Development and Independent Validation of a Prognostic Gene Expression Signature Based on RB1, PTEN, and TP53 in Metastatic Hormone-sensitive Prostate Cancer Patients.

BACKGROUND: Androgen deprivation therapy (ADT) with docetaxel (D) and/or antiandrogen receptor therapies (ARTs) are the standard therapies in metastatic hormone-sensitive prostate cancer (mHSPC). Alterations in the tumor suppressor genes (TSGs) RB1, PTEN, and TP53 are associated with an aggressive evolution and treatment resistance in castration-resistant prostate cancer (CRPC). OBJECTIVE: To study the clinical implications of TSG mRNA expression in mHSPC patients. DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter retrospective biomarker study in mHSPC patients. TSGlow status was defined when two or more out of the three TSGs presented low RNA expression by nCounter in formalin-fixed paraffin-embedded samples and TSGwt for the remaining cases. The microarray data from the CHAARTED trial were analyzed as an independent validation cohort. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Molecular data were correlated with CRPC-free survival (CRPC-FS) and overall survival (OS) by the Kaplan-Meier method and multivariate Cox analysis. RESULTS AND LIMITATIONS: A total of 226 patients were included, of whom 218 were eligible: 93 were treated with ADT and 125 with ADT + D; 75.7% presented de novo stage IV and 67.9% high-volume disease. TSGlow (19.2%) was independently correlated with shorter CRPC-FS (hazard ratio [HR] 1.8, p = 0.002) and OS (HR 2, p = 0.002). In the CHAARTED trial, TSGlow was independently correlated with lower CRPC-FS (HR 2.2, p = 0.02); no differences in clinical outcomes according to treatment were observed in TSGlow patients, while a significant benefit was observed for ADT + D in the TSGwt group for CRPC-FS (HR 0.4, p < 0.001) and OS (HR 0.4, p = 0.001). However, no interaction was observed between TSG signature and treatment in either series. Study limitations are the retrospective design, small sample size, and lack of inclusion of patients treated with ADT + ART. CONCLUSIONS: TSGlow expression correlates with adverse outcomes in patients with mHSPC. The investigation of new therapeutic strategies in these patients is warranted. PATIENT SUMMARY: The low RNA expression of tumor suppressor genes in the tumors is correlated with adverse outcomes in patients with metastatic hormone-sensitive prostate cancer.

Obinutuzumab Pretreatment as a Novel Approach to Mitigate Formation of Anti-Drug Antibodies Against Cergutuzumab Amunaleukin in Patients with Solid Tumors.

PURPOSE: The immunocytokine cergutuzumab amunaleukin (CEA-IL2v) showed manageable safety and favorable pharmacodynamics in phase I/Ib trials in patients with advanced/metastatic carcinoembryonic antigen-positive (CEA+) solid tumors, but this was accompanied by a high incidence of anti-drug antibodies (ADA). We examined B-cell depletion with obinutuzumab as a potential mitigation strategy. EXPERIMENTAL DESIGN: Preclinical data comparing B-cell depletion with rituximab versus obinutuzumab are summarized. Substudies of phase I/Ib trials investigated the effect of obinutuzumab pretreatment on ADA development, safety, pharmacodynamics, and antitumor activity of CEA-IL2v ± atezolizumab in patients with advanced/metastatic or unresectable CEA+ solid tumors who had progressed on standard of care. RESULTS: Preclinical data showed superior B-cell depletion with obinutuzumab versus rituximab. In clinical studies, patients received CEA-IL2v monotherapy with (n = 16) or without (n = 6) obinutuzumab pretreatment (monotherapy study), or CEA-IL2v + atezolizumab + obinutuzumab pretreatment (n = 5; combination study). In the monotherapy study, after four cycles (every 2 weeks treatment), 0/15 evaluable patients administered obinutuzumab pretreatment had ADAs versus 4/6 patients without obinutuzumab. Obinutuzumab pretreatment with CEA-IL2v monotherapy showed no new safety signals and pharmacodynamic data suggested minimal impact on T cells and natural killer cells. Conversely, increased liver toxicity was observed in the combination study (CEA-IL2v + atezolizumab + obinutuzumab pretreatment). CONCLUSIONS: These preliminary findings suggest that obinutuzumab pretreatment before CEA-IL2v administration in patients with CEA+ solid tumors may be a feasible and potent ADA mitigation strategy, with an acceptable safety profile, supporting broader investigation of obinutuzumab pretreatment for ADA mitigation in other settings.

Dual inhibition of MEK and PI3Kß/δ-a potential therapeutic strategy in PTEN-wild-type docetaxel-resistant metastatic prostate cancer.

Background: Docetaxel remains the standard treatment for metastatic castration-resistant prostate cancer (mCRPC). However, resistance frequently emerges as a result of hyperactivation of the PI3K/AKT and the MEK/ERK pathways. Therefore, the inhibition of these pathways presents a potential therapeutic approach. In this study, we evaluated the efficacy of simultaneous inhibition of the PI3K/AKT and MEK/ERK pathways in docetaxel-resistant mCRPC, both in vitro and in vivo. Methods: Docetaxel-sensitive and docetaxel-resistant mCRPC cells were treated with selumetinib (MEK1/2 inhibitor), AZD8186 (PI3Kß/δ inhibitor) and capivasertib (pan-AKT inhibitor) alone and in combination. Efficacy and toxicity of selumetinib+AZD8186 were tested in docetaxel-resistant xenograft mice. CRISPR-Cas9 generated a PTEN-knockdown docetaxel-resistant cell model. Changes in phosphorylation of AKT, ERK and downstream targets were analyzed by Western blot. Antiapoptotic adaptations after treatments were detected by dynamic BH3 profiling. Results: PI3K/AKT and MEK/ERK pathways were hyperactivated in PTEN-wild-type (wt) docetaxel-resistant cells. Selumetinib+AZD8186 decreased cell proliferation and increased apoptosis in PTEN-wt docetaxel-resistant cells. This observation was further confirmed in vivo, where docetaxel-resistant xenograft mice treated with selumetinib+AZD8186 exhibited reduced tumor growth without additional toxicity. Conclusion: Our findings on the activity of selumetinib+AZD8186 in PTEN-wt cells and in docetaxel-resistant xenograft mice provide an excellent rationale for a novel therapeutic strategy for PTEN-wt mCRPC patients resistant to docetaxel, in whom, unlike PTEN-loss patients, a clinical benefit of treatment with single-agent PI3K and AKT inhibitors has not been demonstrated. A phase I-II trial of this promising combination is warranted.

Phase II trial of afatinib in patients with advanced urothelial carcinoma with genetic alterations in ERBB1-3 (LUX-Bladder 1).

BACKGROUND: Preclinical and early clinical data suggest that the irreversible ErbB family blocker afatinib may be effective in urothelial cancers harbouring ERBB mutations. METHODS: This open-label, phase II, single-arm trial (LUX-Bladder 1, NCT02780687) assessed the efficacy and safety of second-line afatinib 40 mg/d in patients with metastatic urothelial carcinoma with ERBB1-3 alterations. The primary endpoint was 6-month progression-free survival rate (PFS6) (cohort A); other endpoints included ORR, PFS, OS, DCR and safety (cohorts A and B). Cohort A was planned to have two stages: stage 2 enrolment was based on observed antitumour activity. RESULTS: Thirty-four patients were enroled into cohort A and eight into cohort B. In cohorts A/B, PFS6 was 11.8%/12.5%, ORR was 5.9%/12.5%, DCR was 50.0%/25.0%, median PFS was 9.8/7.8 weeks and median OS was 30.1/29.6 weeks. Three patients (two ERBB2-amplified [cohort A]; one EGFR-amplified [cohort B]) achieved partial responses. Stage 2 for cohort A did not proceed. All patients experienced adverse events (AEs), most commonly (any/grade 3) diarrhoea (76.2%/9.5%). Two patients (4.8%) discontinued due to AEs and one fatal AE was observed (acute coronary syndrome; not considered treatment-related). CONCLUSIONS: An exploratory biomarker analysis suggested that basal-squamous tumours and ERBB2 amplification were associated with superior response to afatinib. CLINICAL TRIAL REGISTRATION: NCT02780687.

Assessment of aggressive bladder cancer mutations in plasma cell-free DNA.

Background and aims: The spatial and temporal genetic heterogeneity of bladder cancer (BC) makes challenging to find specific drivers of metastatic disease, thus preventing to determine those BC patients at high risk of tumor progression. Our aim was to identify DNA mutations providing aggressive behavior to bladder tumors and analyze them in patients' cell-free DNA (cfDNA) during their follow-up after radical cystectomy (RC) in order to monitor tumor evolution. Methods: Six BC patients who underwent RC and presented disease progression during their follow-up were included. Next-generation sequencing was used to determine somatic mutations in several primary tumor and metastatic specimens from each patient. Shared DNA mutations between primary bladder tumor and metastatic sites were identified in cfDNA samples through droplet digital PCR. Results: Besides BC genetic heterogeneity, specific mutations in at least one of these genes -TERT, ATM, RB1, and FGFR3- were found in primary tumors and their metastases in all patients. These mutations were also identified in the patients' cfDNA at different follow-up time points. Additionally, the dynamic changes of these mutations in cfDNA allowed us to determine tumor evolution in response to treatment. Conclusion: The analysis of BC mutations associated with poor prognosis in plasma cfDNA could be a valuable tool to monitor tumor evolution, thus improving the clinical management of BC patients.

Phase II Trial Evaluating Olaparib Maintenance in Patients with Metastatic Castration-Resistant Prostate Cancer Responsive or Stabilized on Docetaxel Treatment: SOGUG-IMANOL Study.

The SOGUG-IMANOL trial was a phase 2, uncontrolled, Spanish multicenter study to assess the effect of maintenance treatment with olaparib on radiographic progression-free survival (PFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) who achieved partial or complete response or disease stabilization on docetaxel treatment and had a documented germline/somatic mutation in any of the homologous recombination repair (HRR) genes. Patients received olaparib 300 mg orally twice daily. From the screened population (n = 134), 26 (19.4%) somatic mutations were found, and 14 patients were included in the study. The median radiographic PFS was 11.1 (95%CI, 5.7 to 16.5) months. The median PSA-PFS was 3.5 (95%CI, 1.0 to 6.0) months, and the median clinical PFS was 14.7 (95%CI, 1.8 to 27.5 months). Clinical benefit was observed in 12 patients (85.7%, 95%CI 67.4% to 100%), including two patients with partial response and 10 with stable disease. Six patients reported grade 3-5 adverse events: asthenia (n = 3), anemia (n = 2) and neutropenia (n = 1). In this setting, olaparib has been shown to be an efficacious maintenance treatment in terms of radiographic PFS and clinical benefit, becoming a therapeutic option for some patients harboring an HRR gene mutation and in scenarios where further investigation is needed.

Ibrutinib combination therapy for advanced gastrointestinal and genitourinary tumours: results from a phase 1b/2 study.

BACKGROUND: Ibrutinib, a first-in-class inhibitor of Bruton's tyrosine kinase, is approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. Based on encouraging preclinical data, safety and efficacy of ibrutinib combined with companion drugs for advanced renal cell carcinoma (RCC), gastric/gastroesophageal junctional adenocarcinoma (GC), and colorectal adenocarcinoma (CRC) were evaluated. METHODS: Ibrutinib 560 mg or 840 mg once daily was administered with standard doses of everolimus for RCC, docetaxel for GC, and cetuximab for CRC. Endpoints included determination of the recommended phase 2 dose (RP2D) of ibrutinib in phase 1b and efficacy (overall response rate [ORR] for GC and CRC; progression-free survival [PFS] for CRC) in phase 2. RESULTS: A total of 39 (RCC), 46 (GC), and 50 (RCC) patients were enrolled and received the RP2D. Safety profiles were consistent with the individual agents used in the study. Confirmed ORRs were 3% (RCC), 21% (GC), and 19% (CRC). Median (90% CI) PFS was 5.6 (3.9-7.5) months in RCC, 4.0 (2.7-4.2) months in GC, and 5.4 (4.1-5.8) months in CRC. CONCLUSIONS: Clinically meaningful increases in efficacy were not observed compared to historical controls; however, the data may warrant further evaluation of ibrutinib combinations in other solid tumours. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02599324.

Association between the Immunophenotype of Peripheral Blood from mCRPC Patients and the Outcomes of Radium-223 Treatment.

(1) Background: Prostate cancer is the second most common cancer in men, with androgen suppression as the standard treatment. Despite initially responding to castration, most metastatic prostate cancer patients eventually experience progression. In these cases, Radium-223 is the chosen treatment. We hypothesized that the immunophenotype of circulating leukocytes conditions the response to Radium-223 treatment. (2) Material and Methods: In this prospective study, we collected peripheral blood from twelve mCRPC patients and nine healthy donors before (baseline) and during treatment with Radium-223. Immunophenotyping and the percentages of leukocyte-platelet complexes were determined by flow cytometry. The increments or decrements of leukocyte subsets between the baseline and the second Radium-223 injection were also calculated. (3) Results: At baseline, the mCRPC patients had a lower percentages of CD4+ T cells and B cells and higher percentages of NK and neutrophils than the HDs. In addition, they had more OX40+ CD4+ T cells, PD-L1+ CD8low cells, PD-L1+ B cells, PD-L1+ NK cells, and monocyte-platelet complexes than the HDs. Moreover, patients with slow and fast progression had different percentages of PD-L1+ CD8+ T cells. In particular, slow progression patients underwent an increment of PD-L1+ CD8+ T cells after two cycles of Radium-223. (4) Conclusions: The characterization of circulating immune cells before initiating Radium-223 treatment could become a non-invasive indicator of the response.

Results from a Phase 1b/2 Study of Ibrutinib Combination Therapy in Advanced Urothelial Carcinoma.

Ibrutinib is a first-in-class Bruton's tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. We evaluated the safety and efficacy of ibrutinib, alone or combined with standard-of-care regimens, in adults with advanced urothelial carcinoma (UC). Once-daily ibrutinib was administered orally at 840 mg (single-agent or with paclitaxel) or at 560 mg (with pembrolizumab). Phase 1b determined the recommended phase 2 dose (RP2D) of ibrutinib, and phase 2 assessed progression-free survival (PFS), overall response rate (ORR), and safety. Thirty-five, eighteen, and fifty-nine patients received ibrutinib, ibrutinib plus pembrolizumab, and ibrutinib plus paclitaxel at the RP2D, respectively. Safety profiles were consistent with those of the individual agents. The best-confirmed ORRs were 7% (two partial responses) with single-agent ibrutinib and 36% (five partial responses) with ibrutinib plus pembrolizumab. Median PFS was 4.1 months (range, 1.0-37.4+) with ibrutinib plus paclitaxel. The best-confirmed ORR was 26% (two complete responses). In previously treated patients with UC, ORR was higher with ibrutinib plus pembrolizumab than with either agent alone (historical data in the intent-to-treat population). ORR with ibrutinib plus paclitaxel was greater than historical values for single-agent paclitaxel or ibrutinib. These data warrant further evaluation of ibrutinib combinations in UC.

Management of Fibroblast Growth Factor Inhibitor Treatment-emergent Adverse Events of Interest in Patients with Locally Advanced or Metastatic Urothelial Carcinoma.

Background: Erdafitinib is indicated for the treatment of adults with locally advanced/metastatic urothelial carcinoma and susceptible FGFR3/2 alterations progressing on/after one or more lines of prior platinum-based chemotherapy. Objective: To better understand the frequency and management of select treatment-emergent adverse events (TEAEs) to enable optimal fibroblast growth factor receptor inhibitor (FGFRi) treatment. Design setting and participants: Longer-term efficacy and safety results of the BLC2001 (NCT02365597) trial in patients with locally advanced and unresectable or metastatic urothelial carcinoma were studied. Intervention: Erdafitinib schedule of 8 mg/d continuous in 28-d cycles, with uptitration to 9 mg/d if serum phosphate level was <5.5 mg/dl and no significant TEAEs occurred. Outcome measurements and statistical analysis: Adverse events were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The Kaplan-Meier methodology was used for the cumulative incidence of the first onset of TEAEs by grade. Time to resolution of TEAEs was summarized descriptively. Results and limitations: At data cutoff, the median treatment duration was 5.4 mo among 101 patients receiving erdafitinib. Select TEAEs (total; grade 3) were hyperphosphatemia (78%; 2.0%), stomatitis (59%; 14%), nail events (59%; 15%), non-central serous retinopathy (non-CSR) eye disorders (56%; 5.0%), skin events (55%; 7.9%), diarrhea (55%; 4.0%), and CSR (27%; 4.0%). Select TEAEs were mostly of grade 1 or 2, and were managed effectively with dose modifications, including dose reductions or interruptions, and/or supportive concomitant therapies, resulting in few events leading to treatment discontinuation. Further work is needed to determine whether management is generalizable to the nonprotocol/general population. Conclusions: Identification of select TEAEs and appropriate management with dose modification and/or concomitant therapies resulted in improvement or resolution of most TEAEs in patients, allowing for continuation of FGFRi treatment to ensure maximum benefit. Patient summary: Early identification and proactive management are warranted to mitigate or possibly prevent erdafitinib side effects to allow for maximum drug benefit in patients with locally advanced or metastatic bladder cancer.

Safety and efficacy of avelumab plus carboplatin in patients with metastatic castration-resistant prostate cancer in an open-label Phase Ib study.

BACKGROUND: Single-agent PD-1/PD-L1 inhibitors have shown limited efficacy in unselected mCRPC. The evidence of a survival benefit with sipuleucel-T and ipilimumab, provides a rationale to study further increasing immunogenicity in mCRPC through combinations. METHODS: Safety and efficacy avelumab plus carboplatin was investigated in a single-arm Phase Ib study in mCRPC, progressing to at least one taxane and one androgen-receptor inhibitor. The primary endpoint was safety. Secondary endpoints included PSA/radiographic responses, progression-free survival (PFS) and overall survival (OS). Germline/somatic mutation analysis was performed. RESULTS: In total, 26 patients were included. Patients were heavily pretreated: 76.9% received ≥3 and 42.3% ≥4 prior lines. A DNA damage repair (DDR) alteration was found in three patients (11.5%). The safety profile was acceptable with 73% Grade 3-4 treatment-related adverse events. PSA response rate ≥50% was seen in 7.7% of patients. The objective response rate was 17.6%, including one complete response (5.9%). Two of these responders had a known DDR alteration (one BRCA2, one ATM). The median response duration was 6 months. Median radiographic PFS was 6.6 months (95% CI 4.28-9.01), and median OS 10.6 months (95% CI 6.68-NR). CONCLUSIONS: Avelumab plus carboplatin has an acceptable safety profile and was associated with a prolonged OS given the heavily pretreated population.

A Phase I Study of Capivasertib in Combination With Abiraterone Acetate in Patients With Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Although androgen receptor-targeted agents prolong the lives of patients with metastatic prostate cancer, patients develop therapy resistance and most ultimately succumb to the disease. The PI3K/AKT/PTEN pathway has been associated with the development of resistance, raising the possibility that pathway inhibitors may produce a clinical benefit. This open-label phase Ib study examined the safety, tolerability, pharmacokinetics (PK) and preliminary clinical activity of adding capivasertib - a potent, selective inhibitor of AKT1/2/3 - to approved abiraterone acetate therapy. METHODS: Twenty-seven patients with metastatic castration-resistant prostate cancer who had undergone at least 1 prior line of systemic therapy received abiraterone acetate 1000 mg (orally administered once daily), plus oral prednisone 5 mg (twice daily) with capivasertib 400 mg (orally, twice daily, with an intermittent schedule of 4 days on, 3 days off). RESULTS: No dose-limiting toxicity was observed. The most frequent adverse events (all grade) were diarrhea (30%), anemia (26%), asthenia (22%), and nausea (22%). The most frequent grade 3 or higher adverse events were acute kidney injury (19%), hyperglycemia (7%), rash (7%), abdominal pain (7%), and asthenia (7%). Capivasertib and abiraterone PK were consistent with previously reported results from monotherapy dosing. Nine participants (33%) showed a 20% or greater decrease in prostate-specific antigen during study treatment. CONCLUSION: The combination of capivasertib and abiraterone acetate had an acceptable tolerability profile consistent with the known profile of each agent. These data support further evaluation of capivasertib and abiraterone acetate in patients with advanced prostate cancer.

A correlative biomarker study and integrative prognostic model in chemotherapy-naïve metastatic castration-resistant prostate cancer treated with enzalutamide.

BACKGROUND: There is a considerable need to incorporate biomarkers of resistance to new antiandrogen agents in the management of castration-resistant prostate cancer (CRPC). METHODS: We conducted a phase II trial of enzalutamide in first-line chemo-naïve asymptomatic or minimally symptomatic mCRPC and analyzed the prognostic value of TMPRSS2-ERG and other biomarkers, including circulating tumor cells (CTCs), androgen receptor splice variant (AR-V7) in CTCs and plasma Androgen Receptor copy number gain (AR-gain). These biomarkers were correlated with treatment response and survival outcomes and developed a clinical-molecular prognostic model using penalized cox-proportional hazard model. This model was validated in an independent cohort. RESULTS: Ninety-eight patients were included. TMPRSS2-ERG fusion gene was detected in 32 patients with no differences observed in efficacy outcomes. CTC detection was associated with worse outcome and AR-V7 in CTCs was associated with increased rate of progression as best response. Plasma AR gain was strongly associated with an adverse outcome, with worse median prostate specific antigen (PSA)-PFS (4.2 vs. 14.7 m; p < 0.0001), rad-PFS (4.5 vs. 27.6 m; p < 0.0001), and OS (12.7 vs. 38.1 m; p < 0.0001). The clinical prognostic model developed in PREVAIL was validated (C-Index 0.70) and the addition of plasma AR (C-Index 0.79; p < 0.001) increased its prognostic ability. We generated a parsimonious model including alkaline phosphatase (ALP); PSA and AR gain (C-index 0.78) that was validated in an independent cohort. CONCLUSIONS: TMPRSS2-ERG detection did not correlate with differential activity of enzalutamide in first-line mCRPC. However, we observed that CTCs and plasma AR gain were the most relevant biomarkers.

Transcriptional Profile Associated with Clinical Outcomes in Metastatic Hormone-Sensitive Prostate Cancer Treated with Androgen Deprivation and Docetaxel.

(1) Background: Androgen deprivation therapy (ADT) and docetaxel (DX) combination is a standard therapy for metastatic hormone-sensitive prostate cancer (mHSPC) patients. (2) Methods: We investigate if tumor transcriptomic analysis predicts mHSPC evolution in a multicenter retrospective biomarker study. A customized panel of 184 genes was tested in mRNA from tumor samples by the nCounter platform in 125 mHSPC patients treated with ADT+DX. Gene expression was correlated with castration-resistant prostate cancer-free survival (CRPC-FS) and overall survival (OS). (3) Results: High expression of androgen receptor (AR) signature was independently associated with longer CRPC-FS (hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.3-0.9; p = 0.015), high expression of estrogen receptor (ESR) signature with longer CRPC-FS (HR 0.6, 95% CI 0.4-0.9; p = 0.019) and OS (HR 0.5, 95% CI 0.2-0.9, p = 0.024), and lower expression of tumor suppressor genes (TSG) (RB1, PTEN and TP53) with shorter OS (HR 2, 95% CI 1-3.8; p = 0.044). ARV7 expression was independently associated with shorter CRPC-FS (HR 1.5, 95% CI 1.1-2.1, p = 0.008) and OS (HR 1.8, 95% CI 1.2-2.6, p = 0.004), high ESR2 was associated with longer OS (HR 0.5, 95% CI 0.2-1, p = 0.048) and low expression of RB1 was independently associated with shorter OS (HR 1.9, 95% CI 1.1-3.2, p = 0.014). (4) Conclusions: AR, ESR, and TSG expression signatures, as well as ARV7, RB1, and ESR2 expression, have a prognostic value in mHSPC patients treated with ADT+DX.

Efficacy and Safety of Telaglenastat Plus Cabozantinib vs Placebo Plus Cabozantinib in Patients With Advanced Renal Cell Carcinoma: The CANTATA Randomized Clinical Trial.

Importance: Dysregulated metabolism is a hallmark of renal cell carcinoma (RCC). Glutaminase is a key enzyme that fuels tumor growth by converting glutamine to glutamate. Telaglenastat is an investigational, first-in-class, selective, oral glutaminase inhibitor that blocks glutamine utilization and downstream pathways. Preclinically, telaglenastat synergized with cabozantinib, a VEGFR2/MET/AXL inhibitor, in RCC models. Objective: To compare the efficacy and safety of telaglenastat plus cabozantinib (Tela + Cabo) vs placebo plus cabozantinib (Pbo + Cabo). Design, Setting, and Participants: CANTATA was a randomized, placebo-controlled, double-blind, pivotal trial conducted at sites in the US, Europe, Australia, and New Zealand. Eligible patients had metastatic clear-cell RCC following progression on 1 to 2 prior lines of therapy, including 1 or more antiangiogenic therapies or nivolumab plus ipilimumab. The data cutoff date was August 31, 2020. Data analysis was performed from December 2020 to February 2021. Interventions: Patients were randomized 1:1 to receive oral cabozantinib (60 mg daily) with either telaglenastat (800 mg twice daily) or placebo until disease progression or unacceptable toxicity. Main Outcomes and Measures: The primary end point was progression-free survival (Response Evaluation Criteria in Solid Tumors version 1.1) assessed by blinded independent radiology review. Results: A total of 444 patients were randomized: 221 to Tela + Cabo (median [range] age, 61 [21-81] years; 47 [21%] women and 174 [79%] men) and 223 to Pbo + Cabo (median [range] age, 62 [29-83] years; 68 [30%] women and 155 [70%] men). A total of 276 (62%) patients had received prior immune checkpoint inhibitors, including 128 with prior nivolumab plus ipilimumab, 93 of whom had not received prior antiangiogenic therapy. Median progression-free survival was 9.2 months for Tela + Cabo vs 9.3 months for Pbo + Cabo (HR, 0.94; 95% CI, 0.74-1.21; P = .65). Overall response rates were 31% (69 of 221) with Tela + Cabo vs 28% (62 of 223) with Pbo + Cabo. Treatment-emergent adverse event (TEAE) rates were similar between arms. Grade 3 to 4 TEAEs occurred in 160 patients (71%) with Tela + Cabo and 172 patients (79%) with Pbo + Cabo and included hypertension (38 patients [17%] vs 40 patients [18%]) and diarrhea (34 patients [15%] vs 29 patients [13%]). Cabozantinib was discontinued due to AEs in 23 patients (10%) receiving Tela + Cabo and 33 patients (15%) receiving Pbo + Cabo. Conclusions and Relevance: In this randomized clinical trial, telaglenastat did not improve the efficacy of cabozantinib in metastatic RCC. Tela + Cabo was well tolerated with AEs consistent with the known risks of both agents. Trial Registration: ClinicalTrials.gov Identifier: NCT03428217.

Radium-223 for patients with metastatic castration-resistant prostate cancer with asymptomatic bone metastases progressing on first-line abiraterone acetate or enzalutamide: A single-arm phase II trial.

PURPOSE: The paper aims to evaluate the efficacy and safety of 223Ra in patients who progressed after first-line androgen deprivation therapy. PATIENTS AND METHODS: EXCAAPE (NCT03002220) was a multicentre, single-arm, open-label, non-controlled phase IIa trial in 52 patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases who have progressed on abiraterone acetate or enzalutamide, up to six doses of 223Ra (55 kBq/kg of body weight per month). The primary end-point was radiographic progression-free survival (rPFS). Secondary end-points included rPFS based on androgen receptor splice variant 7 (AR-V7) expression in circulating tumour cells (CTCs), overall survival, and safety. RESULTS: Median rPFS was 5.5 months (95% CI 5.3-5.5). Median rPFS of patients with AR-V7(-) CTCs was longer than that of patients with AR-V7(+) CTCs (5.5 versus 2.2 months, respectively; P = 0.056). Median overall survival was 14.8 months (95% CI 11.2-not reached) and was significantly greater for AR-V7(-) patients than for AR-V7(+) patients (14.8 months versus 3.5 months, respectively; P < 0.01). 223Ra was well tolerated; anaemia and thrombocytopenia were the most common grade 3/4 adverse events (5.8% and 11.5%, respectively). CONCLUSIONS: 223Ra seems to be a reasonable treatment for patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases progressing on novel hormonal therapy and had an acceptable safety profile.

Molecular Biomarkers of Prognosis in Advanced Renal Cell Carcinoma Patients Treated With Pazopanib Plus Interferon Alpha (INF-2A) in a Phase I/II Study by the Spanish Oncology Genitourinary Group.

INTRODUCTION: The therapeutic repertoire available for advanced renal cell carcinoma (RCC), including tyrosine kinase inhibitors (TKIs) and immunotherapy, required for molecular biomarkers for response. PATIENTS AND METHODS: This was a phase I to II trial on the combination of pazopanib with interferon-alpha (INF-2A) as first-line treatment for advanced RCC. The primary endpoint was recommended phase II dose (RP2D) and efficacy in terms of objective response rate (ORR, RECIST 1.1 criteria). Secondary endpoints included safety and a translational study of molecular biomarkers in serum and exosomes from peripheral blood samples at three-time points: baseline, 8 weeks of treatment, and progression of the disease. RESULTS: Between July 2011 and July 2017, 53 eligible patients were treated and followed up (I, n = 20; II, n = 33). Pazopanib 800 mg + INF-2A 3 MIUs showed a manageable safety profile; therefore, it was selected for dose expansion. Overall, grade 3/4 toxicities were reported in 24 (72.7%) patients. The ORR was 27.2%. The 12-month OS rate was 83.6% (median not reached), and after 30.9 months of follow-up, 24 (72.7%) patients were still alive. CCL2, IL8, TNF-α, and PD-L1 were significantly overexpressed after treatment initiation, while TGF-ß1 and CCL5 were significantly decreased. TNF-α, endoglin, and PD-L1 expression are correlated with the response after treatment initiation. CONCLUSION: The trial did not reach its pre-specified target ORR. However, OS was longer than expected with pazopanib monotherapy. Changes in the molecular profile suggest a crucial role of vascular remodeling and inflammatory-mediated immune cell infiltration in optimal response to pazopanib plus INF-2A.

Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial.

Early clinical data indicate that some patients with castration-resistant prostate cancer may benefit from program death ligand-1 (PD-L1) inhibition, especially with enzalutamide. The IMbassador250 trial (no. NCT03016312) enrolled 759 men with metastatic castration-resistant prostate cancer whose disease progressed on abiraterone. The addition of atezolizumab to enzalutamide in an open-label randomized trial did not meet the primary endpoint of improved overall survival in unselected patients (stratified hazard ratio 1.12, 95% confidence interval (0.91, 1.37), P = 0.28), despite an acceptable safety profile. In archival tumor samples, prostate tumors showed comparatively low expression of key immune biomarkers. DNA damage-response alterations, phosphatase and tensin homolog status and PD-L1 expression levels were similar between hormone-sensitive and castration-resistant prostate cancers. In planned biomarker analysis, longer progression-free survival was seen with atezolizumab in patients with high PD-L1 IC2/3, CD8 expression and established immune gene signatures. Exploratory analysis linked progression-free survival in the atezolizumab arm with immune genes such as CXCL9 and TAP1, together with other potentially relevant biomarkers including phosphatase and tensin homolog alterations. Together these data indicate that the expected biology associated with response to immune checkpoint inhibitors is present in prostate cancer, albeit in fewer patients. Careful patient selection may be required for immune checkpoint inhibitors to identify subgroups of patients who may benefit from this treatment approach.

Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study.

BACKGROUND: Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was shown to be clinically active and tolerable in patients with advanced urothelial carcinoma and prespecified FGFR alterations in the primary analysis of the BLC2001 study at median 11 months of follow-up. We aimed to assess the long-term efficacy and safety of the selected regimen of erdafitinib determined in the initial part of the study. METHODS: The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America. Eligible patients were aged 18 years or older with locally advanced and unresectable or metastatic urothelial carcinoma, at least one prespecified FGFR alteration, an Eastern Cooperative Oncology Group performance status of 0-2, and progressive disease after receiving at least one systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were ineligible for cisplatin. The selected regimen determined in the initial part of the study was continuous once daily 8 mg/day oral erdafitinib in 28-day cycles, with provision for pharmacodynamically guided uptitration to 9 mg/day (8 mg/day UpT). The primary endpoint was investigator-assessed confirmed objective response rate according to Response Evaluation Criteria In Solid Tumors version 1.1. Efficacy and safety were analysed in all treated patients who received at least one dose of erdafitinib. This is the final analysis of this study. This study is registered with ClinicalTrials.gov, NCT02365597. FINDINGS: Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen. The data cutoff date for this analysis was Aug 9, 2019. Median efficacy follow-up was 24·0 months (IQR 22·7-26·6). The investigator-assessed objective response rate for patients treated with the selected erdafitinib regimen was 40 (40%; 95% CI 30-49) of 101 patients. The safety profile remained similar to that in the primary analysis, with no new safety signals reported with longer follow-up. Grade 3-4 treatment-emergent adverse events of any causality occurred in 72 (71%) of 101 patients. The most common grade 3-4 treatment-emergent adverse events of any cause were stomatitis (in 14 [14%] of 101 patients) and hyponatraemia (in 11 [11%]). There were no treatment-related deaths. INTERPRETATION: With longer follow-up, treatment with the selected regimen of erdafitinib showed consistent activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations. FUNDING: Janssen Research & Development.

Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma.

IMPORTANCE: Interim analyses of the IMmotion151 trial (A Study of Atezolizumab in Combination With Bevacizumab Versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma) reported improved progression-free survival (PFS) for patients with programmed death ligand 1-positive (PD-L1+) metastatic renal cell carcinoma (mRCC) receiving the PD-L1 inhibitor atezolizumab plus the vascular endothelial growth factor (VEGF) inhibitor bevacizumab vs the receptor tyrosine kinase inhibitor sunitinib. Overall survival (OS) results were immature at interim analyses. OBJECTIVE: To report the final OS results, safety, and exploratory biomarker analyses of the association of transcriptomic subgroups with OS in the IMmotion151 trial. DESIGN, SETTING, AND PARTICIPANTS: IMmotion151 was a multicenter, open-label, phase 3 randomized clinical trial that compared the efficacy and safety of atezolizumab plus bevacizumab vs sunitinib in patients with untreated mRCC. IMmotion151 included patients from 152 academic medical centers and community oncology practices in 21 countries. Adult patients with mRCC with components of clear cell or sarcomatoid histologic features, measurable disease (according to Response Evaluation Criteria in Solid Tumors, version 1.1), adequate performance status, hematologic and end organ function, and tumor tissue available for PD-L1 testing were included. IMmotion151 was initiated on May 20, 2015, and the study is ongoing. This final analysis was performed from May 20, 2015, to February 14, 2020. INTERVENTIONS: Receipt of 1200 mg of intravenous (IV) atezolizumab every 3 weeks and 15 mg/kg of IV bevacizumab every 3 weeks or 50 mg orally once daily of sunitinib (4 weeks on and 2 weeks off). MAIN OUTCOMES AND MEASURES: The coprimary end points were PFS (previously reported) in patients with PD-L1+ disease and OS in the intention-to-treat population. Additional exploratory outcomes included OS in the PD-L1+ population, association with transcriptomic subgroups, and safety. RESULTS: The IMmotion151 trial assessed 915 patients with metastatic renal cell carcinoma. Mean (IQR) age was 62 (56-69) years for patients receiving atezolizumab plus bevacizumab and 60 (54-66) years for patients receiving sunitinib; 669 (73.1%) were male and 246 (26.9%) were female. The final analysis showed similar median OS in patients receiving atezolizumab plus bevacizumab vs sunitinib in the intention-to-treat (36.1 vs 35.3 months) and PD-L1+ (38.7 vs 31.6 months) populations. No new safety signals were reported. The additional exploratory outcome of atezolizumab plus bevacizumab vs sunitinib showed improved median OS trends in patients whose tumors were characterized by T-effector/proliferative, proliferative, or small nucleolar RNA transcriptomic profiles (35.4 vs 21.2 months; hazard ratio, 0.70; 95% CI, 0.50-0.98). CONCLUSIONS AND RELEVANCE: The primary end point of PFS was met at interim analyses, although no improvement in OS was observed with atezolizumab plus bevacizumab at the final analysis. Biomarker analyses provided insight into which patients with mRCC may benefit from combined anti-PD-L1 and anti-VEGF therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02420821.