Sylvestre Le Moulec

Cabazitaxel Remains Active in Patients Progressing After Docetaxel Followed by Novel Androgen Receptor Pathway Targeted Therapies.

BACKGROUND Cabazitaxel, abiraterone acetate (AA), and enzalutamide have been approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) following docetaxel chemotherapy. Whether taxanes and next-generation androgen receptor (AR) axis inhibitors are cross-resistant or not is a subject of debate. OBJECTIVE To evaluate the antitumour activity of cabazitaxel in mCRPC pretreated with abiraterone or enzalutamide. DESIGN, SETTING, AND PARTICIPANTS The antitumour activity of cabazitaxel was assessed in patients with mCRPC and progressive disease after treatment with docetaxel and AA. In parallel, cabazitaxel antitumour activity was studied in enzalutamide-resistant models. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Changes in prostate-specific antigen (PSA) levels and progression-free survival were used to determine the activity of cabazitaxel treatment. Cell proliferation, immunofluorescence, and AR transactivation assay were used in enzalutamide-resistant models. RESULTS AND LIMITATIONS A total of 79 patients who had progressive mCRPC after docetaxel (median: 8 cycles; range: 4-12 mo), and AA (median: 4.8 mo; range:1-55 mo) received cabazitaxel 25mg/m(2) every 3 weeks (median: 6 cycles; range:1-15 cycles). A PSA decline ≥30% was achieved in 48 patients (62%; 95% confidence interval [CI], 51-73), and a decline ≥50% was achieved in 28 patients (35%; 95% CI, 25-47). The median progression-free survival and overall survival were 4.4 and 10.9 mo, respectively. In vitro, cabazitaxel decreased cell viability in both enzalutamide-sensitive and enzalutamide-resistant prostate cancer cells within the same range of concentrations. PC3, an AR-negative cell line, exhibited similar sensitivity to cabazitaxel. CONCLUSIONS Cabazitaxel and AR-pathway inhibitors are not cross-resistant. Preclinical data suggest that cabazitaxel activity does not act mainly through AR axis inhibition. PATIENT SUMMARY The antitumour activity of cabazitaxel, a chemotherapy agent, was studied in prostate cancer resistant to conventional hormonal therapy and to more recent endocrine therapies (abiraterone or enzalutamide). Cabazitaxel retained anticancer activity in more than half of the cases.

Phase III Study of Cabozantinib in Previously Treated Metastatic Castration-Resistant Prostate Cancer: COMET-1

PURPOSE Cabozantinib is an inhibitor of kinases, including MET and vascular endothelial growth factor receptors, and has shown activity in men with previously treated metastatic castration-resistant prostate cancer (mCRPC). This blinded phase III trial compared cabozantinib with prednisone in patients with mCRPC. PATIENTS AND METHODS Men with progressive mCRPC after docetaxel and abiraterone and/or enzalutamide were randomly assigned at a two-to-one ratio to cabozantinib 60 mg once per day or prednisone 5 mg twice per day. The primary end point was overall survival (OS). Bone scan response (BSR) at week 12 as assessed by independent review committee was the secondary end point; radiographic progression-free survival (rPFS) and effects on circulating tumor cells (CTCs), bone biomarkers, serum prostate-specific antigen (PSA), and symptomatic skeletal events (SSEs) were exploratory assessments. RESULTS A total of 1,028 patients were randomly assigned to cabozantinib (n = 682) or prednisone (n = 346). Median OS was 11.0 months with cabozantinib and 9.8 months with prednisone (hazard ratio, 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = .213). BSR at week 12 favored cabozantinib (42% v 3%; stratified Cochran-Mantel-Haenszel P < .001). rPFS was improved in the cabozantinib group (median, 5.6 v 2.8 months; hazard ratio, 0.48; 95% CI, 0.40 to 0.57; stratified log-rank P < .001). Cabozantinib was associated with improvements in CTC conversion, bone biomarkers, and post-random assignment incidence of SSEs but not PSA outcomes. Grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone (71% v 56% and 33% v 12%, respectively). CONCLUSION Cabozantinib did not significantly improve OS compared with prednisone in heavily treated patients with mCRPC and progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers but not PSA outcomes.

Bevacizumab in Patients with Nonsquamous Non–Small Cell Lung Cancer and Asymptomatic, Untreated Brain Metastases (BRAIN): A Nonrandomized, Phase II Study

Purpose: The phase II prospective, noncomparative BRAIN study (NCT00800202) investigated efficacy and safety of bevacizumab in chemotherapy-naïve or pretreated patients with non–small cell lung cancer (NSCLC) and asymptomatic untreated brain metastases to provide data in this previously unexplored subgroup. Experimental Design: Patients with stage IV nonsquamous NSCLC, Eastern Cooperative Oncology Group performance status 0–1, and untreated, asymptomatic brain metastases received first-line bevacizumab (15 mg/kg) plus carboplatin (area under the curve ×6) and paclitaxel (200 mg/m2) every 3 weeks (B + CP), or second-line bevacizumab plus erlotinib (150 mg/d; B + E). Six-month progression-free survival (PFS) was the primary endpoint. The trial could be stopped if there were more than three (B + CP) or more than two (B + E) intracranial hemorrhages. Results: In first-line B + CP cohort (n = 67), 6-month PFS rate was 56.5% with a median PFS of 6.7 months [95% confidence interval (CI), 5.7–7.1] and median overall survival (OS) of 16.0 months. Investigator-assessed overall response rate (ORR) was 62.7%: 61.2% in intracranial lesions and 64.2% in extracranial lesions. Because of low enrolment (n = 24), efficacy results for the second-line B + E cohort were exploratory only; 6-month PFS rate was 57.2%, median PFS was 6.3 months (95% CI, 3.0–8.4), median OS was 12.0 months, and ORR was 12.5%. Adverse events were comparable with previous trials of bevacizumab. One grade 1 intracranial hemorrhage occurred and resolved without sequelae. Conclusions: The BRAIN study demonstrates encouraging efficacy and acceptable safety of bevacizumab with first-line paclitaxel and carboplatin in patients with NSCLC and asymptomatic, untreated brain metastases. Clin Cancer Res; 21(8); 1896–903. ©2015 AACR.

Prostate-specific antigen flare induced by cabazitaxel-based chemotherapy in patients with metastatic castration-resistant prostate cancer

BACKGROUND A prostate-specific antigen (PSA) flare occurs in about 15% of metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel. This flare has no standard definition. Its impact on treatment efficacy is unclear. We sought to evaluate the incidence and characteristics of PSA flare on cabazitaxel, and its impact on survival. METHODS Multicentre retrospective review of consecutive patients treated with cabazitaxel second-line chemotherapy for mCRPC. Collection of baseline characteristics, disease history and PSA levels before and during cabazitaxel therapy. Overall survival (OS) and radiological/clinical progression-free survival (PFS) for patient groups corresponding to different definitions of PSA flare estimated by the Kaplan-Meier method and compared using the log-rank test. RESULTS Overall, 125 patients were included. Median PFS and OS were 6.5 and 13.3 months, respectively. Depending upon the definition used, flare incidence ranged from 8.3% to 30.6%. The flare lasted <2.6 months. A PSA flare followed by a ⩾ 50% decrease was associated with a median PFS and OS of 11.2 and 25.2 months, respectively. Median PFS and OS for a ⩾ 30% rather than ⩾ 5 0% decrease were 10.4 and 16.5 months. These outcomes were not significantly different from those in patients with immediate PSA decreases of ⩾ 50% or ⩾ 30% from baseline, but were significantly better than in patients experiencing no PSA decrease (p = 0.006 and 0.015, respectively, for OS). CONCLUSION The PSA response to cabazitaxel, with or without initial flare, was associated with a strong survival benefit. The taxane-induced flare during the first 12 weeks of therapy can be ignored when evaluating PSA response.

Whole-brain radiation therapy in breast cancer patients with brain metastases

Over the past 10 years, improving the outcome of breast cancer patients with brain metastases has become an important challenge. The suboptimal results of whole-brain radiation therapy (WBRT) in these patients have led to the development of irradiation modalities with new technical and biological approaches. By ensuring better sparing of critical organs such as the hippocampus, highly conformal irradiation therapy may partially preserve long-term neurocognitive functions. An additional radiation boost to the tumor bed improves local control. Radiosensitizing agents and radioprotectors that modify response to radiation have also been designed to improve the efficacy of treatment or prevent neurological toxicity. This Review outlines the current strategies and novel developments in WBRT, with a particular focus on new irradiation modalities and experiences of radiosensitization.

An ambispective observational study in the safety and efficacy of abiraterone acetate in the French temporary authorizations for use (ATU): Predictive parameters of response.

149 Background: The Temporary Authorizations for Use (ATU) procedure is an exceptional measure making available medicinal products that have not yet been granted a Marketing Authorisation. Abiraterone acetate (AA) was available for ATU since December 2010 in France. We then decided to evaluate the tolerance and efficacy of this treatment and identify predictive factors of response. METHODS 82 centers were contacted and clinical data were reported in two months (15th July-19th September 2011). Patients were defined as non-responders in case of interruption of AA due to disease progression or death. PSA values were recorded at each medical visit. Reported toxicities were also recorded. Statistical analyses were descriptive and predictive factors were determined. RESULTS A total of 18 centers accepted to participate in this study including 381 patients. Median age at diagnosis was 63 years. The Gleason score (n=320) were 4-6, 7, and 8-10 in 13.4%, 36.9% and 49.7%, respectively. Before AA, the type of metastasis was bone only, organs only, and bone+organs in 45.4%, 7.9% and 46.7%, respectively. Median PSA before CT and before AA was 58.1 and 137.5 ng/ml, respectively. Median duration of hormonotherapy (HT) before any CT was 34 months. Median duration of CT before AA was 6.1 months with a median number of CT lines of one. Median duration of AA was 117 days. In the non-responders group (n=114), median duration of AA was significantly shorter than in the responders group (n=267), 87 days vs 147 days, respectively (p<0.0001). One third of the patients in the responders group presented a PSA increase over time but continued AA as they clinically improved. Only 13 patients stopped AA for grade 3-4 toxicities. GIeason 8-10 and the number of CT lines (>1) before AA were identified as independent predictive factors of non response. CONCLUSIONS This report is the largest ambispective observational study of AA in an ATU process. PSA values during AA treatment were used as a good indicator of progression. GIeason 8-10 and the number of CT lines (>1) before AA were identified as independent predictive factors and therefore could be used for further strategies in this setting.

Stemness markers characterize IGR-CaP1, a new cell line derived from primary epithelial prostate cancer

Deciphering molecular pathways involved in the early steps of prostate oncogenesis requires both in vitro and in vivo models derived from human primary tumors. However the few recognized models of human prostate epithelial cancer originate from metastases. To date, very few models are proposed from primary tumors and immortalizing normal human prostate cells does not recapitulate the natural history of the disease. By culturing human prostate primary tumor cells onto human epithelial extra-cellular matrix, we successfully selected a new prostate cancer cell line, IGR-CaP1, and clonally-derived subclones. IGR-CaP1 cells, that harbor a tetraploid karyotype, high telomerase activity and mutated TP53, rapidly induced subcutaneous xenografts in nude mice. Furthermore, IGR-CaP1 cell lines, all exhibiting negativity for the androgen receptor and PSA, express the specific prostate markers alpha-methylacyl-CoA racemase and a low level of the prostate-specific membrane antigen PSMA, along with the prostate basal epithelial markers CK5 and CK14. More importantly, these clones express high CD44, CD133, and CXCR4 levels associated with high expression of α2β1-integrin and Oct4 which are reported to be prostate cancer stemness markers. RT-PCR data also revealed high activation of the Sonic Hedgehog signalling pathway in these cells. Additionally, the IGR-CaP1 cells possess a 3D sphere-forming ability and a renewal capacity by maintaining their CSC potential after xenografting in mice. As a result, the hormone-independent IGR-CaP1 cellular clones exhibit the original features of both basal prostate tissue and cancer stemness. Tumorigenic IGR-CaP1 clones constitute invaluable human models for studying prostate cancer progression and drug assessment in vitro as well as in animals specifically for developing new therapeutic approaches targeting prostate cancer stem cells.

Gemcitabine or Gemcitabine Plus Oxaliplatin in the First-Line Treatment of Patients With Advanced Transitional Cell Carcinoma of the Urothelium Unfit for Cisplatin-Based Chemotherapy: A Randomized Phase 2 Study of the French Genitourinary Tumor Group (GETUG V01)

BACKGROUND The optimal chemotherapy for patients with advanced transitional cell carcinoma of the urothelium who are not eligible for cisplatin remains to be defined. OBJECTIVE To assess the activity of gemcitabine alone (GEM) or in combination with oxaliplatin (GEMOX) in a randomized phase 2 trial. DESIGN, SETTING, AND PARTICIPANTS The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors criteria. The sample size was based on a two-stage Fleming design with p0=35% and p1=55%. At the end of the first stage designed to register 20 patients on each treatment arm, the observation of seven or more objective responses would have led to the inclusion of 30 more patients in each arm. RESULTS AND LIMITATIONS From July 2004 to March 2009, 44 patients in 10 centers were randomly assigned into the GEM or the GEMOX arm, 22 on each treatment arm. The median age was 76 yr. Seven patients were included for a performance status (PS) of 2 only. The remaining 37 patients had an impaired renal function, 11 of whom also had a PS of 2. The median creatinine clearance was 45 ml/min (range: 30-80 ml/min). The trial was closed after the first part because the GEMOX arm did not reach the targeted objective response rate to proceed further. CONCLUSIONS Oxaliplatin does not add any significant activity (in terms of response rates) compared with gemcitabine alone in patients with advanced transitional cell carcinoma of the urothelium who are ineligible for cisplatin.

Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castration-resistant prostate cancer: a report from the PETRUS prospective study

Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer (mCRPC) patients. We reported the results of prospective PETRUS study of biomarker assessment in paired primary prostatic tumors, metastatic biopsies and circulating tumor cells (CTCs). Among 54 mCRPC patients enrolled, 38 (70%) had biopsies containing more than 50% tumour cells. 28 (52%) patients were analyzed for both tissue samples and CTCs. FISH for AR-amplification and TMPRSS2-ERG translocation were successful in 54% and 32% in metastatic biopsies and primary tumors, respectively. By comparing CellSearch and filtration (ISET)-enrichment combined to four color immunofluorescent staining, we showed that CellSearch and ISET isolated distinct subpopulations of CTCs: CTCs undergoing epithelial-to-mesenchymal transition, CTC clusters and large CTCs with cytomorphological characteristics but no detectable markers were isolated using ISET. Epithelial CTCs detected by the CellSearch were mostly lost during the ISET-filtration. AR-amplification was detected in CellSearch-captured CTCs, but not in ISET-enriched CTCs which harbor exclusively AR gain of copies. Eighty-eight percent concordance for ERG-rearrangement was observed between metastatic biopsies and CTCs even if additional ERG-alteration patterns were detected in ISET-enriched CTCs indicating a higher heterogeneity in CTCs. Molecular screening of metastatic biopsies is achievable in a multicenter context. Our data indicate that CTCs detected by the CellSearch and the ISET-filtration systems are not only phenotypically but also genetically different. Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients.

Response to cabazitaxel in CRPC patients previously treated with docetaxel and abiraterone acetate.

155 Background: Cabazitaxel, which is a tubulin-binding chemotherapy, and the CYP-17 androgen biosynthesis inhibitor abiraterone acetate (AA) are both approved for patients with metastatic castration resistant prostate cancer (CRPC) following docetaxel chemotherapy. Recent preclinical data suggest that taxanes impact AR signalling and could imply cross-resistance between new AR targeting treatments and taxane chemotherapy. The aim of this study is to evaluate the antitumor activity of cabazitaxel after AA. METHODS We retrospectively evaluated antitumor activity of cabazitaxel in patients (pts) with metastatic CRPC and progressive disease after docetaxel and AA. Radiological response by RECIST, PSA response by PCWG2 criteria and symptomatic benefit were examined. RESULTS 89 pts were treated with third-line cabazitaxel, after docetaxel (median 8 cycles; range: 4-12), and AA (median duration of treatment 4.8 months, range: 1-55 months). At cabazitaxel initiation median age was 68 years (range: 53-83), ECOG performance status was 0 or 1 in 70% of pts, and median PSA was 309 ng/ml (range: 3.75-9150). Bone, lymph node and visceral metastases were present in 80 pts (89%), 37 pts (41%), and 12 pts (13%) respectively. An average of 6 cycles of cabazitaxel (range 1-15) were administered. All pts had PSA data available and 44 (49%; 95% CI 39-60%) had a 50% or greater PSA decline. In the 35 pts with RECIST evaluable disease, 7 (20%; 95% CI 8-37%) had a partial response. CONCLUSIONS In men with metastatic CRPC cabazitaxel appears to retain activity in the third-line setting following docetaxel and AA.