177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial.

BACKGROUND: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolongs radiographic progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer previously treated with androgen receptor pathway inhibitor (ARPI) and taxane therapy. We aimed to investigate the efficacy of 177Lu-PSMA-617 in patients with taxane-naive metastatic castration-resistant prostate cancer. METHODS: In this phase 3, randomised, controlled trial conducted at 74 sites across Europe and North America, taxane-naive patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer who had progressed once on a previous ARPI were randomly allocated (1:1) to open-label, intravenous 177Lu-PSMA-617 at a dosage of 7·4 GBq (200 mCi) ± 10% once every 6 weeks for six cycles, or a change of ARPI (to abiraterone or enzalutamide, administered orally on a continuous basis per product labelling). Crossover from ARPI change to 177Lu-PSMA-617 was allowed after centrally confirmed radiographic progression. The primary endpoint was radiographic progression-free survival, defined as the time from randomisation until radiographic progression or death, assessed in the intention-to-treat population. Safety was a secondary endpoint. This study is registered with ClinicalTrials.gov (NCT04689828) and is ongoing. In this primary report of the study, we present primary (first data cutoff) and updated (third data cutoff) analyses of radiographic progression-free survival; all other data are based on the third data cutoff. FINDINGS: Overall, of the 585 patients screened, 468 met all eligibility criteria and were randomly allocated between June 15, 2021 and Oct 7, 2022 to receive 177Lu-PSMA-617 (234 [50%] patients) or ARPI change (234 [50%]). Baseline characteristics were mostly similar between groups; median number of 177Lu-PSMA-617 cycles was 6·0 (IQR 4·0-6·0). Of patients assigned to ARPI change, 134 (57%) crossed over to receive 177Lu-PSMA-617. In the primary analysis (median time from randomisation to first data cutoff 7·26 months [IQR 3·38-10·55]), the median radiographic progression-free survival was 9·30 months (95% CI 6·77-not estimable) in the 177Lu-PSMA-617 group versus 5·55 months (4·04-5·95) in the ARPI change group (hazard ratio [HR] 0·41 [95% CI 0·29-0·56]; p<0·0001). In the updated analysis at time of the third data cutoff (median time from randomisation to third data cutoff 24·11 months [IQR 20·24-27·40]), median radiographic progression-free survival was 11·60 months (95% CI 9·30-14·19) in the 177Lu-PSMA-617 group versus 5·59 months (4·21-5·95) in the ARPI change group (HR 0·49 [95% CI 0·39-0·61]). The incidence of grade 3-5 adverse events was lower in the 177Lu-PSMA-617 group (at least one event in 81 [36%] of 227 patients; four [2%] grade 5 [none treatment related]) than the ARPI change group (112 [48%] of 232; five [2%] grade 5 [one treatment related]). INTERPRETATION: 177Lu-PSMA-617 prolonged radiographic progression-free survival relative to ARPI change, with a favourable safety profile. For patients with PSMA-positive metastatic castration-resistant prostate cancer who are being considered for a change of ARPI after progression on a previous ARPI, 177Lu-PSMA-617 may be an effective treatment alternative. FUNDING: Novartis.

Perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin in muscle-invasive bladder cancer (VESPER): survival endpoints at 5 years in an open-label, randomised, phase 3 study.

BACKGROUND: The optimal perioperative chemotherapy for patients with muscle-invasive bladder cancer is not defined. The VESPER (French Genito-Urinary Tumor Group and French Association of Urology V05) trial reported improved 3-year progression-free survival with dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (dd-MVAC) versus gemcitabine and cisplatin (GC) in patients who received neoadjuvant therapy, but not in the overall perioperative setting. In this Article, we report on the secondary endpoints of overall survival and time to death due to bladder cancer at 5-year follow-up. METHODS: VESPER was an open-label, randomised, phase 3 trial done at 28 university hospitals or comprehensive cancer centres in France, in which adults (age ≤18 years and ≤80 years) with primary bladder cancer and histologically confirmed muscle-invasive urothelial carcinoma were randomly allocated (1:1; block size four) to treatment with dd-MVAC (every 2 weeks for a total of six cycles) or GC (every 3 weeks for a total of four cycles). Overall survival and time to death due to bladder cancer (presented as 5-year cumulative incidence of death due to bladder cancer) was analysed by intention to treat (ITT) in all randomly assigned patients. Overall survival was assessed by the Kaplan-Meier method with the treatment groups compared with log-rank test stratified for mode of administration of chemotherapy (neoadjuvant or adjuvant) and lymph node involvement. Time to death due to bladder cancer was analysed with an Aalen model for competing risks and a Fine and Gray regression model stratified for the same two covariates. Results were presented for the total perioperative population and for the neoadjuvant and adjuvant subgroups. The trial is registered with ClinicalTrials.gov, NCT01812369, and is complete. FINDINGS: From Feb 25, 2013, to March 1, 2018, 500 patients were randomly assigned, of whom 493 were included in the final ITT population (245 [50%] in the GC group and 248 [50%] in the dd-MVAC group; 408 [83%] male and 85 [17%] female). 437 (89%) patients received neoadjuvant chemotherapy. Median follow-up was 5·3 years (IQR 5·1-5·4); 190 deaths at the 5-year cutoff were reported. In the perioperative setting (total ITT population), we found no evidence of association of overall survival at 5 years with dd-MVAC treatment versus GC treatment (64% [95% CI 58-70] vs 56% [50-63], stratified hazard ratio [HRstrat] 0·79 [95% CI 0·59-1·05]). Time to death due to bladder cancer was increased in the dd-MVAC group compared with in the GC group (5-year cumulative incidence of death: 27% [95% CI 21-32] vs 40% [34-46], HRstrat 0·61 [95% CI 0·45-0·84]). In the neoadjuvant subgroup, overall survival at 5 years was improved in the dd-MVAC group versus the GC group (66% [95% CI 60-73] vs 57% [50-64], HR 0·71 [95% CI 0·52-0·97]), as was time to death due to bladder cancer (5-year cumulative incidence: 24% [18-30] vs 38% [32-45], HR 0·55 [0·39-0·78]). In the adjuvant subgroup, the results were not conclusive due to the small sample size. Bladder cancer progression was the cause of death for 157 (83%) of the 190 deaths; other causes of death included cardiovascular events (eight [4%] deaths), deaths related to chemotherapy toxicity (four [2%]), and secondary cancers (four [2%]). INTERPRETATION: Our results on overall survival at 5 years were in accordance with the primary endpoint analysis (3-year progression-free survival). We found no evidence of improved overall survival with dd-MVAC over GC in the perioperative setting, but the data support the use of six cycles of dd-MVAC over four cycles of GC in the neoadjuvant setting. These results should impact practice and future trials of immunotherapy in bladder cancer. FUNDING: French National Cancer Institute.

Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Immune checkpoint inhibitors are the standard of care for first-line treatment of patients with metastatic renal cell carcinoma, yet optimised treatment of patients whose disease progresses after these therapies is unknown. The aim of this study was to determine whether adding atezolizumab to cabozantinib delayed disease progression and prolonged survival in patients with disease progression on or after previous immune checkpoint inhibitor treatment. METHODS: CONTACT-03 was a multicentre, randomised, open-label, phase 3 trial, done in 135 study sites in 15 countries in Asia, Europe, North America, and South America. Patients aged 18 years or older with locally advanced or metastatic renal cell carcinoma whose disease had progressed with immune checkpoint inhibitors were randomly assigned (1:1) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus cabozantinib (60 mg orally once daily) or cabozantinib alone. Randomisation was done through an interactive voice-response or web-response system in permuted blocks (block size four) and stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk group, line of previous immune checkpoint inhibitor therapy, and renal cell carcinoma histology. The two primary endpoints were progression-free survival per blinded independent central review and overall survival. The primary endpoints were assessed in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT04338269, and is closed to further accrual. FINDINGS: From July 28, 2020, to Dec 27, 2021, 692 patients were screened for eligibility, 522 of whom were assigned to receive atezolizumab-cabozantinib (263 patients) or cabozantinib (259 patients). 401 (77%) patients were male and 121 (23%) patients were female. At data cutoff (Jan 3, 2023), median follow-up was 15·2 months (IQR 10·7-19·3). 171 (65%) patients receiving atezolizumab-cabozantinib and 166 (64%) patients receiving cabozantinib had disease progression per central review or died. Median progression-free survival was 10·6 months (95% CI 9·8-12·3) with atezolizumab-cabozantinib and 10·8 months (10·0-12·5) with cabozantinib (hazard ratio [HR] for disease progression or death 1·03 [95% CI 0·83-1·28]; p=0·78). 89 (34%) patients in the atezolizumab-cabozantinib group and 87 (34%) in the cabozantinib group died. Median overall survival was 25·7 months (95% CI 21·5-not evaluable) with atezolizumab-cabozantinib and was not evaluable (21·1-not evaluable) with cabozantinib (HR for death 0·94 [95% CI 0·70-1·27]; p=0·69). Serious adverse events occurred in 126 (48%) of 262 patients treated with atezolizumab-cabozantinib and 84 (33%) of 256 patients treated with cabozantinib; adverse events leading to death occurred in 17 (6%) patients in the atezolizumab-cabozantinib group and nine (4%) in the cabozantinib group. INTERPRETATION: The addition of atezolizumab to cabozantinib did not improve clinical outcomes and led to increased toxicity. These results should discourage sequential use of immune checkpoint inhibitors in patients with renal cell carcinoma outside of clinical trials. FUNDING: F Hoffmann-La Roche and Exelixis.

Extended Safety and Tolerability of Darolutamide for Nonmetastatic Castration-Resistant Prostate Cancer and Adverse Event Time Course in ARAMIS.

BACKGROUND: Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) are usually asymptomatic and seek treatments that improve survival but have a low risk of adverse events. Darolutamide, a structurally distinct androgen receptor inhibitor (ARi), significantly reduced the risk of metastasis and death versus placebo in ARAMIS. We assessed the extended safety and tolerability of darolutamide and the time-course profile of treatment-emergent adverse events (TEAEs) related to ARis and androgen-suppressive treatment. PATIENTS AND METHODS: Patients with nmCRPC were randomized 2:1 to darolutamide (n = 955) or placebo (n = 554). After trial unblinding, patients could receive open-label darolutamide. Tolerability and TEAEs were assessed every 16 weeks. Time interval-specific new and cumulative event rates were determined during the first 24 months of the double-blind period. RESULTS: Darolutamide remained well tolerated during the double-blind and open-label periods, with 98.8% of patients receiving the full planned dose. The incidence of TEAEs of interest in the darolutamide group was low and ≤2% different from that in the placebo group, except for fatigue. When incidences were adjusted for exposure time, there were minimal differences between the darolutamide double-blind and double-blind plus open-label periods. The rate of initial onset and cumulative incidence of grade 3/4 TEAEs and serious TEAEs were similar for darolutamide and placebo groups over 24 months. CONCLUSION: Extended treatment with darolutamide was well tolerated and no new safety signals were observed. Most ARi-associated and androgen-suppressive treatment-related TEAEs occurred at low incidences with darolutamide, were similar to placebo, and showed minimal increase over time with continued treatment. TRIAL NUMBER: ClinicalTrials.gov identifier NCT02200614.

Long-Term Pharmacokinetic Follow-Up of Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer.

This ABIGENE pharmacokinetic (PK) study sought mainly to characterize the unchanged drug PK during long-term abiraterone acetate (AA) administration in advanced prostate cancer patients (81 patients). It was observed that individual AA concentrations remained constant over treatment time, with no noticeable changes during repeated long-term drug administration for up to 120 days. There was no correlation between AA concentrations and survival outcomes. However, a significant association between higher AA concentrations and better clinical benefit was observed (p = 0.041). The safety data did not correlate with the AA PK data. A significant positive correlation (r = 0.40, p < 0.001) was observed between mean AA concentration and patient age: the older the patient, the higher the AA concentration. Patient age was found to impact steady-state AA concentration: the older the patient, the higher the mean AA concentration. Altogether, these data may help to guide future research and clinical trials in order to maximize the benefits of AA metastatic castration-resistant prostate cancer patients.

Body Mass Index, Sarcopenia, and Their Variations in Predicting Outcomes for Patients Treated with Nivolumab for Metastatic Renal Cell Carcinoma.

INTRODUCTION: The advent of immune checkpoint inhibitors (ICIs) such as nivolumab has enabled outcomes for metastatic renal cell carcinoma (mRCC) to be improved. However, only around 25% of patients respond to these therapies without being able to formally identify them. Data on relevant predictive markers are still lacking. The obesity paradox has been shown as a relevant prognostic marker in mRCC with better outcomes for obese patients. Nevertheless, the impact of weight variation and the presence of sarcopenia during ICI treatment is not known for now. METHODS: In a retrospective study, weight and its variations were collected at first day of ICI and at 6 weeks of treatment. Scanographic imagery was used to define the skeletal muscle index (SMI) as a reflect of sarcopenia. The impact of these parameters as predictive and prognostic factors for mRCC with nivolumab was evaluated. RESULTS: A higher body mass index (BMI) at baseline was significantly associated with response at the first scan (p = 0.036). Longer overall survival (OS) was observed for patients with a weight gain compared to the group with weight loss (p = 0.00028). Median OS for sarcopenic patients was 17.2 months and 31.6 months for the non-sarcopenic group of patients, but there was no statistical difference. CONCLUSION: This trial showed that a higher BMI and weight gain during nivolumab treatment were good predictive markers for outcomes in mRCC with nivolumab. Sarcopenia and variations in SMI could thus be of interest, but further studies are required.

Safety and efficacy of temsirolimus as second line treatment for patients with recurrent bladder cancer.

BACKGROUND: Bladder cancer is the 7th cause of death from cancer in men and 10th in women. Metastatic patients have a poor prognosis with a median overall survival of 14 months. Until recently, vinflunine was the only second-line chemotherapy available for patients who relapse. Deregulation of the PI3K/AKT/mTOR pathway was observed in more than 40% of bladder tumors and suggested the use of mTOR as a target for the treatment of urothelial cancers. METHODS: This trial assessed the efficacy of temsirolimus in a homogenous cohort of patients with recurrent or metastatic bladder cancer following first-line chemotherapy. Efficacy was measured in terms of non-progression at two months according to the RECIST v1.1 criteria. Based on a two-stage optimal Simon's design, 15 non-progressions out of 51 evaluable patients were required to claim efficacy. Patients were treated at a weekly dose of 25 mg IV until progression, unacceptable toxicities or withdrawal. RESULTS: Among the 54 patients enrolled in the study between November 2009 and July 2014, 45 were assessable for the primary efficacy endpoint. A total of 22 (48.9%) non-progressions were observed at 2 months with 3 partial responses and 19 stable diseases. Remarkably, 4 patients were treated for more than 30 weeks. Fifty patients experienced at least a related grade1/2 (94%) and twenty-eight patients (52.8%) a related grade 3/4 adverse event. Eleven patients had to stop treatment for toxicity. This led to recruitment being halted by an independent data monitoring committee with regard to the risk-benefit balance and the fact that the primary objective was already met. CONCLUSIONS: While the positivity of this trial indicates a potential benefit of temsirolimus for a subset of bladder cancer patients who are refractory to first line platinum-based chemotherapy, the risk of adverse events associated with the use of this mTOR inhibitor would need to be considered when such an option is envisaged in this frail population of patients. It also remains to identify patients who will benefit the most from this targeted therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01827943 (trial registration date: October 29, 2012); Retrospectively registered.

The New Combination Docetaxel, Prednisone and Curcumin in Patients with Castration-Resistant Prostate Cancer: A Pilot Phase II Study.

OBJECTIVES: Favorable phase I results justified this pilot phase II study to assess the efficacy of docetaxel/curcumin in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (CRPC). METHODS: Thirty patients with progressing CRPC and a rising prostate-specific antigen (PSA) received docetaxel/prednisone in standard conditions for 6 cycles in combination with per os curcumin, 6,000 mg/day (day -4 to day +2 of docetaxel). The co-primary endpoint was the overall response rate determined by PSA and target assessments. An ancillary study assessed the seric values of chromogranin A (CgA) and neuron-specific enolase (NSE). RESULTS: Twenty-six patients received the scheduled treatment, 2 progressed and 2 died before the end of treatment. A PSA response was observed in 59% of patients (14% of PSA normalization) and achieved within the first three cycles for 88% of responders. Partial response was reached for 40% of evaluable patients. The regimen was well tolerated, and no adverse event was attributed to curcumin. Twenty patients were 100% curcumin compliant. The PSA level and objective response rate were not correlated with the serum values of CgA and NSE. CONCLUSION: This study produced additional data on curcumin as a treatment for cancer, with a high response rate, good tolerability and patient acceptability, justifying the interest to conduct a randomized trial.

Everolimus in Metastatic Breast Cancer: Clinical Experience as a Late Treatment Line.

BACKGROUND: Everolimus (Afinitor®) plus exemestane are indicated for hormone receptor-positive, HER2/neu-negative metastatic breast cancer (MBC), in menopausal women without symptomatic visceral disease after recurrence or progression following aromatase inhibitors. But everolimus efficacy as late treatment has not been explored. METHODS: Sixty-three MBC patients progressing under hormonotherapy (HT; n = 30) or after chemotherapy (CT; n = 32) received everolimus plus HT (EHT) and were analyzed for safety, efficacy and overall survival (OS). This cohort was compared with our previous 530 MBC patients stratified by line (PMID 21852136). RESULTS: The median duration of EHT was 27.8 weeks at 5-10 mg/day until clinical progression or toxicity. Median OS was not reached (median follow-up 18 months). Twelve-month survival was 100, 79 and 49% for patients treated with 0 (n = 13), 1-2 (n = 18) and >3 CT (n = 32), respectively. Median time-to-treatment failure was 6.4 months. In 62 EHT patients randomly matched 1:7 with 421 previous patients for age and number of CT, OS improved compared with patients receiving a new CT (p = 0.062). In patients pretreated with <2 CT, EHT gave a better OS than in those with a new CT (p = 0.026). CONCLUSIONS: These results may support the use of EHT whatever the number of previous lines.

Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. METHODS: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. FINDINGS: From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5-12·7) with ipilimumab and 10·0 months (8·3-11·0) with placebo (hazard ratio [HR] 0·85, 0·72-1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1·46 (95% CI 1·10-1·95), for 5-12 months was 0·65 (0·50-0·85), and beyond 12 months was 0·60 (0·43-0·86). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. INTERPRETATION: Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. FUNDING: Bristol-Myers Squibb.

A Randomized, Open-label, Cross-over Phase 2 Trial of Darolutamide and Enzalutamide in Men with Asymptomatic or Mildly Symptomatic Metastatic Castrate-resistant Prostate Cancer: Patient Preference and Cognitive Function in ODENZA.

BACKGROUND: Darolutamide and enzalutamide are second-generation androgen receptor inhibitors with activity in men with castrate-resistant prostate cancer (CRPC) and different toxicity profiles. OBJECTIVE: ODENZA is a prospective, randomized, multicenter, cross-over, phase 2 trial designed to assess preference between darolutamide and enzalutamide in men with asymptomatic or mildly symptomatic metastatic CRPC (mCRPC). DESIGN, SETTING, AND PARTICIPANTS: Patients were randomized 1:1 to receive either darolutamide 1200 mg/d for 12 wk followed by enzalutamide 160 mg/d for 12 wk or enzalutamide followed by darolutamide. In both arms, the second treatment was given in absence of cancer progression. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was patient preference between the two drugs, as assessed by a preference questionnaire (p value calculated with the Prescott test). After week 24, patients entered an extension period during which they received their preferred treatment until progression or toxicity. The main secondary objectives included reasons for patient preference, response at week 12, tolerance of each drug, and measurement compared with baseline of cognitive outcomes assessed using tablet questionnaires. RESULTS AND LIMITATIONS: Overall, 249 patients, with a median age of 72 yr, were randomized. Among the 200 patients who fulfilled the preplanned criteria for the evaluation of the primary endpoint of preference, 97 (49% [41; 56]), 80 (40% [33; 47]), and 23 (12% [7; 16]) chose darolutamide, chose enzalutamide, and had no preference, respectively (p = 0.92). Reduced fatigue, easier administration, and better quality of life were the main criteria that influenced patient choice. A moderate benefit in episodic memory from darolutamide was observed for the acquisition of new information (least square [LS] means difference = 2.2, effect size = 0.5) and for the recall of that information after a brief delay (LS means difference = 0.7, effect size = 0.3). Using the Brief Fatigue Inventory questionnaire, patients reported greater fatigue with enzalutamide (3.3 [3.0; 3.6]) than with darolutamide (2.7 [2.4; 3.0]). There was no difference in terms of depression, seizures, and falls. CONCLUSIONS: The study did not show a difference in preference between the two treatments. In men with mCRPC, darolutamide was associated with a clinically meaningful benefit in episodic memory and less fatigue compared with enzalutamide. PATIENT SUMMARY: Preference between darolutamide and enzalutamide was well balanced in men with castrate-resistant prostate cancer. Darolutamide was associated with a significant benefit in verbal learning and less fatigue compared with enzalutamide.

Activity of Lutetium-177 Prostate-specific Membrane Antigen and Determinants of Outcomes in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Cabazitaxel: The PACAP Study.

BACKGROUND: Both cabazitaxel and lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improve survival in metastatic castration-resistant prostate cancer (mCRPC) after an androgen receptor pathway inhibitor and docetaxel, but there are limited data regarding Lu-PSMA activity after cabazitaxel. OBJECTIVE: To assess the activity of Lu-PSMA and determinants of outcomes after cabazitaxel in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was conducted of consecutive mCRPC patients from eight European centers treated with Lu-PSMA after cabazitaxel. INTERVENTION: Lu-PSMA every 6-8 wk at a dose of 6-7.6 GBq. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was radiographic progression-free survival (rPFS). The secondary endpoints included time to prostate-specific antigen (PSA) progression (TTPSA), overall survival (OS), PSA decline, objective response rate (ORR), clinical benefit, and safety. RESULTS AND LIMITATIONS: Of 126 patients, 68% had International Society of Urological Pathology (ISUP) grade 4-5 disease, 21% had visceral metastases, and 7% had lymph node disease only. DNA damage repair (DDR) alterations were detected in 11/50 (22%) patients with available testing. Patients received a median number of 3 Lu-PSMA cycles (interquartile range 2-4). With a median follow-up of 12.0 mo, the median rPFS was 4.4 mo (95% confidence interval [CI] 3.2-5.4), TTPSA 3.5 mo (95% CI 3.0-4.6), and OS 8.9 mo (95% CI 6.5-12.7). The ORR was 35%, and 55 patients (44%) experienced a PSA decline of ≥50%. The time to castration resistance of <12 mo was associated with shorter rPFS (p = 0.01). A similar trend was observed for ISUP grade 4-5 (p = 0.08), and baseline positron-emission tomography parameters including PSMA mean standardized uptake value (SUV) and maximum SUV (respectively, p = 0.06 and 0.05). The duration of previous cabazitaxel or DDR status did not impact outcomes. Patients experiencing a PSA decline of ≥ 50% on therapy demonstrated longer rPFS, TTPSA, and OS (all p < 0.0001). Limitations include retrospective data collection and investigator-based rPFS assessment. CONCLUSIONS: Lu-PSMA demonstrated a substantial PSA decline but limited rPFS after cabazitaxel in a real-life setting. Adverse baseline characteristics, baseline positron-emission tomography parameters, and quality of PSA response may help identify patients less likely to benefit from Lu-PSMA. PATIENT SUMMARY: Lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improved outcomes in patients with castration-resistant prostate cancer, but there are limited data about its activity after cabazitaxel, a chemotherapy that is also the standard of care in this setting. We conducted a study across eight European centers and showed substantial responses on Lu-PSMA after cabazitaxel, although activity was short lived in a heavily pretreated population. Our findings prompt for real-life evaluation of Lu-PSMA in earlier settings to define the best therapeutic sequence.

COVID-19 Infection despite Previous Vaccination in Cancer Patients and Healthcare Workers: Results from a French Prospective Multicenter Cohort (PAPESCO-19).

In a multicenter prospective cohort of cancer patients (CP; n = 840) and healthcare workers (HCWs; n = 935) vaccinated against COVID-19, we noticed the following: i/after vaccination, 4.4% of HCWs and 5.8% of CP were infected; ii/no characteristic was associated with post-vaccine COVID-19 infections among HCWs; iii/CP who developed infections were younger, more frequently women (NS), more frequently had gastrointestinal, gynecological, or breast cancer and a localized cancer stage; iv/CP vaccinated while receiving chemotherapy or targeted therapy had (NS) more breakthrough infections after vaccination than those vaccinated after these treatments; the opposite was noted with radiotherapy, immunotherapy, or hormonotherapy; v/most COVID-19 infections occurred either during the Alpha wave (11/41 HCW, 20/49 CP), early after the first vaccination campaign started, or during the Omicron wave (21/41 HCW, 20/49 CP), more than 3 months after the second dose; vi/risk of infection was not associated with values of antibody titers; vii/the outcome of these COVID-19 infections after vaccination was not severe in all cases. To conclude, around 5% of our CPs or HCWs developed a COVID-19 infection despite previous vaccination. The outcome of these infections was not severe.

Abigene, a Prospective, Multicentric Study of Abiraterone Acetate Pharmacogenetics in Metastatic Castration-Resistant Prostate Cancer.

Abiraterone acetate (AA) is the first-in-class of drugs belonging to the second-generation of agents inhibiting androgen neosynthesis in advanced prostate cancer. A cumulative experience attests that germinal gene polymorphisms may play a role in the prediction of anticancer agent pharmacodynamics variability. In the present prospective, multicentric study, gene polymorphisms of CYP17A1 (AA direct target) and the androgen transporter genes SLCO2B1 and SLCO1B3 (potential modulators of AA activity) were confronted with AA pharmacodynamics (treatment response and toxicity) in a group of 137 advanced prostate cancer patients treated in the first line by AA. The median follow-up was 56.3 months (95% CI [52.5-61]). From multivariate analysis, rs2486758 C/C (CYP17A1) and PSA (≥10 ng/mL) were associated with a shorter 3-year biological PFS (HR = 4.05, IC95% [1.46-11.22]; p = 0.007 and HR = 2.08, IC95% [1.31-3.30]; p = 0.002, respectively). From a multivariate analysis, the rs743572 (CYP17A1) and performance status were independently associated with significant toxicity (OR = 3.78 (IC95% [1.42-9.75]; p = 0.006 and OR = 4.54; IC95% [1.46-13.61]; p = 0.007, respectively). Host genome characteristics may help to predict AA treatment efficacy and identify patients at risk for toxicity.

Refining the Characterization and Outcome of Pathological Complete Responders after Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: Lessons from the Randomized Phase III VESPER (GETUG-AFU V05) Trial.

Neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy and pelvic lymph node dissection is the optimal treatment for patients with muscle-invasive bladder cancer. In recent years, the VESPER trial showed a statistically significant higher progression-free survival with dd-MVAC (dose dense methotrexate, vinblastine, doxorubicin, and cisplatin) compared to GC (gemcitabine and cisplatin). In the present report, we refine the characterization and outcome of patients whose cystectomy specimens were pathologically free of cancer (pathological complete response, pCR). We confirm that these patients portend a better outcome as compared to patients with invasive disease (≥pT1N0) at cystectomy. Nested variant and lymphovascular invasion were identified as adverse predictive factors of pCR. Progression-free survival probability three years after pCR on cystectomy was about 85%, regardless of the NAC regimen. A lower creatinine clearance and the delivery of less than four cycles were associated with a higher risk of relapse. Predicting the efficacy of NAC remains a major challenge. The planned analysis of molecular subtypes in the VESPER trial could help predict which patients may achieve complete response and better outcome.

Adrenal Metastases Are Associated with Poor Outcomes in Patients with Metastatic Clear Cell Renal Cell Carcinoma Treated with Nivolumab in the GETUG-AFU-26 NIVOREN Phase 2 Trial.

BACKGROUND: Glandular metastases (GMs; adrenal gland, pancreas, thyroid, ovary, breast, or prostate) are rare in metastatic clear cell renal cell carcinoma (mccRCC). Previous studies have indicated that GM patients treated with antiangiogenic therapy experience significantly longer overall survival (OS). OBJECTIVES: To assess outcomes for mccRCC with or without GMs treated with nivolumab. DESIGN, SETTING, AND PARTICIPANTS: The GETUG-AFU-26 NIVOREN phase 2 trial evaluated the activity and safety of nivolumab in patients with mccRCC who experienced failure of antiangiogenic therapies (NCT03013335). In this ancillary study, patients were divided into two groups according to the presence or absence of at least one GM. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was OS; secondary outcomes were progression-free survival (PFS) and the objective response rate (ORR). Survival was estimated using the Kaplan-Meier method. Univariate and multivariable Cox regression models are used to estimate the hazard ratio (HR) with 95% confidence interval (CI) for survival outcomes. Subgroup analyses were performed for patients with pancreatic metastases and patients with adrenal metastases. RESULTS AND LIMITATIONS: Among 720 patients treated with nivolumab between February 2016 and July 2017, 217 had GMs, of whom 151/217 had adrenal metastases and 86/217 had pancreatic metastasis. Patients with adrenal metastases had worse 12-mo OS (64% vs 71.1%) and 6-mo PFS (27.2% vs 36.6%) and a lower objective response rate (12.5%, 95% CI 7.6%-19.0%, vs 23.2%, 95% CI 19.8-27.0%; p = 0.005) than patients without adrenal metastases. Conversely, univariate analysis showed that patients with pancreatic metastases had significantly better 12-mo OS (82.3% vs 67.9%; HR 0.59, 95% CI 0.40-0.85) in comparison to patients with nonpancreatic GMs. On multivariable analysis, only adrenal metastasis remained associated with adverse prognosis. CONCLUSIONS: Adrenal metastasis is an independent prognostic factor for poor response and survival in the GETUG-AFU-26 NIVOREN trial. Limited activity with nivolumab was observed for patients with mccRCC with adrenal metastases. These results warrant an evaluation of the prognostic value of adrenal metastases in patients treated with immunotherapy combinations with ipilimumab or tyrosine kinase inhibitors. PATIENT SUMMARY: Our study showed that metastasis in the adrenal glands could be an independent factor associated with poor response to immunotherapy and survival for patients with metastatic kidney cancer. It would be useful to evaluate the prognostic value of adrenal gland metastasis in patients treated with immunotherapy combinations or immunotherapy agents combined with drugs called tyrosine kinase inhibitors.

COVID-19 Vaccination Campaign in Cancer Patients and Healthcare Workers-Results from a French Prospective Multicenter Cohort (PAPESCO-19).

In this prospective, real-life cohort study, we followed 523 cancer patients (CP) and 579 healthcare workers (HCW) from two cancer centers to evaluate the biological and clinical results of the COVID-19 vaccination campaign. Seventy percent of the CP and 90% of the HCW received an mRNA vaccine or the AZD1222 vaccine. Seropositivity was high after the first vaccine among HCW and poor among CP. The second dose resulted in almost 100% seropositivity in both cohorts. Antibody response was higher after the second injection than the first in both populations. Despite at least two doses, 8 CP (1.5%) and 14 HCW (2.4%) were infected, corresponding either to a weak level of antibody or a new strain of virus (particularly the Omicron variant of concern). Sixteen CP and three HCW were hospitalized but none of them died from COVID-19. To conclude, this study showed that two doses of COVID-19 vaccines were crucially necessary to attain sufficient seropositivity. However, the post-vaccination antibody level declines in individuals from the two cohorts and could not totally prevent new SARS-CoV-2 infections.

COVID-19 Infections in Cancer Patients Were Frequently Asymptomatic: Description From a French Prospective Multicenter Cohort (PAPESCO-19).

Background: Cancer patients (CPs) are considered more vulnerable and as a high mortality group regarding COVID-19. In this analysis, we aimed to describe asymptomatic COVID (+) CPs and associated factors. Methods: We conducted a prospective study in CPs and health care workers (HCWs) in 4 French cancer centers (PAPESCO [PAtients et PErsonnels de Santé des Centres de Lutte Contre le Cancer pendant l'épidémie de COvid-19] study). This analysis used data recorded between June 17, 2020 and November 30, 2020 in CPs (first 2 waves, no variants). At inclusion and quarterly, CPs reported the presence of predefined COVID-19 symptoms and had a blood rapid diagnostic test; a reverse transcription polymerase chain reaction (RT-PCR) was done in case of suspected infection. Results: A total 878 CPs were included; COVID-19 prevalence was similar in both CPs (8%) and HCWs (9.5%); of the 70 CPs (8%) who were COVID (+), 29 (41.4%) were and remained asymptomatic; 241/808 of the COVID (-) (29.8%) were symptomatic. 18 COVID (+) were hospitalized (2% of CPs), 1 in intensive care unit (ICU) and 1 died (0.1% of CPs and 2.4% of symptomatic COVID [+] CPs). Only the inclusion center was associated with clinical presentation (in Nancy, Angers, Nantes, and Clermont-Ferrand: 65.4%, 35%, 28.6%, and 10% CPs were asymptomatic, respectively). Conclusions: Seroprevalence of COVID-19 in CPs was similar to that observed in HCWs; mortality related to COVID-19 among CPs was 0.1%. More than 40% of COVID (+) CPs were asymptomatic and one third of COVID (-) CPs had symptoms. Only geographic origin was associated with the presence or absence of symptoms. Social distancing and protective measures must be applied in CPs at home and when hospitalized.

[Metastatic renal cell carcinoma: Management of toxicities of combinations]. / Cancer du rein métastatique : gestion des toxicités des combinaisons.

New combinations of antiangiogenic tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) or dual ICI have been shown to be effective in phase III trials compared to sunitinib in the first-line treatment of metastatic renal cell cancer. While ICI doublet is already used in other indications, TKI/ICI combinations are more recent and the management of their adverse effects (AEs) are less well known, particularly with regard to the accountability of each therapeutic class. The objective of this article is to analyze the safety data from the main phase III studies to provide clinicians with practical advice for managing the AEs from these combinations. Their management depends largely on the type of combination and their grade. In the case of a TKI/ICI combination, discontinuation of the 2 molecules is considered from grade 2. Rapid improvement in symptoms suggests that the AE is related to the TKI. It is then possible, after resolution, to reintroduce the TKI, if needed by reducing the dose, and to continue the ICI. Otherwise, the blame falls on the ICI and treatment usually involves corticosteroids. Management also depends on the type of AE and its severity. In some cases (dysthyroidism), treatment with TKI/ICI may be continued. In other situations (cardiac or neurological toxicity), it should be discontinued from grade 1 and hospitalization and corticosteroid therapy should be considered immediately. In all cases, information and education are integral parts of the prevention and proper management of potential AEs.

Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial.

PURPOSE: The optimal perioperative chemotherapy regimen for patients with nonmetastatic muscle-invasive bladder cancer is not defined. PATIENTS AND METHODS: Between February 2013 and March 2018, 500 patients were randomly assigned in 28 French centers and received either six cycles of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) once every 2 weeks or four cycles of gemcitabine and cisplatin (GC) once every 3 weeks before surgery (neoadjuvant group) or after surgery (adjuvant group). We report the primary end point of the GETUG-AFU V05 VESPER trial (ClinicalTrials.gov identifier: NCT01812369): progression-free survival (PFS) at 3 years. Secondary end points were time to progression and overall survival. RESULTS: Four hundred thirty-seven patients (88%) received neoadjuvant chemotherapy; 60% of patients received the planned six cycles in the dd-MVAC arm, 84% received four cycles in the GC arm, and thereafter, 91% and 90% of patients underwent surgery, respectively. Organ-confined response (< ypT3N0) was observed more frequently in the dd-MVAC arm (77% v 63%, P = .001). In the adjuvant group, 40% of patients received six cycles in the dd-MVAC arm, and 81% of patients received four cycles in the GC arm. For all patients in the clinical trial, 3-year PFS was improved in the dd-MVAC arm, but the study did not meet its primary end point (3-year rate: 64% v 56%, hazard ratio [HR] = 0.77 [95% CI, 0.57 to 1.02], P = .066); nevertheless, the dd-MVAC arm was associated with a significantly longer time to progression (3-year rate: 69% v 58%, HR = 0.68 [95% CI, 0.50 to 0.93], P = .014). In the neoadjuvant group, PFS at 3 years was significantly higher in the dd-MVAC arm (66% v 56%, HR = 0.70 [95% CI, 0.51 to 0.96], P = .025). CONCLUSION: In the VESPER trial, dd-MVAC improved 3-years PFS over GC. In the neoadjuvant group, a better bladder tumor local control and a significant improvement in 3-year PFS were observed in the dd-MVAC arm.