Treatment-free survival outcomes from the phase II study of nivolumab and salvage nivolumab/ipilimumab in advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A).

BACKGROUND: As part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both with and without toxicity. Significant TFS was reported for the nivolumab/ipilimumab arms of the CheckMate 067 and 214 trials for patients with advanced melanoma or renal cell carcinoma (aRCC), respectively, where immunotherapy was often halted for toxicity rather than a predefined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16-260 trial, which was designed to reduce toxicity and cap immunotherapy duration. METHODS: Data were analyzed from 128 patients with clear-cell aRCC treated with first-line nivolumab monotherapy for up to 2 years. Salvage nivolumab/ipilimumab for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (29% of patients). TFS was defined as the area between Kaplan-Meier curves for a time from registration to protocol therapy cessation and for a time from registration to subsequent systemic therapy initiation or death, estimated from 36-month mean times. The time on or off protocol treatment with grade 3+treatment-related adverse events (TRAEs) was also captured. RESULTS: At 36 months from enrollment, 68.3% of patients were alive: 96.8% of International Metastatic RCC Database Consortium (IMDC) favorable-risk patients and 56.6% of those with intermediate/poor-risk, respectively. The 36-month mean time on protocol therapy was 11.5 months including 0.6 months with grade 3+TRAEs (16.0 months for favorable-risk patients and 9.6 months for intermediated/poor-risk patients). The 36-month mean TFS for the whole population was 9.4 months (12.9 months including 1.5 months with grade 3+TRAEs for favorable-risk and 8.0 months including 1.0 months with grade 3+TRAEs for intermediate/poor-risk). At 36 months, 65.6% of favorable-risk patients and 27.1% of intermediate/poor-risk patients were alive and subsequent systemic treatment-free. CONCLUSIONS: Nivolumab monotherapy with salvage nivolumab/ipilimumab in non-responders is an active treatment approach in treatment-naïve patients with aRCC and, similar to nivolumab/ipilimumab in CheckMate 214, results in substantial TFS and toxicity-free TFS. TFS was greatest in patients with favorable-risk disease, supporting the use of an immunotherapy-only regimen in this population.

Natural Killer Cell Infiltration in Prostate Cancers Predict Improved Patient Outcomes.

BACKGROUND: Natural killer (NK) cells are non-antigen specific innate immune cells that can be redirected to targets of interest using multiple strategies, although none are currently FDA-approved. We sought to evaluate NK cell infiltration into tumors to develop an improved understanding of which histologies may be most amenable to NK cell-based therapies currently in the developmental pipeline. METHODS: DNA (targeted/whole-exome) and RNA (whole-transcriptome) sequencing was performed from tumors from 45 cancer types (N = 90,916 for all cancers and N = 3365 for prostate cancer) submitted to Caris Life Sciences. NK cell fractions and immune deconvolution were inferred from RNA-seq data using quanTIseq. Real-world overall survival (OS) and treatment status was determined and Kaplan-Meier estimates were calculated. Statistical significance was determined using X2 and Mann-Whitney U tests, with corrections for multiple comparisons where appropriate. RESULTS: In both a pan-tumor and prostate cancer (PCa) -specific setting, we demonstrated that NK cells represent a substantial proportion of the total cellular infiltrate (median range 2-9% for all tumors). Higher NK cell infiltration was associated with improved OS in 28 of 45 cancer types, including (PCa). NK cell infiltration was negatively correlated with common driver mutations and androgen receptor variants (AR-V7) in primary prostate biopsies, while positively correlated with negative immune regulators. Higher levels of NK cell infiltration were associated with patterns consistent with a compensatory anti-inflammatory response. CONCLUSIONS: Using the largest available dataset to date, we demonstrated that NK cells infiltrate a broad range of tumors, including both primary and metastatic PCa. NK cell infiltration is associated with improved PCa patient outcomes. This study demonstrates that NK cells are capable of trafficking to both primary and metastatic PCa and are a viable option for immunotherapy approaches moving forward. Future development of strategies to enhance tumor-infiltrating NK cell-mediated cytolytic activity and activation while limiting inhibitory pathways will be key.

The GLP-1 receptor is expressed in vivo by human metastatic prostate cancer.

Objectives: The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, reduces human prostate cancer incidence, and similar GLP-1 receptor agonists reduce in vitro proliferation and in vivo growth of prostate cancer cell lines. Primary human prostate cancer expresses the GLP-1 receptor (GLP-1R) in vitro. Cancer evolves with stage, and whether advanced-stage human prostate cancer expresses GLP-1R is unknown. We hypothesised and aimed to prove that human metastatic castrate-resistant prostate cancer (mCRPC) expresses the GLP-1R in vivo. We hypothesised that mCRPC would thus be detectable by positron emission tomography/computed tomography (PET/CT) using a radiotracer bound to a GLP-1R ligand, as in exendin PET/CT. Materials and methods: Men with mCRPC, with more than one prostate-specific membrane antigen (PSMA)-avid lesion on PET/CT scanning (pathognomic in that setting for prostate cancer lesions), were approached to undergo PET/CT with gallium68-Dota-exendin-4. We documented PET/CT PSMA-avid lesions, which were also PET/CT exendin avid, as evidence of in vivo GLP-1R expression. Results: Out of the 24 men referred, three did not meet the inclusion criteria. Seventeen declined, largely because the study offered them no therapeutic benefit. Among the four men imaged, three had no exendin-avid lesions, while one had six osseous PSMA-avid lesions, three of which were also exendin avid. Conclusions: We demonstrated in vivo GLP-1R expression by human mCPRC, detecting PET/CT lesions avid for both PSMA and exendin, in one of four participants. GLP-1R expression may thus occur even in advanced-stage prostate cancer. Our data contribute to growing evidence supporting the testing of GLP-1 receptor agonists for therapeutic benefit in prostate cancer.

Anti-PD-1 immunotherapy with androgen deprivation therapy induces robust immune infiltration in metastatic castration-sensitive prostate cancer.

When compared to other malignancies, the tumor microenvironment (TME) of primary and castration-resistant prostate cancer (CRPC) is relatively devoid of immune infiltrates. While androgen deprivation therapy (ADT) induces a complex immune infiltrate in localized prostate cancer, the composition of the TME in metastatic castration-sensitive prostate cancer (mCSPC), and the effects of ADT and other treatments in this context are poorly understood. Here, we perform a comprehensive single-cell RNA sequencing (scRNA-seq) profiling of metastatic sites from patients participating in a phase 2 clinical trial (NCT03951831) that evaluated standard-of-care chemo-hormonal therapy combined with anti-PD-1 immunotherapy. We perform a longitudinal, protein activity-based analysis of TME subpopulations, revealing immune subpopulations conserved across multiple metastatic sites. We also observe dynamic changes in these immune subpopulations in response to treatment and a correlation with clinical outcomes. Our study uncovers a therapy-resistant, transcriptionally distinct tumor subpopulation that expands in cell number in treatment-refractory patients.

Adjuvant everolimus after surgery for renal cell carcinoma (EVEREST): a double-blind, placebo-controlled, randomised, phase 3 trial.

BACKGROUND: Patients undergoing resection of renal cell carcinoma are at risk of disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin inhibitor everolimus administered after surgery. METHODS: In this randomised, double-blind, phase 3 trial, we enrolled adults with histologically confirmed renal cell carcinoma who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence at 398 academic and community institution centres in the USA. After nephrectomy, patients were randomly assigned (1:1) via a central web-based application using a dynamic balancing algorithm to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival. Efficacy analyses included all eligible, randomly assigned patients; safety analysis included all patients who received treatment. This trial is registered with ClinicalTrials.gov, NCT01120249 and is closed to new participants. FINDINGS: Between April 1, 2011, and Sept 15, 2016, a total of 1545 patients were randomly assigned to receive everolimus (n=775) or placebo (n=770), of whom 755 assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months (IQR 61-92), recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% [95% CI 63-70] vs 63% [60-67]; stratified log-rank p=0·050; stratified hazard ratio [HR] 0·85, 95% CI 0·72-1·00; p=0·051) but did not meet the prespecified p value for statistical significance of 0·044. Recurrence-free survival was longer with everolimus than with placebo in the very-high-risk group (HR 0·79, 95% CI 0·65-0·97; p=0·022) but not in the intermediate-high-risk group (0·99, 0·73-1·35; p=0·96). Grade 3 or higher adverse events occurred in 343 (46%) of 740 patients who received everolimus and 79 (11%) of 723 who received placebo. INTERPRETATION: Postoperative everolimus did not improve recurrence-free survival compared with placebo among patients with renal cell carcinoma at high risk of recurrence after nephrectomy. These results do not support the adjuvant use of everolimus for renal cell carcinoma after surgery. FUNDING: US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation.

Flutamide With or Without PROSTVAC in Non-metastatic Castration Resistant (M0) Prostate Cancer.

BACKGROUND: Before 2018, there was no standard of care for non-metastatic (M0) castration resistant prostate cancer nmCRPC. Androgen receptor antagonists (ARAs) were commonly used sequentially nmCRPC. METHODS: This was a multicenter, randomized clinical trial comparing the ARA flutamide+/-PROSTVAC, a pox viral vaccine targeting PSA that includes T-cell co-stimulatory molecules. Eligible men had negative CT and Tc99 bone scans, and rising PSA on ADT. Previous treatment with ARA was a stratification factor. Patients were also evaluated for antigen-specific immune responses using intracellular cytokine staining. RESULTS: Thirty-three patients randomized to flutamide and 31 to flutamide+vaccine. The median age was 71.8 and 69.8 years, respectively. The median time to treatment failure after a median potential follow-up of 46.7 months was, 4.5 months (range 2-70) for flutamide alone vs. 6.9 months (2.5-40; P = .38) with flutamide+vaccine. Seven patients in each arm had a >50% PSA response. Antigen-specific responses were similar in both arms (58% of patients in flutamide alone and 56% in flutamide+vaccine). The treatments were well tolerated. The most common side effect > grade 2 was injection site reaction seen in 29/31 vaccine patients which were self-limiting. CONCLUSION: The combination of flutamide+PROSTVAC did not improve outcomes in men with nmCRPC compared with flutamide alone. (ClinicalTrials.gov Identifier: NCT00450463).

A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850.

BACKGROUND: Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. This phase I trial identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers. PATIENTS AND METHODS: Patients with refractory solid tumors were enrolled utilizing a 3+3 dose-escalation design. Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles. Restaging evaluations were performed every 2 cycles. RESULTS: 35 patients were enrolled over 4 dose levels. The MTD was declared at dose level 3 (riluzole: 100 mg PO BID; sorafenib: 400 mg AM/200 mg PM). Pharmacokinetic analyses did not reveal definitive evidence of drug-drug interactions. Consistent decreases in phospho-forms of ERK and AKT in tumor tissue analyses with accompanying decrease in GRM1 expression and increase in pro-apoptotic BIM suggest target engagement by the combination. Best responses included a partial response in 1 (2.9%) patient with pancreatic acinar cell carcinoma with a KANK4-RAF1 fusion, and stable disease in 11 (36%) patients. CONCLUSION: Combination therapy with riluzole and sorafenib was safe and tolerable in patients with advanced solid tumors. The partial response in a patient with a RAF1 fusion suggests that further exploration in a genomically selected cohort may be warranted.

Phase II study of nivolumab and salvage nivolumab/ipilimumab in treatment-naïve patients with advanced non-clear cell renal cell carcinoma (HCRN GU16-260-Cohort B).

BACKGROUND: To determine the efficacy and toxicity of nivolumab monotherapy in treatment-naïve patients with non-clear cell renal cell carcinoma (nccRCC) and the efficacy of nivolumab/ipilimumab salvage therapy in patients with tumors unresponsive to initial nivolumab monotherapy. METHODS: Eligible patients with treatment-naïve nccRCC received nivolumab until progressive disease (PD), toxicity, or completion of 96 weeks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 weeks (prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B). Patients were required to submit tissue from a metastatic lesion obtained within 12 months prior to study entry and prior to Part B for correlative studies. RESULTS: 35 patients with nccRCC were enrolled: 19 (54%) had papillary, 6 (17%) had chromophobe and 10 (29%) had unclassified histology. At median follow-up of 22.9 months, RECIST-defined objective response rate (ORR) was 5 of 35 (14.3% 95% CI 4.8% to 30.3%) (complete response (CR) 2 (5.7%) and partial response (PR) 3 (8.6%)). ORR by histology was: papillary-1/19 (5%); chromophobe-1/6 (17%); and unclassified-3/10 (30%). Nine patients (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified and 1 papillary) responding. ORR was 0/18, 3/11 (27%) and 2/6 (33%) for patients with tumor progammed death ligand 1 (PD-L1) expression of <5%, ≥5% or not measured, respectively. Median progression-free survival was 4.0 (2.7-4.3) months. Two of five responders have progressed. Thirty-two patients had PD or prolonged SD and therefore, were potentially eligible for salvage nivolumab/ipilimumab (Part B), but 15 patients did not enroll due to grade 2-3 toxicity (6) on nivolumab, symptomatic disease progression (5), or other reasons including no biopsy tissue (4). In the 17 Part B patients, there was one PR (6%) (unclassified/non-sarcomatoid). Grade >3 treatment-related adverse events were seen in 7/35 (20%) on nivolumab and 7/17 (41%) on salvage nivolumab/ipilimumab with one patient experiencing sudden death. CONCLUSIONS: Nivolumab monotherapy has limited activity in treatment-naïve nccRCC with most responses (4 of 5) seen in patients with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivolumab studies. Salvage treatment with nivolumab/ipilimumab was provided in half of these patients with minimal activity. TRIAL REGISTRATION NUMBER: NCT03117309.

Concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with localized urothelial cancer of bladder: results from phase II study, BTCRC-GU15-023.

BACKGROUND: Patients with bladder cancer (BC) who are cisplatin ineligible or have unresectable disease have limited treatment options. Previously, we showed targeting programmed death-ligand 1 (PD-L1) with durvalumab (durva) and radiation therapy (RT) combination was safe in BC. We now report results from a phase II study evaluating the toxicity and efficacy of durva and RT in localized BC. METHODS: This is a single-arm, multi-institutional phase II study; N=26. Enrolled patients had pure or mixed urothelial BC (T2-4 N0-2 M0) with unresectable tumors and were unfit for surgery or cisplatin ineligible. Patients received durva concurrently with RT ×7 weeks, followed by adjuvant durva × 1 year. PRIMARY ENDPOINTS: (A) progression-free survival (PFS) at 1 year and (B) disease control rate (DCR) post adjuvant durva. Key secondary endpoints: (A) complete response (CR) post durvaRT (8 weeks), (B) overall survival (OS), (C) PFS and (D) toxicity. Correlative studies included evaluation of baseline tumor and blood (baseline, post durvaRT) for biomarkers. RESULTS: Median follow-up was 27 months. Evaluable patients: 24/26 post durvaRT, 22/26 for DCR post adjuvant durva, all patients for PFS and OS. Post adjuvant durva, DCR was seen in 72.7%, CR of 54.5%. 1-year PFS was 71.5%, median PFS was 21.8 months. 1-year OS was 83.8%, median OS was 30.8 months. CR at 8 weeks post durvaRT was 62.5%. Node positive (N+) patients had similar median PFS and OS. DurvaRT was well tolerated. Grade ≥3 treatment-related adverse events: anemia, high lipase/amylase, immune-nephritis, transaminitis, dyspnea (grade 4-COPD/immune), fatigue, rash, diarrhea and scleritis. No difference in outcome was observed with PD-L1 status of baseline tumor. Patients with CR/PR or SD had an increase in naïve CD4 T cells, a decrease in PD-1+CD4 T cells at baseline and an increase in cytokine-producing CD8 T cells, including interferon gamma (IFNγ) producing cells, in the peripheral blood. CONCLUSION: Durva with RT followed by adjuvant durva was safe with promising efficacy in localized BC patients with comorbidities, including N+ patients. Larger randomized studies, like S1806 and EA8185, are needed to evaluate the efficacy of combining immunotherapy and RT in BC. TRIAL REGISTRATION NUMBER: NCT02891161.

Phase II Study of Nivolumab and Salvage Nivolumab/Ipilimumab in Treatment-Naive Patients With Advanced Clear Cell Renal Cell Carcinoma (HCRN GU16-260-Cohort A).

PURPOSE: To determine the value of tumor cell programmed death-ligand 1 (PD-L1) expression as a predictive biomarker of nivolumab monotherapy efficacy in treatment-naive patients with clear cell renal cell carcinoma (ccRCC) and the efficacy of salvage nivolumab/ipilimumab in patients with tumors unresponsive to nivolumab monotherapy. METHODS: Eligible patients with treatment-naive ccRCC received nivolumab until progressive disease (PD), toxicity, or completing 96 treatment weeks (part A). Patients with PD before or stable disease at 48 weeks could receive salvage nivolumab/ipilimumab (part B). The primary end point was improvement in 1-year progression-free survival in patients with tumor PD-L1 expression > 20% versus 0%. RESULTS: One hundred twenty-three patients were enrolled. The objective response rate (ORR) was 34.1% (95% CI, 25.8 to 43.2). ORR by International Metastatic RCC Database Consortium category was favorable-risk 57.1%, intermediate-risk/poor-risk 25.0%, and by sarcomatoid features 36.4%. The ORR was 26.9%, 50.0%, and 75.0% for patients with the tumor PD-L1 expression of 0, 1-20, or > 20%, respectively (trend test P value = .002). The median duration of response was 27.6 (19.3 to not reached) months, with 26 of 42 responders including 17 of 20 with favorable-risk disease remaining progression-free. The 1-year progression-free survival was 34.6% and 75.0% in the PD-L1 = 0% and > 20% categories, respectively (P = .050). Ninety-seven patients with PD or prolonged stable disease were potentially eligible for part B, and 35 were enrolled. The ORR for part B was 11.4%. Grade ≥ 3 treatment-related adverse events occurred in 35% of patients on nivolumab and 43% of those on salvage nivolumab/ipilimumab. CONCLUSION: Nivolumab monotherapy is active in treatment-naive ccRCC. Although efficacy appears to be less than that of nivolumab/ipilimumab in patients with intermediate-risk/poor-risk disease, favorable-risk patients had notable benefit. Efficacy correlated with tumor PD-L1 status. Salvage nivolumab/ipilimumab was frequently not feasible and of limited benefit.

ADXS31142 Immunotherapy ± Pembrolizumab Treatment for Metastatic Castration-Resistant Prostate Cancer: Open-Label Phase I/II KEYNOTE-046 Study.

BACKGROUND: ADXS31-142 is an attenuated Listeria monocytogenes-based immunotherapy targeting prostate-specific antigen (PSA), being evaluated as monotherapy and combined with pembrolizumab for metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: The 2-part phase I/II KEYNOTE-046 study enrolled men with mCRPC who have progressed after 2 or fewer prior systemic treatment regimens in the metastatic setting. In Part A, intravenous ADXS31-142 monotherapy was given every 3 weeks (q3w) to 3 dose-escalation cohorts. In Part B, ADXS31-142 (1 × 109 colony-forming units) plus pembrolizumab (200 mg) was administered intravenously q3w for 3 doses with a fourth pembrolizumab dose 3 weeks later (12-week cycles) for up to 24 months or until progression/toxicity. Endpoints included safety, overall response rate, progression-free survival (PFS), overall survival (OS), and immunogenicity. RESULTS: Fifty patients received ADXS31-142 alone (n = 13) or with pembrolizumab (n = 37). Among the 37 RECIST-evaluable patients (n = 8 Part A; n = 29 Part B), there were no objective responses. Median PFS was 2.2 months (95% CI: 0.8-7.4) with monotherapy and 5.4 months (95% CI: 2.3-7.9) with the combination; median OS was 7.8 months (95% CI: 4.4-18.5) and 33.7 months (95% CI: 15.4-not evaluable), respectively. Promising OS benefit was observed in combination-treated patients who had received prior docetaxel (16.0 months, 95% CI: 6.4-34.6; n = 20) and those with visceral metastasis (16.4 months, 95% CI 4.0-not evaluable; n = 11). All patients had ≥1 treatment-related adverse event, mostly grade 1/2 manageable events. No additive toxicity was observed with combination treatment. CONCLUSIONS: Combining ADXS31-142 with pembrolizumab was safe and well tolerated. The observed OS in mCRPC warrants further testing of this combination. CLINICAL TRIAL REGISTRATION: NCT02325557.

A phase I study of veliparib with cyclophosphamide and veliparib combined with doxorubicin and cyclophosphamide in advanced malignancies.

PURPOSE: Veliparib (V), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, potentiates effects of alkylating agents and topoisomerase inhibitors in preclinical tumor models. We conducted a phase I trial of V with iv cyclophosphamide (C) and V plus iv doxorubicin (A) and C. METHODS: Objectives were to establish the maximum tolerated dose (MTD) of the combinations, characterize V pharmacokinetics (PK) in the presence and absence of C, measure PAR in peripheral blood mononuclear cells (PBMCs) and γH2AX in circulating tumor cells (CTCs). In Group 1, dose escalations of V from 10 to 50 mg every 12 h Days 1-4 plus C 450 to 750 mg/m2 Day 3 in 21-day cycles were evaluated. In Group 2, V doses ranged from 50 to 150 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 in 21-day cycles. In Group 3, patients received AC Day 1 plus V Days 1-7, and in Group 4, AC Day 1 plus V Days 1-14 was given in 21-day cycles to evaluate effects on γH2AX foci. RESULTS: Eighty patients were enrolled. MTD was not reached for V and C. MTD for V and AC was V 100 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 every 21 days. V PK appears to be dose-dependent and has no effect on the PK of C. Overall, neutropenia and anemia were the most common adverse events. Objective response in V and AC treated groups was 22% (11/49). Overall clinical benefit rate was 31% (25/80). PAR decreased in PBMCs. Percentage of γH2AX-positive CTCs increased after treatment with V and AC. CONCLUSION: V and AC can be safely combined. Activity was observed in patients with metastatic breast cancer.

Randomized Phase 2 Trial of Abiraterone Acetate Plus Prednisone, Degarelix, or the Combination in Men with Biochemically Recurrent Prostate Cancer After Radical Prostatectomy.

BACKGROUND: Phase 2 trial endpoints that can be utilized in high-risk biochemical recurrence (BCR) after prostatectomy as a way of more rapidly identifying treatments for phase 3 trials are urgently needed. The efficacy of abiraterone acetate plus prednisone (AAP) in BCR is unknown. OBJECTIVE: To compare the rates of complete biochemical responses after testosterone recovery after 8 mo of AAP and degarelix, a gonadotropin-releasing hormone antagonist, alone or in combination. DESIGN SETTING AND PARTICIPANTS: Patients with BCR (prostate-specific antigen [PSA] ≥1.0 ng/ml, PSA doubling time ≤9 mo, no metastases on standard imaging, and testosterone ≥150 ng/dl) after prostatectomy (with or without prior radiotherapy) were included in this study. INTERVENTION: Patients were randomized to AAP (arm 1), AAP with degarelix (arm 2), or degarelix (arm 3) for 8 mo, and monitored for 18 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was undetectable PSA with testosterone >150 ng/dl at 18 mo. Secondary endpoints were undetectable PSA at 8 mo and time to testosterone recovery. RESULTS AND LIMITATIONS: For the 122 patients enrolled, no difference was found between treatments for the primary endpoint (arm 1: 5.1% [95% confidence interval {CI}: 1-17%], arm 2: 17.1% [95% CI: 7-32%], arm 3: 11.9% [95% CI: 4-26%]; arm 1 vs 2, p = 0.93; arm 2 vs 3, p = 0.36). AAP therapy showed the shortest median time to testosterone recovery (36.0 wk [95% CI: 35.9-36.1]) relative to degarelix (52.9 wk [95% CI: 49.0-56.0], p < 0.001). Rates of undetectable PSA at 8 mo differed between AAP with degarelix and degarelix alone (p = 0.04), but not between AAP alone and degarelix alone (p = 0.12). Limitations of this study include a lack of long-term follow-up. CONCLUSIONS: Rates of undetectable PSA levels with testosterone recovery were similar between arms, suggesting that increased androgen suppression with AAP and androgen deprivation therapy (ADT) is unlikely to eradicate recurrent disease compared with ADT alone. PATIENT SUMMARY: We evaluated the use of abiraterone acetate plus prednisone (AAP) and androgen deprivation therapy (ADT), AAP alone, or ADT alone in men with biochemically recurrent, nonmetastatic prostate cancer. While more men who received the combination had an undetectable prostate-specific antigen (PSA) level at 8 mo on treatment, once men came off treatment and testosterone level rose, there was no difference in the rates of undetectable PSA levels. This suggests that the combination is not able to eradicate disease any better than ADT alone.

Overcoming Immune Resistance in Prostate Cancer: Challenges and Advances.

The use of immunotherapy has become a critical treatment modality in many advanced cancers. However, immunotherapy in prostate cancer has not been met with similar success. Multiple interrelated mechanisms, such as low tumor mutational burden, immunosuppressive cells, and impaired cellular immunity, appear to subvert the immune system, creating an immunosuppressive tumor microenvironment and leading to lower treatment efficacy in advanced prostate cancer. The lethality of metastatic castrate-resistant prostate cancer is driven by the lack of therapeutic regimens capable of generating durable responses. Multiple strategies are currently being tested to overcome immune resistance including combining various classes of treatment modalities. Several completed and ongoing trials have shown that combining vaccines or checkpoint inhibitors with hormonal therapy, radiotherapy, antibody-drug conjugates, chimeric antigen receptor T cell therapy, or chemotherapy may enhance immune responses and induce long-lasting clinical responses without significant toxicity. Here, we review the current state of immunotherapy for prostate cancer, as well as tumor-specific mechanisms underlying therapeutic resistance, with a comprehensive look at the current preclinical and clinical immunotherapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and impaired cellular immunity that have largely limited the utility of immunotherapy in advanced prostate cancer.

Marginal improvement in survival among patients diagnosed with metastatic prostate cancer in the second-line antiandrogen therapy era.

Since 2004, multiple blockbuster drugs have been approved for men with metastatic prostate cancer. Nevertheless, it has been reported that no improvement in survival was observed between 2004 and 2009. Herein, we have analyzed the SEER database to assess the survival outcome of metastatic prostate cancer patients since 2000. The results demonstrated that there was an improvement in both overall and prostate cancer-specific survival for 4 months among men diagnosed with metastatic prostate cancer from 2010 to 2016 when compared to those in the pre-2010 period. Interestingly, this survival benefit was limited to patients with bone and visceral metastasis (M1b and M1c stages). Collectively, our observation suggests that despite the new treatment agents such as second-line antiandrogen therapies introduced in the modern era, the improvement in survival of metastatic prostate cancer patients has been surprisingly small.

Telemedicine in management of genitourinary malignancies: Patient and physician perspectives.

PURPOSE: The rapid expansion of telemedicine has presented a challenge for the care of patients with genitourinary malignancies. We sought to assess patient and physician perspectives on the use of telemedicine for genitourinary cancer care. METHODS: We conducted a prospective cross-sectional study of patients who had telemedicine visits with urology, medical oncology, or radiation oncology for management of genitourinary malignancies from July-August 2020. Patients and physicians each received a questionnaire regarding the telemedicine experience. Responses were scored on a 5-point Likert scale. The primary outcomes of the study were patient and physician satisfaction. RESULTS: Of the 115 patients who enrolled, we received 96 patient responses and 46 physician responses. Overall, 77% of patients and 70% of physicians reported being "extremely satisfied" with the telemedicine encounter. Satisfaction was high among all components of the encounter including patient-physician communication, counseling, shared decision making, time spent, timeliness and efficiency, and convenience. Additionally, 78% of patients and 85% of physicians "strongly agreed" that they were able to discuss sensitive topics about cancer care as well as they could at an in-person visit. Nine telemedicine visits (9%) encountered technological barriers. Technological barriers were associated with lower overall satisfaction scores among both patients and physicians (p ≤ 0.01). CONCLUSION: We observed high levels of patient and physician satisfaction for telemedicine visits for management of genitourinary malignancies. Technological barriers were encountered by 9% of patients and were associated with decreased satisfaction.

Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV­201): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Locally advanced or metastatic urothelial carcinoma is generally incurable and has scarce treatment options, especially for cisplatin-ineligible patients previously treated with PD-1 or PD-L1 therapy. Enfortumab vedotin is an antibody-drug conjugate directed at Nectin-4, a protein highly expressed in urothelial carcinoma. We aimed to evaluate the efficacy and safety of enfortumab vedotin in the post-immunotherapy setting in cisplatin-ineligible patients. METHODS: EV-201 is a multicentre, single-arm, phase 2 study of enfortumab vedotin in patients with locally advanced or metastatic urothelial carcinoma previously treated with PD-1 or PD-L1 inhibitors. Cohort 2 included adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status score of 2 or less who were considered ineligible for cisplatin at enrolment and who had not received platinum-containing chemotherapy in the locally advanced or metastatic setting. Enfortumab vedotin was given intravenously at a dose of 1·25 mg/kg on days 1, 8, and 15 of every 28-day cycle. The primary endpoint was confirmed objective response rate per Response Evaluation Criteria in Solid Tumours version 1.1 assessed by blinded independent central review. Efficacy and safety were analysed in all patients who received at least one dose of enfortumab vedotin. EV-201 is an ongoing study and the primary analysis is complete. This study is registered with Clinicaltrials.gov, NCT03219333. FINDINGS: Between Oct 8, 2017, and Feb 11, 2020, 91 patients were enrolled at 40 sites globally, of whom 89 received treatment. Median follow-up was 13·4 months (IQR 11·3-18·9). At data cutoff (Sept 8, 2020), the confirmed objective response rate was 52% (46 of 89 patients; 95% CI 41-62), with 18 (20%) of 89 patients achieving a complete response and 28 (31%) achieving a partial response. 49 (55%) of 89 patients had grade 3 or worse treatment-related adverse events. The most common grade 3 or 4 treatment-related adverse events were neutropenia (eight [9%] patients), maculopapular rash (seven [8%] patients), and fatigue (six [7%] patients). Treatment-related serious adverse events occurred in 15 (17%) patients. Three (3%) patients died due to acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndrome (one [1%] each) within 30 days of first dose and these deaths were considered by the investigator to be related to treatment; a fourth death from pneumonitis occurred more than 30 days after the last dose and was also considered to be related to treatment. INTERPRETATION: Treatment with enfortumab vedotin was tolerable and confirmed responses were seen in 52% of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma who were previously treated with PD-1 or PD-L1 inhibitors. These patients have few treatment options, and enfortumab vedotin could be a promising new therapy for a patient population with a high unmet need. FUNDING: Astellas Pharma Global Development and Seagen.

A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial.

BACKGROUND: MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC. METHODS: We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057. FINDINGS: Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6-12) than in the sunitinib group (5·6 months, 3-7; hazard ratio for progression or death 0·60, 0·37-0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group. INTERPRETATION: Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC. FUNDING: National Institutes of Health and National Cancer Institute.

TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer.

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

An Empirical Antigen Selection Method Identifies Neoantigens That Either Elicit Broad Antitumor T-cell Responses or Drive Tumor Growth.

Neoantigens are critical targets of antitumor T-cell responses. The ATLAS bioassay was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in Escherichia coli, pulsing autologous dendritic cells in an ordered array, and testing the patient's T cells for recognition in an overnight assay. Profiling of T cells from patients with lung cancer revealed both stimulatory and inhibitory responses to individual neoantigens. In the murine B16F10 melanoma model, therapeutic immunization with ATLAS-identified stimulatory neoantigens protected animals, whereas immunization with peptides associated with inhibitory ATLAS responses resulted in accelerated tumor growth and abolished efficacy of an otherwise protective vaccine. A planned interim analysis of a clinical study testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified stimulatory neoantigens showed that it is well tolerated. In an adjuvant setting, immunized patients generated both CD4+ and CD8+ T-cell responses, with immune responses to 99% of the vaccinated peptide antigens. SIGNIFICANCE: Predicting neoantigens in silico has progressed, but empirical testing shows that T-cell responses are more nuanced than straightforward MHC antigen recognition. The ATLAS bioassay screens tumor mutations to uncover preexisting, patient-relevant neoantigen T-cell responses and reveals a new class of putatively deleterious responses that could affect cancer immunotherapy design.This article is highlighted in the In This Issue feature, p. 521.