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.

Long survival of patients with metastatic clear cell renal cell carcinoma. Results of real life study of 344 patients.

The treatment landscape in metastatic renal cell carcinoma has changed fundamentally over the last decade by the development of antiangiogenic agents, mammalian target of rapamycin inhibitors and immunotherapy. Outside of the context of a clinical trial, the treatments are used sequentially. We describe results under real-life conditions of a sequential treatment strategy, before the era of immunotherapy. All patients were treated according to their prognostic score (either Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium) for advanced renal cell carcinoma. A treatment strategy involving 1 to 4 lines was determined including a rechallenge criterion for the repeat use of a treatment class. Three hundred forty-four patients were included over 3 years. Overall survival was 57 months in patients with good or intermediate prognosis and 19 months in patients with poor prognosis. In the former group, the proportions of patients treated with 2 to 4 treatment lines were 70%, 38% and 16%, respectively. The best objective response rates for lines 1 to 4 were 46%, 36%, 16% and 17%, respectively. Grade III/IV toxicity did not appear to be cumulative. The recommended strategy was followed in 68% of patients. A large proportion of patients with good or intermediate prognosis who progress after two lines of treatment still have a performance status good enough to receive a systemic treatment, which justifies such a strategy. Overall survival of patients with good and intermediate prognosis was long, suggesting a benefit from the applied approach. These results might be used as selection criterion for the treatment of patients in the era of immune checkpoint inhibitors.

Effect of Adding Docetaxel to Androgen-Deprivation Therapy in Patients With High-Risk Prostate Cancer With Rising Prostate-Specific Antigen Levels After Primary Local Therapy: A Randomized Clinical Trial.

IMPORTANCE: Androgen-deprivation therapy (ADT) plus docetaxel is the standard of care in hormone-naive metastatic prostate cancer but is of uncertain benefit in a nonmetastatic, high-risk prostate cancer setting. OBJECTIVE: To assess the benefit of ADT plus docetaxel in patients presenting with rising prostate-specific antigen (PSA) levels after primary local therapy and high-risk factors but no evidence of metastatic disease. DESIGN, SETTING, AND PARTICIPANTS: This open-label, phase 3, randomized superiority trial comparing ADT plus docetaxel vs ADT alone enrolled patients from 28 centers in France between June 4, 2003, and September 25, 2007; final follow-up was conducted April 12, 2017, and analysis was performed May 2 to July 31, 2017. Patients had undergone primary local therapy for prostate cancer, were experiencing rising PSA levels, and were considered to be at high risk of metastatic disease. Stratification was by prior local therapy and PSA-level doubling time (≤6 vs >6 months), and intention-to-treat analysis was used. INTERVENTIONS: Patients were randomly assigned to receive ADT (1 year) plus docetaxel, 70 mg/m2 (every 3 weeks [6 cycles]), or ADT alone (1 year). MAIN OUTCOMES AND MEASURES: The primary outcome was PSA progression-free survival (PSA-PFS). Secondary end points were PSA response, radiologic PFS, overall survival, safety, and quality of life. RESULTS: Overall, 254 patients were randomized (1:1) to the trial; median age, 64 years in the ADT plus docetaxel arm, 66 years in the ADT alone arm. At a median follow-up of 30.0 months, the median PSA-PFS was 20.3 (95% CI, 19.0-21.6) months in the ADT plus docetaxel arm vs 19.3 (95% CI, 18.2-20.8) months in the ADT alone arm (hazard ratio [HR], 0.85; 95% CI, 0.62-1.16; P = .31). At a median follow-up of 10.5 years, there was no significant between-arm difference in radiologic PFS (HR, 1.03; 95% CI, 0.74-1.43; P = .88). Overall survival data were not mature. The most common grade 3 or 4 hematologic toxic effects in the ADT plus docetaxel arm were neutropenia (60 of 125 patients [48.0%]), febrile neutropenia (10 [8.0%]), and thrombocytopenia (4 [3.0%]). There was no significant between-arm difference in overall quality of life. CONCLUSIONS AND RELEVANCE: Compared with ADT alone, combined ADT plus docetaxel therapy with curative intent did not significantly improve PSA-PFS in patients with high-risk prostate cancer and rising PSA levels and no evidence of metastatic disease. TRIAL REGISTRATION: French Health Products Safety Agency identifier: 030591; ClinicalTrials.gov identifier: NCT00764166.

Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma.

BACKGROUND: Nivolumab-ipilimumab demonstrated a survival benefit over sunitinib in first-line setting for metastatic renal cell carcinomas (mRCCs) and is becoming a new standard of care for naïve patients with intermediate or poor risk prognosis (International mRCC Database Consortium). The efficacy of subsequent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) after nivolumab-ipilimumab failure remains unclear. METHODS: Medical records of mRCC patients treated with nivolumab-ipilimumab, who received subsequent TKI, as part of Checkmate 214 study were reviewed in 13 institutions. Baseline characteristics, outcome data including progression-free survival (PFS), response, overall survival (OS) and toxicities were retrospectively collected. RESULTS: Overall 33 patients received subsequent TKI after nivolumab-ipilimumab failure. Median follow-up from start of subsequent TKI is 22 months (19-NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months [5-13]. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months [5-16] and 7 months (5-NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (≥6 months) with 8 versus 5 months for short responder (<6 months) (p = 0.03). OS rate was 54% at 12 months. Toxicity was as expected: 42% developed at least one toxicity grade ≥3. CONCLUSION: This is the first report of outcomes with TKI, after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence.

Metastatic chromophobe renal cell carcinoma treated with targeted therapies: A Renal Cross Channel Group study.

BACKGROUND: Treatment of non-clear cell renal cell carcinoma (RCC) remains controversial despite several recent prospective studies of targeted therapies (TT). Often Vascular Endothelial growth Factor (VEGF) and Mammalian Target of Rapamycin (mTOR) inhibitors are used, extrapolating the data from use of these agents in clear cell RCC. METHODS: We performed a retrospective data analysis within the Renal Cross Channel Group to determine metastatic chromophobe RCC (mChRCC) outcomes in the TT era. The end-points were overall response, overall survival (OS) and time to treatment failure (TTF). The two latter were estimated using the Kaplan-Meier method. RESULTS: 91 mChRCC patients from 26 centres were included. Median follow-up from the date of first metastasis was 6.1 years (range: 0-13.9). Median OS was 37.9 months (95% confidence interval [CI]: 21.4-46.8) from the diagnosis of metastatic disease. Among the 61 patients who received TT, 50 (82%) were treated with anti-angiogenic (AA) and 11 with mTOR inhibitors. Median TTF and OS in patients receiving a first line of AA was 8.7 months (95% CI: 5.2-10.9) and 22.9 months (95% CI: 17.8-49.2) versus 1.9 months (95% CI: 1.0-6.0) and 3.2 months (95% CI: 2.3-not evaluable) with mTOR inhibitors, respectively. A stratified log-rank test was used to compare AA and mTOR inhibitors TT, while controlling the effect of the International Metastatic RCC Database Consortium risk group and no significant difference between AA and mTOR inhibitors was observed for TTF (p = 0.26) or for OS (p = 0.55). CONCLUSION: We report the largest retrospective cohort of patients with mChRCC treated with TT and no significant difference between AA and mTOR inhibitors was observed for TTF and OS.

Androgen Deprivation Therapy (ADT) Plus Docetaxel Versus ADT Alone in Metastatic Non castrate Prostate Cancer: Impact of Metastatic Burden and Long-term Survival Analysis of the Randomized Phase 3 GETUG-AFU15 Trial.

BACKGROUND: The role of chemotherapy in metastatic non castrate prostate cancer (mNCPC) is debated. Survival benefits of docetaxel (D) added to androgen-deprivation therapy (ADT) were shown in the CHAARTED trial in patients with metastatic high-volume disease (HVD). OBJECTIVE: To assess the impact of metastatic burden and to update overall survival (OS) data of the GETUG-AFU15 study. DESIGN, SETTING, AND PARTICIPANTS: Randomized phase 3 trial of ADT plus D versus ADT alone in 385 mNCPC patients; median follow-up of 7 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary end point was OS. Secondary end points were biochemical progression-free survival (bPFS) and radiographic progression-free survival (rPFS). Retrospective analysis was by tumor volume. RESULTS AND LIMITATIONS: After a median follow-up of 83.9 mo, median OS in the overall population was 62.1 mo (95% confidence interval [CI], 49.5-73.7) and 48.6 mo (95% CI, 40.9-60.6) for ADT plus D and ADT arms, respectively (hazard ratio [HR]: 0.88 [95% CI, 0.68-1.14]; p=0.3). Median OS in ADT plus D and ADT arms, respectively, was for HVD patients: 39.8 mo (95% CI, 28.0-53.4) versus 35.1 mo (95% CI, 29.9-43.6) (HR: 0.78 [95% CI, 0.56-1.09]; p=0.14), for low-volume disease (LVD) patients; median was not reached (NR; 95% CI, 69.5-NR) and 83.4 mo (95% CI, 61.8-NR) (HR: 1.02 [95% CI, 0.67-1.55]; p=0.9). For upfront metastatic patients, OS was 52.6 mo (95% CI, 43.3-66.8) and 41.5 mo (95% CI, 36.3-54.5), respectively (HR: 0.93 [95% CI, 0.69-1.25]; p=0.6). The bPFS (HR: 0.73 [95% CI, 0.56-0.94]; p=0.014) and rPFS (HR: 0.75 [95% CI, 0.58-0.97]; p=0.030) were significantly longer in the ADT plus D arm. Limitations included the retrospective analysis of metastatic extent and the lack of statistical power to detect a significant difference in subgroups. CONCLUSIONS: The post hoc analyses of the GETUG-AFU15 study demonstrated a nonsignificant 20% reduction in the risk of death in the HVD subgroup. Patients with LVD had no survival improvement with early D. PATIENT SUMMARY: In this study, docetaxel added to castration did not improve survival in patients with metastatic hormone-sensitive prostate cancer, partly due to methodological issues. However, early chemotherapy should be discussed with all patients, given the data of three randomized trials including GETUG-AFU15.

Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2.

AIM: To investigate the efficacy and safety of gemcitabine and platinum salt, with or without trastuzumab, in patients with locally advanced or metastatic urothelial carcinoma overexpressing Her2. METHODS: The main eligibility criterion was Her2 overexpression on immunohistochemistry (IHC 2+ or 3+) of primary tumour tissue confirmed by fluorescence in situ hybridisation (FISH). Patients were randomised to Arm A: gemcitabine 1000mg/m(2) (days 1 and 8) plus either cisplatin (70mg/m(2)) or carboplatin (AUC=5) (day 1 every 3 weeks) or Arm B: added trastuzumab (8mg/kg loading dose, then 6 mg/kg every 21 days until progression). The primary end-point was progression-free survival (PFS). RESULTS: Among 563 screened patients, 75 (13.3%) were Her2 positive (IHC 2+/3+ and FISH+) and 61 met all eligibility criteria (median age, 64 years; 54/61 males; 50/61 baseline ECOG-PS 0-1; 11 locally advanced and 50 metastatic). There was no significant difference between Arms A and B in median PFS (10.2 versus 8.2 months, respectively, p=0.689), objective response rate (65.5% versus 53.2%, p=0.39), and median overall survival (15.7 versus 14.1 months, respectively, p=0.684). In an exploratory analysis, trastuzumab-treated patients receiving cisplatin rather than carboplatin-based chemotherapy fared better (PFS: 10.6 versus 8.0; OS: 33.1 versus 9.5 months). Myelosuppression was the main grade 3/4 toxicity. A case of grade 3 cardiotoxicity and one death from febrile neutropenia occurred in arm B. CONCLUSION: The unexpectedly low incidence of Her2 overexpression precluded the detection of a significant difference in efficacy on addition of trastuzumab to platinum-based chemotherapy with gemcitabine. However, the satisfactory tolerance of the combination warrants further studies, especially of the cisplatin-based combination, in well-defined patient subsets.

Prognostic Factors for Survival in Noncastrate Metastatic Prostate Cancer: Validation of the Glass Model and Development of a Novel Simplified Prognostic Model.

BACKGROUND: The Glass model developed in 2003 uses prognostic factors for noncastrate metastatic prostate cancer (NCMPC) to define subgroups with good, intermediate, and poor prognosis. OBJECTIVE: To validate NCMPC risk groups in a more recently diagnosed population and to develop a more sensitive prognostic model. DESIGN, SETTING, AND PARTICIPANTS: NCMPC patients were randomized to receive continuous androgen deprivation therapy (ADT) with or without docetaxel in the GETUG-15 phase 3 trial. Potential prognostic factors were recorded: age, performance status, Gleason score, hemoglobin (Hb), prostate-specific antigen, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), metastatic localization, body mass index, and pain. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: These factors were used to develop a new prognostic model using a recursive partitioning method. Before analysis, the data were split into learning and validation sets. The outcome was overall survival (OS). RESULTS AND LIMITATIONS: For the 385 patients included, those with good (49%), intermediate (29%), and poor (22%) prognosis had median OS of 69.0, 46.5 and 36.6 mo (p=0.001), and 5-yr survival estimates of 60.7%, 39.4%, and 32.1%, respectively (p=0.001). The most discriminatory variables in univariate analysis were ALP, pain intensity, Hb, LDH, and bone metastases. ALP was the strongest prognostic factor in discriminating patients with good or poor prognosis. In the learning set, median OS in patients with normal and abnormal ALP was 69.1 and 33.6 mo, and 5-yr survival estimates were 62.1% and 23.2%, respectively. The hazard ratio for ALP was 3.11 and 3.13 in the learning and validation sets, respectively. The discriminatory ability of ALP (concordance [C] index 0.64, 95% confidence interval [CI] 0.58-0.71) was superior to that of the Glass risk model (C-index 0.59, 95% CI 0.52-0.66). The study limitations include the limited number of patients and low values for the C-index. CONCLUSION: A new and simple prognostic model was developed for patients with NCMPC, underlying the role of normal or abnormal ALP. PATIENT SUMMARY: We analyzed clinical and biological factors that could affect overall survival in noncastrate metastatic prostate cancer. We showed that normal or abnormal alkaline phosphatase at baseline might be useful in predicting survival.

Patients' self-assessment versus investigators' evaluation in a phase III trial in non-castrate metastatic prostate cancer (GETUG-AFU 15).

BACKGROUND: Toxicity, which is a key parameter in the evaluation of cancer treatments, can be underestimated by clinicians. We investigated differences between patients and physicians in reporting adverse events of androgen deprivation therapy (ADT) with or without docetaxel in a multicentre phase III trial in non-castrate metastatic prostate cancer. METHODS: The 385 patients included were invited to complete a 26-symptom questionnaire 3 and 6 months after the start of treatment, among which eighteen symptoms were also assessed by physicians, reported in medical records and graded using the Common Toxicity Criteria of the National Cancer Institute. Positive and negative agreements as well as Kappa concordance coefficients were computed. FINDINGS: Data were available for 220 and 165 patients at 3 and 6 months respectively. Physicians systematically under-reported patients' symptoms. Positive agreement rates (at respectively 3 and 6 months) for the five most commonly reported symptoms were: 61.0% and 64.3% hot flushes, 50.0% and 43.6% fatigue, 29.4% and 31.1% sexual dysfunction, 24.4% and 14.4% weigh gain/loss, 16.7% and 19.3% for joint/muscle pain. For symptoms most frequently reported as disturbing or very disturbing by patients, the clinicians' failure to report them ranged from 50.8% (hot flushes) to 89.5% (joint/muscle pain) at 3 months, and from 48.2% (hot flushes) to 88.4% (joint/muscle pain) at 6 months. INTERPRETATION: Physicians often failed to report treatment-related symptoms, even the most common and disturbing ones. Patients' self-evaluation of toxicity should be used in clinical trials to improve the process of drug assessment in oncology. FUNDING: French Health Ministry and Institut National du Cancer (PHRC), Sanofi-Aventis, Astra-Zeneca, and Amgen.

Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial.

BACKGROUND: Early chemotherapy might improve the overall outcomes of patients with metastatic non-castrate (ie, hormone-sensitive) prostate cancer. We investigated the effects of the addition of docetaxel to androgen-deprivation therapy (ADT) for patients with metastatic non-castrate prostate cancer. METHODS: In this randomised, open-label, phase 3 study, we enrolled patients in 29 centres in France and one in Belgium. Eligible patients were older than 18 years and had histologically confirmed adenocarcinoma of the prostate and radiologically proven metastatic disease; a Karnofsky score of at least 70%; a life expectancy of at least 3 months; and adequate hepatic, haematological, and renal function. They were randomly assigned to receive to ADT (orchiectomy or luteinising hormone-releasing hormone agonists, alone or combined with non-steroidal antiandrogens) alone or in combination with docetaxel (75 mg/m(2) intravenously on the first day of each 21-day cycle; up to nine cycles). Patients were randomised in a 1:1 ratio, with dynamic minimisation to minimise imbalances in previous systemic treatment with ADT, chemotherapy for local disease or isolated rising concentration of serum prostate-specific antigen, and Glass risk groups. Patients, physicians, and data analysts were not masked to treatment allocation. The primary endpoint was overall survival. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00104715. FINDINGS: Between Oct 18, 2004, and Dec 31, 2008, 192 patients were randomly allocated to receive ADT plus docetaxel and 193 to receive ADT alone. Median follow-up was 50 months (IQR 39-63). Median overall survival was 58·9 months (95% CI 50·8-69·1) in the group given ADT plus docetaxel and 54·2 months (42·2-not reached) in that given ADT alone (hazard ratio 1·01, 95% CI 0·75-1·36). 72 serious adverse events were reported in the group given ADT plus docetaxel, of which the most frequent were neutropenia (40 [21%]), febrile neutropenia (six [3%]), abnormal liver function tests (three [2%]), and neutropenia with infection (two [1%]). Four treatment-related deaths occurred in the ADT plus docetaxel group (two of which were neutropenia-related), after which the data monitoring committee recommended treatment with granulocyte colony-stimulating factor. After this recommendation, no further treatment-related deaths occurred. No serious adverse events were reported in the ADT alone group. INTERPRETATION: Docetaxel should not be used as part of first-line treatment for patients with non-castrate metastatic prostate cancer. FUNDING: French Health Ministry and Institut National du Cancer (PHRC), Sanofi-Aventis, AstraZeneca, and Amgen.

Prospective multicenter phase II study of gemcitabine plus platinum salt for metastatic collecting duct carcinoma: results of a GETUG (Groupe d'Etudes des Tumeurs Uro-Génitales) study.

PURPOSE: Collecting duct carcinoma of the kidney is a rare and aggressive neoplasm of the distal collecting tubules for which there is no established treatment. Since the histology of collecting duct carcinoma is similar to that of urothelial carcinoma, the standard chemotherapy regimen defined by a gemcitabine and platinum salts combination was prospectively investigated in patients with metastatic collecting duct carcinoma. MATERIALS AND METHODS: A total of 23 patients with metastatic collecting duct carcinoma with no prior systemic chemotherapy were treated with 1,250 mg/m(2) gemcitabine on days 1 and 8 plus 70 mg/m(2) cisplatin or carboplatin (AUC 5) in patients with renal insufficiency on day 1. The drugs were repeated every 21 days for 6 cycles according to toxicity and efficacy. The objective response rate was the primary end point. RESULTS: There were 1 complete and 5 partial responses for an objective response rate of 26% (95% CI 8 to 44). Median progression-free and overall survival was 7.1 (95% CI 3 to 11.3) and 10.5 months (95% CI 3.8 to 17.1), respectively. Toxicity was mainly hematological with grade 3-4 neutropenia and thrombocytopenia in 52% and 43% of patients, respectively. The severity of granulocytopenia and the number of metastatic sites were associated with overall survival on univariate and multivariate analyses. CONCLUSIONS: To our knowledge this is the first prospective, multicenter, phase II study showing that the platinum salts combination is an active and safe regimen as first line treatment in patients with metastatic collecting duct carcinoma. This platinum based chemotherapy should be considered the standard regimen in these patients.