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.

Neuroendocrine Carcinoma of the Urinary Bladder: A Large, Retrospective Study From the French Genito-Urinary Tumor Group.

BACKGROUND: Neuroendocrine carcinoma of the urinary bladder (NCUB) is rare, accounting for < 1% of bladder cancer cases, with scarce reported data available. MATERIALS AND METHODS: We retrospectively reviewed the data from patients with NCUB treated at French institutions. The objectives were to describe the patient characteristics, treatments received, and outcomes (ie, disease-free survival [DFS], progression-free survival, overall survival [OS]) and investigate the prognostic factors. RESULTS: From 1997 to 2017, we included 236 patients, 173 with early-stage NCUB and 63 with advanced-stage NCUB. For those with early-stage disease, the median DFS was better for the patients who had received cisplatin-based chemotherapy compared with carboplatin (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.1-3.46), with no difference found between the neoadjuvant and adjuvant settings (HR, 1.1; 95% CI, 0.61-1.97). The median OS was 36 months (95% CI, 29-43 months) for stage I and II, 26 months (95% CI, 18 months to not reached) for stage IIIA, 16 months (95% CI, 12-21 months) for stage IIIB. The HR for stage IIIB compared with stage I/II was 2.6 (95% CI, 1.5-4.4). The DFS at 6 months was associated with OS (HR, 7.8; 95% CI, 4.1-15.0). For patients with metastases at diagnosis who had received chemotherapy, the median progression-free survival was 9 months (95% CI, 8-11) for first-line cisplatin and 6 months (95% CI, 4-13 months) for carboplatin; the median OS was 13 months (95% CI, 9-15 months). A high-risk Bajorin score (HR, 11.5; 95% CI, 1.2-112.6) and the use of carboplatin (HR, 2.26; 95% CI, 1.03-4.96) were associated with worse outcomes. CONCLUSIONS: In early-stage disease, a shorter DFS was associated with worse OS, and the use of cisplatin was associated with better OS. For the patients with metastases at diagnosis, a high-risk Bajorin score and the use of carboplatin were associated with worse outcomes.

A risk-adapted study of cisplatin and etoposide, with or without ifosfamide, in patients with metastatic seminoma: results of the GETUG S99 multicenter prospective study.

BACKGROUND: Whether patients with good prognosis and intermediate/poor prognosis advanced seminoma should be treated differently has not been defined. OBJECTIVE: To assess a risk-adapted chemotherapy regimen in patients with advanced seminoma. DESIGN, SETTING, AND PARTICIPANTS: A total of 132 patients were included in this prospective study. Patients with a good prognosis according to the International Germ Cell Cancer Collaboration Group (IGGCCG) were treated with four cycles of cisplatin-etoposide (EP). Patients with an intermediate prognosis according to the IGCCCG (or a poor prognosis according to the Medical Research Council classification) were treated with four cycles of VIP (EP and ifosfamide) and granulocyte colony-stimulating factor (G-CSF). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Survival curves were estimated using the Kaplan-Meier method. RESULTS AND LIMITATIONS: The median follow-up was 4.5 yr (range: 0.4-11.6 yr). Among 108 patients (82%) with a good prognosis who received EP, grade 3-4 toxicity included neutropenia (47%) and neutropenic fever (12%). Among the 24 patients (18%) with an intermediate/poor prognosis who received VIP plus G-CSF, toxicity included grade 3-4 neutropenia (36%), neutropenic fever (23%), thrombocytopenia (23%), anemia (23%), and a toxicity-related death (n=1; 4%). The 3-yr progression-free survival (PFS) rate was 93% (range: 85-97%) in the good prognosis group and 83% (range: 63-93%) in the intermediate/poor prognosis group (p=0.03 for PFS). The 3-yr overall survival (OS) rate was 99% (range: 92-100%) and 87% (range: 67-95%), respectively (p<0.005 for OS). Only four patients died of seminoma or its treatment. CONCLUSIONS: A risk-adapted chemotherapy policy for advanced seminoma yielded an excellent outcome with a 3-yr OS rate of 96%.

Prospective analysis of the impact of VEGF-A gene polymorphisms on the pharmacodynamics of bevacizumab-based therapy in metastatic breast cancer patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Functional polymorphisms on the VEGF-A gene, known to be linked to cancer risk or to VEGF-A plasma concentrations, have been identified. So far, limited knowledge has been published on the relationships between toxicity/efficacy of bevacizumab-based therapy and VEGF-A polymorphisms (tumoral DNA). We therefore prospectively tested the impact of these five gene polymorphisms (blood DNA) on the pharmacodynamics of bevacizumab-based treatment administered in metastatic breast cancer patients. WHAT THIS STUDY ADDS: • Present data obtained from a prospective study suggest a role for VEGF-A 936C > T polymorphism as a potential predictor of time to progression in breast cancer patients receiving bevacizumab-containing therapy. Also, the VEGF-A-634G > C polymorphism was linked to bevacizumab-related toxicity. AIMS To test prospectively the impact of VEGF-A gene polymorphisms on the pharmacodynamics of bevacizumab-chemotherapy in breast cancer patients. METHODS: As part of the single-arm MO19391 trial, 137 women with locally recurrent or metastatic breast cancer receiving first-line bevacizumab-containing therapy were analysed. Patients received bevacizumab associated (76%) or not (24%) with taxane-based chemotherapy. Clinical evaluation included clinical response, time to progression (TTP) and a toxicity score corresponding to the sum of each maximum observed toxicity grade (hypertension, haemorrhage, arterial and venous thrombo-embolism). Functional VEGF-A polymorphisms at position -2578 C > A, -1498 T > C, -1154 G > A, -634 G > C and 936 C > T were analysed by PCR-RFLP (blood DNA). RESULTS: Overall response rate (complete response (CR) + partial response (PR)) was 61%. Median TTP was 11 months. None of the VEGF-A polymorphisms was significantly linked to clinical response. Analysis of the 936C > T polymorphism revealed that the 96 patients homozygous for the 936C allele exhibited a marked tendency for a shorter TTP (median 9.7 months) than the 32 patients bearing the 936T allele (median 11.5 months, P= 0.022) of which 30 were CT and two were homozygous TT. Other polymorphisms did not influence TTP. VEGF-A-634 G > C was significantly related to the toxicity score with 39%, 49% and 81% of patients with score >1 in GG, GC and CC patients, respectively (P= 0.01). CONCLUSIONS: The role for VEGF-A 936C > T polymorphism as a potential marker of TTP in breast cancer patients receiving bevacizumab-containing therapy concords with the known impact of VEGF-A 936C > T polymorphism on VEGF-A expression.

Sequential addition of an anthracycline-based regimen to docetaxel as neoadjuvant chemotherapy in patients with operable breast cancer.

BACKGROUND: The objective of this phase II study was to attempt to maximize response and survival in patients with bulky, operable breast cancer by combining sequential neoadjuvant docetaxel to a semi-intensive anthracycline-based regimen. PATIENTS AND METHODS: Eligible patients (N = 53) were included to receive 4 cycles of docetaxel, followed by a maximum of 4 cycles of TNCF (THP [theprubican]-doxorubicin/vinorelbine/cyclophosphamide/5-fluorouracil) every 21 days before definitive surgery and radiation therapy. RESULTS: After a median number of 4 cycles of docetaxel and 2 cycles of TNCF, the overall clinical response rate was 81.1%, including a 13.2% complete remission rate and only 2 incidences of progressive disease. Breast conservation was achieved in 87% of patients. According to Chevallier classification, a pathologic complete response in breast and axilla was confirmed in 6 patients (11.3%) and in 9 patients (17%) using the Sataloff's classification. The important myelosuppression observed in this trial was expected but limited by the prophylactic use of growth factors. After a median follow-up of 40.4 months, only 5 recurrences were documented, with a median time to first recurrence of 12.8 months. CONCLUSION: Despite disappointing results of this trial for pathologic complete response rate, possibly because of the order of drug administration, clinical response, breast conservation, and survival were optimized.

High prognostic significance of residual disease after neoadjuvant chemotherapy: a retrospective study in 710 patients with operable breast cancer.

Prognostic factors are used to help clinical decision-making in selecting the appropriate treatment for individual patients. The purpose of this retrospective study was to identify one or more factors associated with overall survival (OS) and disease-free survival (DFS), in 710 patients with operable breast cancer, subjected to neoadjuvant chemotherapy followed by surgery, radiotherapy and adjuvant treatments. At a median follow-up of 7.6 years, univariate analysis showed that pathological complete response (pCR) was significantly related to survival (p < 0.003), as well as accepted prognostic factors, as SBR and MSBR grades, hormonal receptors or node involvement at surgery, who remained significant in our study (p < 0.001). The revised Nottingham prognostic index (NPI) and related indices (BGI, MNPI and MBGI) were also significantly associated to survival (p < 0.003). In multivariate analysis, node involvement and MSBR grade remained prognostic factors for OS and DFS (p < 0.0003 and p < 0.02, respectively). The MNPI and pCR were significantly related with OS (p = 0.04) and pts with hormonal receptor-positive tumours had a better DFS than others (p = 0.004). Among all clinical and pathological parameters, axillary dissection after neoadjuvant chemotherapy is still important to determine node involvement, a major prognostic factor. Moreover, MSBR grade seemed to be more accurate and predictive of long-term outcome than the standard SBR grade. It is concluded that, outside any other 'biological' factor, residual disease in breast and nodes must be strongly considered after an induction chemotherapy so as to choose adjuvant treatment for the individual patient.

Pathological and clinical response of a primary chemotherapy regimen combining vinorelbine, epirubicin, and paclitaxel as neoadjuvant treatment in patients with operable breast cancer.

This phase II study investigated the efficacy and tolerability of a primary chemotherapy regimen combining vinorelbine, epirubicin, and paclitaxel (VEP protocol) in women with stage II/III operable breast cancer. Patients (n = 50) were treated with six cycles of VEP according to the following schedule: vinorelbine (Navelbine); Pierre Fabre, Boulogne, France; http://www.pierre-fabre.com) 20 mg/m2, epirubicin (Farmorubicin; Pharmacia, New York, NY; http://www.pnu.com) 35 mg/m2 given on days 1 and 8, paclitaxel (Taxol; Bristol-Myers Squibb, New York, NY; http://www.bmsoncology.com) 175 mg/m2 given on day 9, and G-CSF 5 mg/kg/day given on days 10-20 of a 21-day cycle, followed by surgery and radiotherapy. After six cycles of VEP, the pathological response rate (pCR) in breast was confirmed in six patients (12%; 95% confidence interval [CI]: 3-21)) using Chevallier's classification and in nine patients (18%; 95% CI: 7.4-28.6) using Sataloff's classification. The clinical response rate was 42% (95% CI: 28.3-55.7), including 26% complete responses. Breast conservation was achieved in 68% of patients. After a median follow-up of 48 months (range, 34-62 months), 16 relapses were observed. The overall and disease-free survivals at 5 years were 54.1% (95% CI: 40.3-67.9) and 38% (95% CI: 24.1-51.9), respectively. The principal toxicities of VEP were grade 3/4 neutropenia observed in 30% of patients and grade 3 anemia observed in 12% of patients. There was no case of severe cardiac toxicity, thrombocytopenia, or any other serious adverse events. In conclusion, whereas this regimen was relatively well tolerated, it appears inferior to other regimens and its use is not recommended.