Jean-Christophe Eymard

Randomized Phase II Trial of Everolimus in Combination With Tamoxifen in Patients With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer With Prior Exposure to Aromatase Inhibitors: A GINECO Study

PURPOSE Cross-talk between signal transduction pathways likely contributes to hormone resistance in metastatic breast cancer (mBC). Everolimus, an oral inhibitor of the mammalian target of rapamycin, has restored sensitivity in endocrine-resistance models and shown anticancer activity in early-phase mBC clinical trials. This analysis evaluated efficacy and safety of everolimus in combination with tamoxifen in patients with mBC resistant to aromatase inhibitors (AIs). PATIENTS AND METHODS This open-label, phase II study randomly assigned postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative, AI-resistant mBC to tamoxifen 20 mg/d plus everolimus 10 mg/d (n = 54) or tamoxifen 20 mg/d alone (n = 57). Randomization was stratified by primary and secondary hormone resistance. Primary end point was clinical benefit rate (CBR), defined as the percentage of all patients with a complete or partial response or stable disease at 6 months. No formal statistical comparison between groups was planned. RESULTS The 6-month CBR was 61% (95% CI, 47 to 74) with tamoxifen plus everolimus and 42% (95% CI, 29 to 56) with tamoxifen alone. Time to progression (TTP) increased from 4.5 months with tamoxifen alone to 8.6 months with tamoxifen plus everolimus, corresponding to a 46% reduction in risk of progression with the combination (hazard ratio [HR], 0.54; 95% CI, 0.36 to 0.81). Risk of death was reduced by 55% with tamoxifen plus everolimus versus tamoxifen alone (HR, 0.45; 95% CI, 0.24 to 0.81). The main toxicities associated with tamoxifen plus everolimus were fatigue (72% v 53% with tamoxifen alone), stomatitis (56% v 7%), rash (44% v 7%), anorexia (43% v 18%), and diarrhea (39% v 11%). CONCLUSION This study suggests that tamoxifen plus everolimus increased CBR, TTP, and overall survival compared with tamoxifen alone in postmenopausal women with AI-resistant mBC.

Docetaxel reintroduction in patients with metastatic castration-resistant docetaxel-sensitive prostate cancer: a retrospective multicentre study

To investigate the potential benefit of reintroducing docetaxel chemotherapy in patients with progressive metastatic castration‐resistant prostate cancer (mCRPC) who had initially responded to first‐line docetaxel‐based regimen.

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.

The use of estramustine phosphate in the modern management of advanced prostate cancer.

What’s known on the subject? and What does the study add?

Prior long response to androgen deprivation predicts response to next-generation androgen receptor axis targeted drugs in castration resistant prostate cancer

BACKGROUND There is an urgent need for qualified predictive biomarkers of sensitivity for the treatments used in patients with castration-resistant prostate cancer (CRPC). We attempted to identify ready-to-use clinical predictors of improved outcome in metastatic CRPC (mCRPC) patients treated with next generation androgen receptor (AR) axis targeted drugs. PATIENTS AND METHODS We reviewed a cohort of patients who received AR axis targeted drugs for CRPC at two major French cancer centres. The predictive role of several clinical, biological and radiological parameters on progression-free survival (PFS) was studied. RESULTS The study cohort consisted of 173 patients. Median duration of response to initial androgen deprivation therapy (ADT) (time to castration resistance, TTCRPC) was 17.8 months. The 50% prostate-specific antigen (PSA) response rate to AR axis targeted drugs was 16% (95% confidence interval (CI): 6-27) and 41% (95% CI: 30-47) in patients with TTCRPC of under and over 12 months respectively (p=0.005). Median PFS was 2.8 months (95% CI: 2.1-3.9) and 5.8 (95% CI: 4.6-7.8; HR: 0.58, p=0.002). In patients treated with post-docetaxel enzalutamide (n=57), median PFS was 2.8 months and 8.6 months, (Hazard ratio (HR)=3.1; 95% CI: 1.6-5.8, p=0.0016) according to TTCRPC, whereas no difference was observed in placebo-treated patients (n=27). The 50% PSA response rate to enzalutamide was 8% (95% CI: 0-38) and 58% (95% CI: 42-73) in patients with a TTCRPC of under and over 12 months respectively (p<0.001). CONCLUSION The previous duration of response to ADT is a predictor of sensitivity to next generation AR axis targeted drugs in patients with mCRPC.

A phase III trial of personalized chemotherapy based on serum tumor marker decline in poor-prognosis germ-cell tumors: Results of GETUG 13.

LBA4500 Background: Poor-prognosis GCT (IGCCCG, J Clin Oncol 1997) remains a challenge with no improvement in the 50% survival demonstrated in phase III trials for 25 years. Day 21 serum tumor marker decline rate identified a subgroup of patients (pts) with a better outcome (J Clin Oncol 2004, 22: 3868-76). The hypothesis we tested in this study is that treatment allocation based on early tumor marker decline will improve the progression-free survival (PFS). METHODS Pts with IGCCCG poor-prognosis GCT were treated with a first cycle of BEP. AFP and hCG were assessed at day 18-21: 1) Pts with a favorable decline continued BEP for a total of 4 courses (Fav-BEP); 2) Pts with an unfavorable decline were randomized to receive either BEP (Unfav-BEP) or a dose-dense regimen (Unfav-dose-dense), consisting of paclitaxel-BEP plus day-10 oxaliplatin x 2 cycles, followed by 2 cycles of cisplatin, ifosfamide, and continuous infusion bleomycin (depending on lung function) + G-CSF. The primary endpoint was PFS (hypothesis: 20% difference, type 1 error: 5%, power 80%, 196 randomized pts needed). RESULTS 263 pts were enrolled and 254 were evaluable at day 21 (6 early deaths, 3 withdrawals): 51 pts (20%) had favorable tumor marker decline and 203 had unfavorable decline (randomized: 105 Unfav-dose-dense arm, 98 Unfav-BEP). The prognostic value of early tumor marker decline (Fav-BEP vs Unfav-BEP) was confirmed: 70% vs 48% for 3-year PFS (p=0.01), and 84% vs 65% for overall survival (OS) (p=0.02). The 3-year PFS was 59% in the Unfav-dose-dense arm vs 48% in the Unfav-BEP arm (p=0.05; HR: 0.66 [0.44-1.00]). 3-year OS was 73% and 65%, respectively. More ≥ grade 2 neurotoxicity (21% vs 4%) and more hematotoxicity occurred in the dose-dense arm, with no excess febrile neutropenia (17% each arm) or toxic deaths (1 each arm). Salvage high-dose chemotherapy + stem-cell transplant were required in 6% in the Unfav-dose-dense arm and 16% in the Unfav-BEP arm (p=0.01). CONCLUSIONS An algorithm of individualized treatment intensification determined by the rate of early tumor marker decline reduces the risk of progression or death in men with poor-prognosis GCT. CLINICAL TRIAL INFORMATION NCT00104676.

Everolimus for patients with metastatic renal cell carcinoma refractory to anti-VEGF therapy: results of a pooled analysis of non-interventional studies.

AIM To assess the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who failed one or two anti-VEGF therapies. PATIENTS AND METHODS Data from four prospective, non-interventional studies conducted in Germany, France, Greece and Austria were pooled for this analysis. Patients with mRCC of any histology (clear cell or non-clear cell) were included. VEGF-refractory patients received everolimus 10mg/day until disease progression or unacceptable toxicity. The primary objective was to determine everolimus efficacy as measured by time to progression (TTP; from baseline to progression). RESULTS The overall population comprised 632 patients; 493 patients received everolimus in the second-line setting. Most patients were of favourable/intermediate MSKCC risk (91%), had clear cell mRCC (89%), and had undergone nephrectomy (89%). Median TTP was 6.3months (95% confidence interval [CI], 5.9-6.8) for the overall population and 6.4months (95% CI, 5.8-6.9) for the second-line everolimus population. Similarly, median progression-free survival was 5.5months (95% CI, 5.0-6.1) for the overall population and 5.8months (95% CI, 5.0-6.4) for second-line everolimus population. Best tumour response (n=349) was complete or partial remission in 12% of patients and stable disease in 59% of patients. Overall population median overall survival (OS) was 11.2months (95% CI, 9.0-not reached). Commonly reported adverse events (AEs) (any grade) were stomatitis (25%), anaemia (15%) and asthenia (11%). CONCLUSIONS Results of this pooled analysis provide evidence of safety and effectiveness of second-line everolimus in routine clinical use and support everolimus as a standard of care for VEGF-refractory patients with mRCC.

Everolimus for patients with metastatic renal cell carcinoma (mRCC) refractory to anti-VEGF therapy: Preliminary results of a pooled analysis of noninterventional studies.

392 Background: In RECORD-1, the oral mTOR inhibitoreverolimus significantly improved PFS compared with placebo in patients with mRCC refractory to 1 or 2 prior VEGFr-TKIs. Here, we provide prospective data from European countries on everolimus use in patients with mRCC after failure of anti-VEGF therapy. METHODS To evaluate the safety and efficacy of everolimus in routine clinical practice, data were pooled from 4 prospective, noninterventional studies conducted in Germany, France, Greece, and Austria. RESULTS Data from the first 6 months of treatment are available for 534 patients. At baseline, median time since diagnosis of first metastasis from RCC was 1.8 years, and 91% of patients were of favorable or intermediate MSKCC risk prognosis. Predominantly clear cell mRCC was evident in 90% of patients, and most patients had prior nephrectomy (89%). Best overall response by investigator assessment was partial response in 13%, stable disease in 56%, and progressive disease in 32%. Overall, 77% of patients experienced ≥1 adverse event (AE) and 22% experienced ≥1 serious AE. AEs occurring in >5% of patients included stomatitis (25%), anemia (13%), asthenia (9%), fatigue (8%), pneumonitis (8%), rash (8%), diarrhea (7%), decreased appetite (7%), hypertriglyceridemia (6%), dyspnea (6%), nausea (6%), and peripheral edema (5%). Serious AEs occurring in >2% of patients included stomatitis (3.4%), general health deterioration (2.2%), anemia (2.1%), dyspnea (2.1%), and pneumonitis (2.1%). Median everolimus duration was 4.8 months. Treatment was discontinued due to disease progression in 50% of patients and AEs in 24% of patients. A similar proportion of patients had Karnofsky performance status ≥70 at baseline (86%) and at end of analysis (80%). Updated data will be available in February 2012. CONCLUSIONS Preliminary results of this pooled analysis of 4 European studies substantiate the safety of everolimus reported in the pivotal RECORD-1 trial and provide evidence for the effectiveness of everolimus in routine use. The results support the use of everolimus as a standard of care for VEGF-refractory patients with mRCC.

Clinical benefits of non-taxane chemotherapies in unselected patients with symptomatic metastatic castration-resistant prostate cancer after docetaxel: the GETUG-P02 study.

To evaluate the overall benefits of non‐taxane chemotherapies in a non‐selected population including unfit patients presenting with symptoms and pain.

Who dies from prostate cancer in a Western country? A multicenter analysis.

211 Background: In the last 30 years, a major shift in initial staging has occurred for men with prostate cancer (CaP) in many Western countries, with the incidence of detectable metastases at diagnosis decreasing from more than half the cases in the 1970s to currently less than 10%. Still, prostate cancer is the second killing neoplasm in men. We used two prospective databases of patients with castration-resistant prostate cancer (CRPC) to describe the natural history of metastatic CRPC in the modern era. METHODS The outcome of 190 men with CaP treated for metastatic disease from 2007-2011 was studied. Characteristics of patients who died from CaP were analyzed. RESULTS After a median follow-up of 6.8 years, 112 patients had died from CaP and 109 were assessable for presence of metastasis at initial diagnosis. Of these 109 pts, 53 (49%) had detectable metastasis at diagnosis: 43 pts (81%), 6 pts (11%) and 17 pts (32%) had bone, visceral; and lymph nodes metastases, respectively. Overall, 10 pts (19%) had more than one metastatic site. Median time to CRPC was 16 months (range: 3-122 months) and median overall survival was 5 years (CI 95%: 4.6 - 6.6 years) for these pts with detectable metastasis at diagnosis. Among patients with localized CaP at diagnosis (n=56; 51%), 23 pts (41%) had T stage ≥ 3, 23 pts (41%) had a Gleason score ≥ 8. Their median PSA was 15 ng/ml (4-400). Overall, 39 pts (70%) were classified as having a high-risk CaP. 13 patients (23%) dying from CaP had an initial Gleason score ≤ 6. The median overall survival was 7 years (CI 95%: 6.1 - 9.1 years). CONCLUSIONS In the modern era, approximately half of the patients eventually dying from CaP had detectable metastases at diagnosis. The paradigm of patients progressing from localized disease to metastatic disease and eventually death is represented only in the other half. Further efforts should be made to conduct clinical trials in patients with newly diagnosed metastatic prostate cancer.