Jean Marc Ferrero

Multinational, Double-Blind, Phase III Study of Prednisone and Either Satraplatin or Placebo in Patients With Castrate-Refractory Prostate Cancer Progressing After Prior Chemotherapy: The SPARC Trial

PURPOSEnThis multinational, double-blind, randomized, placebo-controlled, phase III trial assessed the efficacy and tolerability of the oral platinum analog satraplatin in patients with metastatic castrate-refractory prostate cancer (CRPC) experiencing progression after one prior chemotherapy regimen.nnnPATIENTS AND METHODSnNine hundred fifty patients were randomly assigned (2:1) to receive oral satraplatin (n = 635) 80 mg/m(2) on days 1 to 5 of a 35-day cycle and prednisone 5 mg twice daily or placebo (n = 315) and prednisone 5 mg twice daily. Primary end points were progression-free survival and overall survival (OS). The secondary end point was time to pain progression (TPP).nnnRESULTSnA 33% reduction (hazard ratio [HR] = 0.67; 95% CI, 0.57 to 0.77; P < .001) was observed in the risk of progression or death with satraplatin versus placebo. This effect was maintained irrespective of prior docetaxel treatment. No difference in OS was seen between the satraplatin and placebo arms (HR = 0.98; 95% CI, 0.84 to 1.15; P = .80). Compared with placebo, satraplatin significantly reduced TPP (HR = 0.64; 95% CI, 0.51 to 0.79; P < .001). Satraplatin was generally well tolerated, although myelosuppression and GI disorders occurred more frequently with satraplatin.nnnCONCLUSIONnOral satraplatin delayed progression of disease and pain in patients with metastatic CRPC experiencing progression after initial chemotherapy but did not provide a significant OS benefit. Satraplatin was generally well tolerated. These results suggest activity for satraplatin in patients with CRPC who experience progression after initial chemotherapy.

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

BACKGROUNDnEarly 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.nnnMETHODSnIn 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.nnnFINDINGSnBetween 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.nnnINTERPRETATIONnDocetaxel should not be used as part of first-line treatment for patients with non-castrate metastatic prostate cancer.nnnFUNDINGnFrench Health Ministry and Institut National du Cancer (PHRC), Sanofi-Aventis, AstraZeneca, and Amgen.

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

BACKGROUNDnToxicity, 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.nnnMETHODSnThe 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.nnnFINDINGSnData 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.nnnINTERPRETATIONnPhysicians 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.nnnFUNDINGnFrench Health Ministry and Institut National du Cancer (PHRC), Sanofi-Aventis, Astra-Zeneca, and Amgen.

Sunitinib Stimulates Expression of VEGFC by Tumor Cells and Promotes Lymphangiogenesis in Clear Cell Renal Cell Carcinomas

Sunitinib is an antiangiogenic therapy given as a first-line treatment for renal cell carcinoma (RCC). While treatment improves progression-free survival, most patients relapse. We hypothesized that patient relapse can stem from the development of a lymphatic network driven by the production of the main growth factor for lymphatic endothelial cells, VEGFC. In this study, we found that sunitinib can stimulate vegfc gene transcription and increase VEGFC mRNA half-life. In addition, sunitinib activated p38 MAPK, which resulted in the upregulation/activity of HuR and inactivation of tristetraprolin, two AU-rich element-binding proteins. Sunitinib stimulated a VEGFC-dependent development of lymphatic vessels in experimental tumors. This may explain our findings of increased lymph node invasion and new metastatic sites in 30% of sunitinib-treated patients and increased lymphatic vessels found in 70% of neoadjuvant treated patients. In summary, a therapy dedicated to destroying tumor blood vessels induced the development of lymphatic vessels, which may have contributed to the treatment failure. Cancer Res; 77(5); 1212-26. ©2017 AACR.

Cisplatin Nephrotoxicity: A Multivariate Analysis of Potential Predisposing Factors

Study Objective. To evaluate the usefulness of biologic and pharmacologic parameters for early identification of cisplatin‐induced renal dysfunction.

Effect of Neoadjuvant Chemotherapy on the Surgical Treatment of Patients With Locally Advanced Breast Cancer Requiring Initial Mastectomy.

BACKGROUNDnThe aim of this study was to assess the rate of breast-conserving surgery (BCS) after neoadjuvant chemotherapy (nCT) in patients for whom mastectomy (MT) was, initially, the only conceivable surgical option.nnnPATIENTS AND METHODSnBetween 2007 and 2012, 168 patients from a single center received nCT. Among these patients, we focused on the ones who received nCT (n = 119, [70.8%]) to decrease tumor size and thus to potentially allow a conservative surgical treatment. For these patients, MT was initially the only possible surgical treatment.nnnRESULTSnAmong the 119 patients included, 118 presented with an invasive ductal carcinoma. The mean tumor size before nCT, measured using magnetic resonance imaging, was 41.6 mm (range, 15-110 mm) and 25.3 mm (range, 0-90 mm) after nCT. Eighty-six patients (72.3%) underwent BCS, and oncoplastic techniques were used in 29 patients (33.6%). Only 4.3% (5 patients) of patients who were treated with BCS needed additional surgery because of positive surgical margins. The median follow-up was 41.1 months (95% confidence interval [CI], 35.2-48.3). Five-year overall survival after BCS and MT were 77% (95% CI, 63-92) and 77% (95% CI, 63-95) respectively. Five-year disease-free survival after BCS and MT were 74% (95% CI, 64-86) and 59% (95% CI, 40-89) (not significant), respectively.nnnCONCLUSIONnnCT for selective patients with chemosensitive breast tumor leads to a significant MT to BCS conversion rate. The type of surgery does not seem to affect the patients overall and disease-free survival rates. Oncoplastic procedures can help to extend BCS after nCT.

Anticancer Activity and Tolerance of Treatments Received Beyond Progression in Men Treated Upfront with Androgen Deprivation Therapy With or Without Docetaxel for Metastatic Castration-naïve Prostate Cancer in the GETUG-AFU 15 Phase 3 Trial

BACKGROUNDnAndrogen deprivation therapy (ADT) plus docetaxel is the standard of care in fit men with metastatic castration-naive prostate cancer (mCNPC) following results from GETUG-AFU 15, CHAARTED, and STAMPEDE. No data are available on the efficacy of treatments used for metastatic castration-resistant prostate cancer (mCRPC) in men treated upfront with ADT plus docetaxel for mCNPC.nnnOBJECTIVEnTo investigate the efficacy and tolerance of subsequent treatments in patients treated upfront with chemo-hormonal therapy for mCNPC.nnnDESIGN, SETTING, AND PARTICIPANTSnRetrospective data from the GETUG-AFU 15 phase 3 trial were collected for treatments received for mCRPC.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnFor the first three lines of salvage treatment for mCRPC we investigated the biochemical progression-free survival, maximum prostate-specific antigen (PSA) decline, overall survival, and tolerance.nnnRESULTS AND LIMITATIONSnOverall, 245 patients received at least one treatment for mCRPC. For docetaxel used in first-line, a PSA decline ≥50% was observed in 25/66 (38%) and in 4/20 patients (20%) who had received upfront ADT alone and ADT plus docetaxel (p=0.14). The median biochemical progression-free survival was 6.0 mo (95% confidence interval: 3.6-7.7) and 4.1 mo (95% confidence interval: 1.3-4.9), respectively. For docetaxel used in first- or second-line, a PSA decline ≥50% was observed in 36/80 (45%) and in 4/29 patients (14%) who had received upfront ADT alone and ADT plus docetaxel (p=0.07). PSA declines ≥50% were observed with bicalutamide in 12/28 (43%) and 4/23 patients (17%) who had received upfront ADT alone and ADT plus docetaxel. Among men treated upfront with ADT plus docetaxel who received abiraterone or enzalutamide for mCRPC, 10/19 patients (53%) achieved a PSA decline ≥50%. Few grade 3-4 events occurred. Study limitations include the observational design and retrospective characteristics of this analysis, without standardized therapeutic salvage protocols, and the limited number of patients in some of the treatment subgroups.nnnCONCLUSIONSnDocetaxel rechallenge following progression to mCRPC after upfront ADT plus docetaxel for mCNPC was active only in a limited number of patients. Available data on abiraterone and enzalutamide support maintained efficacy in this setting. The lack of standardized therapeutic protocols for men developing mCRPC limits the comparability between patients.nnnPATIENT SUMMARYnRechallenging docetaxel at castration-resistance was active only in a limited number of patients treated upfront with chemo-hormonal therapy for metastatic castration-naive prostate cancer. Anticancer activity was suggested with abiraterone or enzalutamide in this setting.

Hormone receptors status: a strong determinant of the kinetics of brain metastases occurrence compared with HER2 status in breast cancer

Breast cancer (BC) metastatic behavior varies according to the hormone receptors (HR) and HER2 statuses. Indeed, patients with triple-negative (TN) and HER2+ tumors are at higher risk of brain metastases (BM). The objective of this multinational cohort was to evaluate BM kinetics depending on the BC subtype. We retrospectively analyzed a series of BC patients with BM diagnosed in four European institutions (1996–2016). The delay between BC and BM diagnoses (BM-free survival) according to tumor biology was estimated with the Kaplan–Meier method. A multivariate analysis was performed using the Cox proportional hazards regression model. 649 women were included: 32.0% HER2−/HR+, 24.8% TN, 22.2% HER2+/HR− and 21.0% HER2+/HR+ tumors. Median age at BM diagnosis was 56 (25–85). In univariate analysis, BM-free survival differed depending on tumor biology: HER2−/HR+ 5.3xa0years (95% CI 4.6–5.9), HER2+/HR+ 4.4xa0years (95% CI 3.4–5.2), HER2+/HR− 2.6xa0years (95% CI 2.2–3.1) and TN 2.2xa0years (95% CI 1.9–2.7) (pu2009<u20090.001). It was significantly different between HR+ and HR- tumors (5.0 vs. 2.5 years, pu2009<u20090.001), and between HER2+ and HER2− tumors (3.2 vs. 3.8 years, pu2009=u20090.039). In multivariate analysis, estrogen-receptors (ER) and progesterone-receptors (PR) negativity, but not HER2 status, were independently associated with BM-free survival (hazard ratiou2009=u20091.36 for ER, pu2009=u20090.013, 1.31 for PR, pu2009=u20090.021, and 1.01 for HER2+ vs. HER2− tumors, pu2009=u20090.880). HR− and HER2+ tumors are overrepresented in BC patients with BM, supporting a higher risk of BM in these biological subtypes. HR status, but not HER2 status, impacts the kinetics of BM occurrence.

First results of a phase II trial to assess the efficacy of efavirenz in patients with metastatic androgen-independent prostate cancer.

251 Background: This Phase II trial assessed the efficacy of efavirenz, a non-nucleoside reverse transcriptase inhibitor in patients with asymptomatic HRPC [hormone refractory prostate cancer] who progressed, before docetaxel based chemotherapy. Preclinical studies showed that efavirenz, via Line-1 inhibition, could block proliferation and induced re-differentiation of prostate cancer cell line. We then investigated if efavirenz treatment can delay biological and clinical progression.nnnMETHODSnThe primary objective was to assess the efficacy of efavirenz in patients, with no clinical symptom related to disease progression. Each patient received efavirenz 600 mg/day until objective biological progression or study discontinuation. It was possible to increase the dose (up to 1200 mg daily) in case of PSA progression at 3 months. Efficacy was measured in terms of 3-month non-progression. Based on a 2-stage Simons design, a total of 16 non-progressions out of 54 eligible patients were required to claim efficacy.nnnRESULTSn61 patients were enrolled in the study with 53 eligible for the primary endpoint. At baseline, median age was 71 years and median PSA level was 49.6 ng/mL. A total of 15/53 (28%) non-progressions were observed at 3 months. As patients are still being followed, overall survival, PSA progression free survival and symptomatic progression free survival at one year will be presented. Sixty patients were assessable for toxicity. Of these, 9 (15%) experienced at least one grade III/IV toxicity i.e. neuropsychiatric adverse events already reported in efavirenz-treated HIV patients. With regard to pharmacokinetics (PK), preliminary data indicates variability in the 3-month efavirenz concentration. Ongoing preliminary analyses suggest a better response in patients with elevated (>3000ng/ml) plasmatic concentration.nnnCONCLUSIONSnCurrent analyses do not allow to claim efficacy of Efavirenz at the 600 mg dose. The ongoing analysis of the relationship between plasmatic concentration of efavirenz and treatment efficacy could confirm that higher doses of efavirenz may constitute an efficient treatment. A phase I dose escalation study is currently being performed.

External validation of Modified Breast Graded Prognostic Assessment for breast cancer patients with brain metastases: A multicentric European experience

BACKGROUNDnSeveral prognostic scores have been developed to estimate survival of breast cancer (BC) patients with brain metastases (BM). Modified Breast Graded Prognostic Assessment (GPA), based on a single-institution cohort of 1552 patients, has been proposed as refinement of Breast-GPA. In addition to age, tumour subtype and KPS, Modified Breast-GPA comprises number of BM. This study was designed to validate Modified Breast-GPA.nnnPATIENTS AND METHODSnClinical data of 668 BC patients diagnosed with BM at four institutions between 1996 and 2016 were reviewed. Patients were classified by Breast-GPA and Modified Breast-GPA. Overall survival (OS) was calculated from time of BM diagnosis to death or last follow-up. Cox proportional models were used to calculate hazard-ratios and their 95% CI. The performances of Breast-GPA and Modified Breast-GPA were compared using Harrells concordance index.nnnRESULTSnMedian age at BM diagnosis was 56 years (range 24-85). At last follow-up, 632 patients (94.6%) had died. Median OS was 8.1 months (95% CI 6.9-9.4). The number of BM (1-3 vs. >3) was significantly associated with OS in univariate analysis (pxa0<xa00.001) and having >3 BM was identified as a negative prognostic factor in multivariate analysis. Both Breast-GPA and Modified Breast-GPA accurately predicted OS (pxa0<xa00.001 for both scores). Performance of Modified Breast-GPA was better: concordance indices were 0.6390 (95% CI, 0.6381 to 0.6399) and 0.6647 (95% CI, 0.6639 to 0.6655) for Breast-GPA and Modified Breast-GPA, respectively (pxa0<xa00.001).nnnCONCLUSIONSnThis work provides the first external independent validation of Modified Breast-GPA and confirms its better performance as compared to Breast-GPA.