERIALS AND METHODS: A modified Delphi method was utilized, involving a panel of 12 experts in UC from European and United States centers, including oncologists, urologists, pathologists, and translational scientists. An initial survey, conducted before the meeting, delivered 15 statements to the panel. A consensus was defined when ≥70% agreement was reached for each statement. Statements not meeting the consensus threshold were discussed during the meeting. RESULTS: Nine of the 15 statements covering patient selection, cancer characteristics, and type of NGS assay, achieved a consensus during the survey. The remaining six statements addressing the optimal timing of NGS use, the ideal source of tumor biospecimen for NGS testing, and the subsequent need to evaluate the germline nature of certain genomic findings were discussed during the meeting, leading to unanimous agreement at the end of the conference. CONCLUSION: This consensus-building effort addressed multiple unanswered questions regarding the use of NGS in UC. The opinion of experts was in favor of broader use of NGS. In a setting where recommendations/guidelines may be limited, these insights may aid clinicians to provide informed counselling and raise the bar of precision and personalized therapy.

Adjuvant Chemotherapy and Survival After Radical Cystectomy in Histologic Subtype Bladder Cancer.

OBJECTIVES: Patients with histologic subtype bladder cancer (HSBC) suffer worse outcomes than those with conventional urothelial carcinoma (UC). We sought to characterize the use of adjuvant chemotherapy (AC) in HSBC after radical cystectomy (RC) using the National Cancer Database (NCDB). MATERIALS AND METHODS: We retrospectively queried the NCDB (2006-2019) for patients with non-metastatic bladder cancer (BC) who underwent RC (N = 45,797). Patients were stratified by histologic subtype and receipt of AC. Multivariable logistic regression determined associations of demographic and clinicopathologic features with receipt of AC. Multivariable Cox regression evaluated associations between receipt of any AC and overall survival (OS). RESULTS: We identified 4,469 patients with HSBC classified as squamous, adenocarcinoma, small cell, sarcomatoid, micropapillary, or plasmacytoid. Squamous comprised 31% of the HSBC cohort, followed by small cells and micropapillary. Black patients were presented with a higher prevalence of adenocarcinoma (119/322, 37.0%). Use of AC was highest in plasmacytoid and small cell (30% each) and lowest in squamous (11%). Neuroendocrine histology was independently associated with greater odds of receiving AC (HR 1.6, 95% CI 1.37-1.87), while squamous cell histology was associated with lower odds (HR 0.61, 95% CI 0.53-0.71). On multivariable Cox regression analysis, treatment with AC was associated with significantly longer OS (HR 0.69, 95% CI 0.59-0.81) and for squamous, sarcomatoid, and micropapillary cohorts after stratified by subtype. CONCLUSIONS: AC was variably used among patients with HSBC and was associated with OS benefit in such patients.

Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial.

BACKGROUND: The KEYNOTE-057 trial evaluated activity and safety of pembrolizumab in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer who were ineligible for or declined radical cystectomy. In cohort A (patients with carcinoma in situ, with or without papillary tumours) of the KEYNOTE-057 study, pembrolizumab monotherapy led to a complete response rate of 41% at 3 months, and 46% of responders maintained a response lasting at least 12 months. Here, we evaluate pembrolizumab monotherapy in cohort B of patients with papillary tumours without carcinoma in situ. METHODS: KEYNOTE-057 is a single-arm, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. Cohort B eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary tumours (high-grade Ta or any-grade T1) without carcinoma in situ. Transurethral resection of bladder tumour within 12 weeks of first pembrolizumab dose was required. Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. Primary endpoint was 12-month disease-free survival of high-risk non-muscle-invasive bladder cancer or progressive disease as assessed by cystoscopy, cytology, and central pathology and radiology review. Activity was assessed in all patients who received at least one dose of the study drug and had a baseline evaluation. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. FINDINGS: Between April 12, 2016, and June 17, 2021, 132 patients (104 [79%] men and 28 [21%] women) who had received a median of ten (IQR 9-15) previous BCG instillations were enrolled into cohort B of the study. Patients received a median of 10 cycles (IQR 6-27) of pembrolizumab. At data cutoff date, Oct 20, 2022, median follow-up was 45·4 months (IQR 36·4-59·3) and five (4%) of 132 patients remained on treatment. The 12-month disease-free survival was 43·5% (95% CI 34·9-51·9). Treatment-related adverse events occurred in 97 (73%) of 132 patients; 19 (14%) had a grade 3 or 4 treatment-related adverse event; the most common grade 3 or 4 treatment-related adverse events were colitis (in three [2%] patients) and diarrhoea (in two [2%]). 17 (13%) of 132 patients experienced serious treatment-related adverse events, of which colitis (three patients [2%]) was most common. No treatment-related deaths occurred. INTERPRETATION: Pembrolizumab monotherapy showed antitumour activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer without carcinoma in situ and could potentially be a suitable treatment option for patients who decline or are ineligible for radical cystectomy. Findings will need to be confirmed in a randomised controlled trial. FUNDING: Merck Sharp & Dohme.

Evaluating Debio 1347 in Patients with FGFR Fusion-Positive Advanced Solid Tumors from the FUZE Multicenter, Open-Label, Phase II Basket Trial.

PURPOSE: This multicenter phase II basket trial investigated the efficacy, safety, and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion. PATIENTS AND METHODS: Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2), or another histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events. RESULTS: Between March 22, 2019, and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, 4 in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted, and the trial was terminated. In total, 3 of 58 evaluable patients had partial responses, representing an objective response rate of 5%, with a further 26 (45%) having stable disease (≥6 weeks duration). Grade ≥3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events. CONCLUSIONS: Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors. See related commentary by Hage Chehade et al., p. 4549.

A plain language summary of the TROPHY-U-01 study: sacituzumab govitecan use in people with locally advanced or metastatic urothelial cancer.

WHAT IS THIS SUMMARY ABOUT?: Sacituzumab govitecan (brand name: TRODELVY®) is a new treatment being studied for people with a type of bladder cancer, called urothelial cancer, that has progressed to a locally advanced or metastatic stage. Locally advanced and metastatic urothelial cancer are usually treated with platinum-based chemotherapy. Metastatic urothelial cancer is also treated with immune checkpoint inhibitors. There are few treatment options for people whose cancer gets worse after receiving these treatments. Sacituzumab govitecan is a suitable treatment option for most people with urothelial cancer because it aims to deliver an anti-cancer drug directly to the cancer in an attempt to limit the potential harmful side effects on healthy cells. This is a summary of a clinical study called TROPHY-U-01, focusing on the first group of participants, referred to as Cohort 1. All participants in Cohort 1 received sacituzumab govitecan. WHAT ARE THE KEY TAKEAWAYS?: All participants received previous treatments for their metastatic urothelial cancer, including a platinum-based chemotherapy and a checkpoint inhibitor. The tumor in 31 of 113 participants became significantly smaller or could not be seen on scans after sacituzumab govitecan treatment; an effect that lasted for a median of 7.2 months. Half of the participants were still alive 5.4 months after starting treatment, without their tumor getting bigger or spreading further. Half of them were still alive 10.9 months after starting treatment regardless of tumor size changes. Most participants experienced side effects. These side effects included lower levels of certain types of blood cells, sometimes with a fever, and loose or watery stools (diarrhea). Side effects led 7 of 113 participants to stop taking sacituzumab govitecan. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: The study showed that sacituzumab govitecan had significant anti-cancer activity. Though most participants who received sacituzumab govitecan experienced side effects, these did not usually stop participants from continuing sacituzumab govitecan. Doctors can help control these side effects using treatment guidelines, but these side effects can be serious.Clinical Trial Registration: NCT03547973 (ClinicalTrials.gov) (TROPHY-U-1).

Frequency and Nature of Genomic Alterations in ERBB2-Altered Urothelial Bladder Cancer.

BACKGROUND: Human epidermal growth factor-2 (HER2) overexpression is an oncogenic driver in many solid tumors, including urothelial bladder cancer (UBC). In addition, activating mutations in the ERBB2 gene have been shown to play an oncogenic role similar to ERBB2 amplification. OBJECTIVE: To describe and compare the frequency and nature of genomic alterations (GA) of ERBB2-altered (mutations, amplification) and ERBB2 wild-type UBC. PATIENTS AND METHODS: Using a hybrid capture-based comprehensive profiling assay, 9518 UBC cases were grouped by ERBB2 alteration and evaluated for all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genome-wide loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by immunohistochemistry (Dako 22C3). Categorical statistical comparisons were performed using Fisher's exact tests. RESULTS: A total of 602 (6.3%) UBC cases featured ERBB2 extracellular domain short variant (SV) GA (ECDmut+), 253 (2.7%) cases featured ERBB2 kinase domain SV GA (KDmut+), 866 (9.1%) cases had ERBB2 amplification (amp+), and 7797 (81.9%) cases were ERBB2 wild-type (wt). European genetic ancestry of ECDmut+ was higher than ERBB2wt. Numerous significant associations were observed when comparing GA by group. Notably among these, CDKN2A/MTAP loss were more frequent in ERBB2wt versus ECDmut+ and amp+. ERBB3 GA were more frequent in ECDmut+ and KDmut+ than ERBB2wt. TERT GA were more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. TOP2A amplification was significantly more common in ECDmut+ and amp+ versus ERBB2wt, and TP53 SV GA were significantly higher in ERBB2 amp+ versus ERBB2wt. Mean TMB levels were significantly higher in ECDmut+, KDmut+, and amp+ than in ERBB2wt. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBEC) signature was more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. No significant differences were observed in PD-L1 status between groups, while gLOH-high status was more common in amp+ versus ERBB2wt. MSI-high status was more frequent in KDmut+ versus ERBB2wt, and in ERBB2wt than in amp+. CONCLUSIONS: We noted important differences in co-occurring GA in ERBB2-altered (ECDmut+, KDmut+, amp+) versus ERBB2wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the ERBB2-altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance mechanisms for ERBB2-altered UBC.

Genomic Correlates of Prostate-Specific Membrane Antigen Expression and Response to 177Lu-PSMA-617: A Retrospective Multicenter Cohort Study.

PURPOSE: While 177Lu-PSMA-617 (LuPSMA) is an effective therapy for many patients with metastatic castration-resistant prostate cancer (mCRPC), biomarkers associated with outcomes are not well defined. We hypothesized that prostate cancer mutational profile may associate with clinical activity of LuPSMA. We devised a study to evaluate associations between mCRPC mutational profile with LuPSMA clinical outcomes. METHODS: This was a multicenter retrospective analysis of patients with mCRPC with next-generation sequencing (NGS) who received LuPSMA. PSA50 response (ie, ≥50% decline in prostate-specific antigen [PSA]) rate, PSA progression free survival (PSA PFS), and overall survival (OS) were compared between genetically defined subgroups. RESULTS: One hundred twenty-six patients with NGS results who received at least one cycle of LuPSMA were identified. The median age was 73 (IQR, 68-78) years, 124 (98.4%) received ≥1 prior androgen receptor-signaling inhibitor, and 121 (96%) received ≥1 taxane-based chemotherapy regimen. Fifty-eight (46%) patients with a DNA damage repair gene mutation (DNA damage response group) and 59 (46.8%) with a mutation in TP53, RB1, or PTEN tumor suppressor genes (TSG group) were identified. After adjusting for relevant confounders, the presence of ≥1 TSG mutation was associated with shorter PSA PFS (hazard ratio [HR], 1.93 [95% CI, 1.05 to 3.54]; P = .034) and OS (HR, 2.65 [95% CI, 1.15 to 6.11]; P = .023). There was improved OS favoring the DNA damage response group (HR, 0.37 [95% CI, 0.14 to 0.97]; P = .044) on multivariable analysis. Univariate analysis of patients with ATM mutations had significantly higher rates of PSA50 response, PSA PFS, and OS. CONCLUSION: Outcomes on LuPSMA varied on the basis of mutational profile. Prospective studies to define the clinical activity of LuPSMA in predefined genomic subgroups are justified.