PURPOSE: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Mutations in DNA damage repair genes are associated with pathologic downstaging after NAC. We hypothesized that a combination of biomarker selection and clinical staging would identify patients for cystectomy-sparing active surveillance (AS). PATIENTS AND METHODS: We conducted a single-arm, phase II, noninferiority trial to evaluate a risk-adapted approach for MIBC. Patients with cT2-T3N0M0 MIBC underwent NAC with accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC). Pre-NAC transurethral bladder tumor specimens were sequenced for mutations in ATM , ERCC2 , FANCC , and RB1 . Patients with ≥1 mutation and cT0 post-NAC began AS. The primary end point was metastasis-free survival (MFS) at 2 years for the entire cohort with the null hypothesis rejected if the lower bound exact one-sided 95% CI exceeds 64%. RESULTS: Seventy patients were enrolled, 33 (47%) had a mutation, and 25 (36%) began per-protocol AS. With a median follow-up of 40 months, the 2-year MFS for all patients was 72.9% (lower bound exact one-sided 95% CI, 62.8). The 2-year MFS was 76.0% in the AS group (95% CI, 54.2 to 88.4) and 71.1% (95% CI, 55.5 to 82.1) in the remaining patients. In the AS group, 17 patients (68%) had some recurrence and 12 (48%) were metastasis-free with an intact bladder. The 2-year overall survival (OS) was 84.3% (95% CI, 73.4 to 91.0); OS was 88.0% (95% CI, 67.3 to 96.0) and 82.2% (95% CI, 67.6 to 90.7) in the AS and not-AS groups, respectively. CONCLUSION: Patients with MIBC treated with AMVAC followed by a risk-adapted approach to local consolidation achieved a 2-year MFS rate of 73%. The primary end point was not met, but 17% of all enrolled patients and 48% of the AS group avoided cystectomy without metastatic disease.

The tumor microenvironment (TME) plays an important role in cancer growth and progression. Paradoxically, the TME is capable of acting as both a potential barrier and facilitator of tumor proliferation by affecting various processes including local growth resistance, immune system interactions, and the formation of distant metastases. This important interaction between cancer cells and their local environment, composed of immune cells, angiogenic cells, lymphatic endothelial cells and cancer-associated fibroblasts is paramount to determine a cancer cell's ability to grow and ultimately metastasize. It is essential to understand this complex interplay in order to define treatment modalities to target the TME as part of anti-cancer therapy. Graphical abstract Composition of the tumor microenvironment and associated actionable targets.

Prostate cancer is the most common cancer among men and the second leading cause of cancer-related deaths in men in the United States. The treatment paradigm for prostate cancer has evolved with the emergence of a variety of novel therapies which have improved survival; however, treatment-related toxicities are abundant and durable responses remain rare. Immune checkpoint inhibitors have shown modest activity in a small subset of patients with prostate cancer and have not had an impact on most men with advanced disease. The discovery of prostate-specific membrane antigen (PSMA) and the understanding of its specificity to prostate cancer has identified it as an ideal tumor-associated antigen and has revived the enthusiasm for immunotherapeutics in prostate cancer. T-cell immunotherapy in the form of bispecific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR) T-cell therapy have shown exceptional success in treating various hematologic malignancies, and are now being tested in patients with prostate cancer with drug design centered on various target ligands including not just PSMA, but others as well including six-transmembrane epithelial antigen of the prostate 1 (STEAP1) and prostate stem cell antigen (PSCA). This summative review will focus on the data surrounding PSMA-targeting T-cell therapies. Early clinical studies with both classes of T-cell redirecting therapies have demonstrated antitumor activity; however, there are multiple challenges with this class of agents, including dose-limiting toxicity, ‘on-target, off-tumor’ immune-related toxicity, and difficulty in maintaining sustained immune responses within a complex and overtly immunosuppressive tumor microenvironment. Reflecting on experiences from recent trials has been key toward understanding mechanisms of immune escape and limitations in developing these drugs in prostate cancer. Newer generation BiTE and CAR T-cell constructs, either alone or as part of combination therapy, are currently under investigation with modifications in drug design to overcome these barriers. Ongoing innovation in drug development will likely foster successful implementation of T-cell immunotherapy bringing transformational change to the treatment of prostate cancer.

PURPOSE: Orteronel (TAK-700) is a nonsteroidal 17,20-lyase inhibitor suppressing androgen synthesis. We evaluated the clinical benefit of orteronel when added to androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone-sensitive prostate cancer. METHODS: In this open-label randomized phase III study, patients with metastatic hormone-sensitive prostate cancer were randomly assigned 1:1 to ADT with orteronel (300 mg oral twice daily; experimental arm) or ADT with bicalutamide (50 mg oral once daily; control arm). The primary objective was the comparison of overall survival (OS), targeting a 33% improvement in median survival. A stratified log-rank test with a one-sided P ≤ .022 would indicate statistical significance. Secondary end points were progression-free survival (PFS), prostate-specific antigen (PSA) level at 7 months (≤ 0.2 v 0.2 to ≤ 4 v > 4 ng/mL), and adverse event profile. RESULTS: Among 1,279 patients included in the analysis, 638 were randomly assigned to the ADT plus orteronel arm and 641 to the control arm. The median age was 68 years; 49% had extensive disease. After a median follow-up of 4.9 years, there was a significant improvement in PFS (median 47.6 v 23.0 months, hazard ratio 0.58; 95% CI, 0.51 to 0.67; P < .0001) and PSA response at 7 months ( P < .0001), but not in OS (median 81.1 v 70.2 months, hazard ratio 0.86; 95% CI, 0.72 to 1.02; P = .040, one-sided). More grade 3/4 adverse events occurred in the experimental versus the control arms (43% v 14%). Postprotocol life-prolonging therapy was received by 77.4% of patients in the control arm and 61.3% of patients in the orteronel arm. CONCLUSION: The study did not meet the primary end point of improved OS with orteronel. The lack of correlation of PFS and PSA response with OS raises concerns over assumption of their consistent surrogacy for OS in the context of extensive postprotocol therapy in this setting.

Purpose: On the basis of preclinical evidence of epigenetic contribution to sensitivity and resistance to immune checkpoint inhibitors (ICI), we hypothesized that guadecitabine (hypomethylating agent) and atezolizumab [anti–programmed cell death ligand 1 (PD-L1)] together would potentiate a clinical response in patients with metastatic urothelial carcinoma (UC) unresponsive to initial immune checkpoint blockade therapy. Patients and Methods: We designed a single arm phase II study (NCT03179943) with a safety run-in to identify the recommended phase II dose of the combination therapy of guadecitabine and atezolizumab. Patients with recurrent/advanced UC who had previously progressed on ICI therapy with programmed cell death protein 1 or PD-L1 targeting agents were eligible. Preplanned correlative analysis was performed to characterize peripheral immune dynamics and global DNA methylation, transcriptome, and immune infiltration dynamics of patient tumors. Results: Safety run-in enrolled 6 patients and phase II enrolled 15 patients before the trial was closed for futility. No dose-limiting toxicity was observed. Four patients, with best response of stable disease (SD), exhibited extended tumor control (8–11 months) and survival (>14 months). Correlative analysis revealed lack of DNA demethylation in tumors after 2 cycles of treatment. Increased peripheral immune activation and immune infiltration in tumors after treatment correlated with progression-free survival and SD. Furthermore, high IL6 and IL8 levels in the patients’ plasma was associated with short survival. Conclusions: No RECIST responses were observed after combination therapy in this trial. Although we could not detect the anticipated tumor-intrinsic effects of guadecitabine, the addition of hypomethylating agent to ICI therapy induced immune activation in a few patients, which associated with longer patient survival.

BACKGROUND: Metastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis. METHODS: We analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites. RESULTS: We included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC. CONCLUSION: We demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.