The Impact of an Enrolment in Clinical Trial on Tolerance and Pathological Response for Patients Treated by Neoadjuvant MVAC Against an Invasive Bladder Cancer. A Retrospective Comparative Study.

INTRODUCTION: MVAC (Methotrexate, Vinblastine, Adriamycin, and Cisplatin) neoadjuvant chemotherapy a standard treatment for invasive bladder cancer is associated with mainly haematological toxicities. Randomized clinical trials remain a gold standard for treatment outcomes and efficacy assessment. Patients enrolled in clinical trials are selected and tend to benefit from a stricter follow-up unlike everyday clinical practice patients. Conversely, real-life observational studies better define the effectiveness of treatments in clinical routine practice. The aim of this study is to analyse the impact of clinical trial monitoring on MVAC-related toxicities. MATERIAL AND METHODS: Patients with an infiltrative localized bladder cancer treated by MVAC neoadjuvant chemotherapy between 2013 and 2019 were enrolled, and divided into 2 groups: patients included in a clinical trial namely "VESPER study" during their treatment and patients treated in clinical routine practice. RESULTS: Out of 59 patients were enrolled in this retrospective study, 13 patients were included in a clinical trial. Clinical characteristics were similar between the 2 groups. Comorbidities were more frequent in the nonclinical trial group (NCTG). Completed 6 cures treatment proportion was higher in the clinical trial group (CTG) (69.2% vs. 50%). Yet, in this group, patients had more doses reduction (38.5% vs. 19.6%). The proportion of complete pathologic response was higher in patients enrolled in clinical trial (53.8% vs. 39.1%). Statistically, the expected stricter monitoring due to clinical trial enrolment had no impact on the complete pathologic response and clinically relevant toxicities. DISCUSSION: When compared to conventional clinical practice, clinical trial enrolment induced no significant difference on the pathologic complete response or toxicity rate. Further large prospective studies are needed to confirm these data.

Perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin in muscle-invasive bladder cancer (VESPER): survival endpoints at 5 years in an open-label, randomised, phase 3 study.

BACKGROUND: The optimal perioperative chemotherapy for patients with muscle-invasive bladder cancer is not defined. The VESPER (French Genito-Urinary Tumor Group and French Association of Urology V05) trial reported improved 3-year progression-free survival with dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (dd-MVAC) versus gemcitabine and cisplatin (GC) in patients who received neoadjuvant therapy, but not in the overall perioperative setting. In this Article, we report on the secondary endpoints of overall survival and time to death due to bladder cancer at 5-year follow-up. METHODS: VESPER was an open-label, randomised, phase 3 trial done at 28 university hospitals or comprehensive cancer centres in France, in which adults (age ≤18 years and ≤80 years) with primary bladder cancer and histologically confirmed muscle-invasive urothelial carcinoma were randomly allocated (1:1; block size four) to treatment with dd-MVAC (every 2 weeks for a total of six cycles) or GC (every 3 weeks for a total of four cycles). Overall survival and time to death due to bladder cancer (presented as 5-year cumulative incidence of death due to bladder cancer) was analysed by intention to treat (ITT) in all randomly assigned patients. Overall survival was assessed by the Kaplan-Meier method with the treatment groups compared with log-rank test stratified for mode of administration of chemotherapy (neoadjuvant or adjuvant) and lymph node involvement. Time to death due to bladder cancer was analysed with an Aalen model for competing risks and a Fine and Gray regression model stratified for the same two covariates. Results were presented for the total perioperative population and for the neoadjuvant and adjuvant subgroups. The trial is registered with ClinicalTrials.gov, NCT01812369, and is complete. FINDINGS: From Feb 25, 2013, to March 1, 2018, 500 patients were randomly assigned, of whom 493 were included in the final ITT population (245 [50%] in the GC group and 248 [50%] in the dd-MVAC group; 408 [83%] male and 85 [17%] female). 437 (89%) patients received neoadjuvant chemotherapy. Median follow-up was 5·3 years (IQR 5·1-5·4); 190 deaths at the 5-year cutoff were reported. In the perioperative setting (total ITT population), we found no evidence of association of overall survival at 5 years with dd-MVAC treatment versus GC treatment (64% [95% CI 58-70] vs 56% [50-63], stratified hazard ratio [HRstrat] 0·79 [95% CI 0·59-1·05]). Time to death due to bladder cancer was increased in the dd-MVAC group compared with in the GC group (5-year cumulative incidence of death: 27% [95% CI 21-32] vs 40% [34-46], HRstrat 0·61 [95% CI 0·45-0·84]). In the neoadjuvant subgroup, overall survival at 5 years was improved in the dd-MVAC group versus the GC group (66% [95% CI 60-73] vs 57% [50-64], HR 0·71 [95% CI 0·52-0·97]), as was time to death due to bladder cancer (5-year cumulative incidence: 24% [18-30] vs 38% [32-45], HR 0·55 [0·39-0·78]). In the adjuvant subgroup, the results were not conclusive due to the small sample size. Bladder cancer progression was the cause of death for 157 (83%) of the 190 deaths; other causes of death included cardiovascular events (eight [4%] deaths), deaths related to chemotherapy toxicity (four [2%]), and secondary cancers (four [2%]). INTERPRETATION: Our results on overall survival at 5 years were in accordance with the primary endpoint analysis (3-year progression-free survival). We found no evidence of improved overall survival with dd-MVAC over GC in the perioperative setting, but the data support the use of six cycles of dd-MVAC over four cycles of GC in the neoadjuvant setting. These results should impact practice and future trials of immunotherapy in bladder cancer. FUNDING: French National Cancer Institute.

Refining the Characterization and Outcome of Pathological Complete Responders after Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: Lessons from the Randomized Phase III VESPER (GETUG-AFU V05) Trial.

Neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy and pelvic lymph node dissection is the optimal treatment for patients with muscle-invasive bladder cancer. In recent years, the VESPER trial showed a statistically significant higher progression-free survival with dd-MVAC (dose dense methotrexate, vinblastine, doxorubicin, and cisplatin) compared to GC (gemcitabine and cisplatin). In the present report, we refine the characterization and outcome of patients whose cystectomy specimens were pathologically free of cancer (pathological complete response, pCR). We confirm that these patients portend a better outcome as compared to patients with invasive disease (≥pT1N0) at cystectomy. Nested variant and lymphovascular invasion were identified as adverse predictive factors of pCR. Progression-free survival probability three years after pCR on cystectomy was about 85%, regardless of the NAC regimen. A lower creatinine clearance and the delivery of less than four cycles were associated with a higher risk of relapse. Predicting the efficacy of NAC remains a major challenge. The planned analysis of molecular subtypes in the VESPER trial could help predict which patients may achieve complete response and better outcome.

Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial.

PURPOSE: The optimal perioperative chemotherapy regimen for patients with nonmetastatic muscle-invasive bladder cancer is not defined. PATIENTS AND METHODS: Between February 2013 and March 2018, 500 patients were randomly assigned in 28 French centers and received either six cycles of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) once every 2 weeks or four cycles of gemcitabine and cisplatin (GC) once every 3 weeks before surgery (neoadjuvant group) or after surgery (adjuvant group). We report the primary end point of the GETUG-AFU V05 VESPER trial (ClinicalTrials.gov identifier: NCT01812369): progression-free survival (PFS) at 3 years. Secondary end points were time to progression and overall survival. RESULTS: Four hundred thirty-seven patients (88%) received neoadjuvant chemotherapy; 60% of patients received the planned six cycles in the dd-MVAC arm, 84% received four cycles in the GC arm, and thereafter, 91% and 90% of patients underwent surgery, respectively. Organ-confined response (< ypT3N0) was observed more frequently in the dd-MVAC arm (77% v 63%, P = .001). In the adjuvant group, 40% of patients received six cycles in the dd-MVAC arm, and 81% of patients received four cycles in the GC arm. For all patients in the clinical trial, 3-year PFS was improved in the dd-MVAC arm, but the study did not meet its primary end point (3-year rate: 64% v 56%, hazard ratio [HR] = 0.77 [95% CI, 0.57 to 1.02], P = .066); nevertheless, the dd-MVAC arm was associated with a significantly longer time to progression (3-year rate: 69% v 58%, HR = 0.68 [95% CI, 0.50 to 0.93], P = .014). In the neoadjuvant group, PFS at 3 years was significantly higher in the dd-MVAC arm (66% v 56%, HR = 0.70 [95% CI, 0.51 to 0.96], P = .025). CONCLUSION: In the VESPER trial, dd-MVAC improved 3-years PFS over GC. In the neoadjuvant group, a better bladder tumor local control and a significant improvement in 3-year PFS were observed in the dd-MVAC arm.

The Anti-Nectin 4: A Promising Tumor Cells Target. A Systematic Review.

The Nectin cell adhesion protein 4 (Nectin-4) is overexpressed in multiple human malignancies. Such aberrant expression is correlated with cancer progression and poor prognostic. Nectin-4 has emerged as a potential biomarker and promising targeted therapy. This review aimed to gather the current state of the literature about Nectin-4 relevance in preclinical tumor models and to summarize its clinical relevance regarding cancer. A systematic assessment of literature articles was performed by searching in PUBMED (MEDLINE) from the database inception to May 2021, following PRISMA guidelines. Preclinical models unanimously demonstrated membrane and cytoplasmic location of the Nectin-4. Furthermore, Nectin-4 was overexpressed whatever the location of the solid tumors. Interestingly, a heterogeneity of Nectin-4 expression has been highlighted in bladder urothelial carcinoma. High serum Nectin-4 level was correlated with treatment efficiency and disease progression. Finally, generated anti-drug-conjugated targeting Nectin-4 induced cell death in multiple tumor cell lines. Nectin-4 emerges as a promising target for anticancer drugs development because of its central role in tumorigenesis, and lymphangiogenesis. Enfortumab vedotin targeting Nectin-4 demonstrated encouraging results and should be extended to other types of solid tumors.

TAXOMET: A French Prospective Multicentric Randomized Phase II Study of Docetaxel Plus Metformin Versus Docetaxel Plus Placebo in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Docetaxel (DOCE) is a standard of care in metastatic castration-resistant prostate cancer (mCRPC). Several retrospective studies suggested a decrease in Prostate Cancer incidence and mortality with metformin (MET). MET has also demonstrated anti-tumor activity in Prostate Cancer preclinical models, with increased apoptosis when added to DOCE. We aimed at exploring the role of MET in combination with DOCE in mCRPC. PATIENTS AND METHODS: Non-diabetic mCRPC patients were randomly assigned to receive DOCE 75 mg/m2 every 21 days + prednisone (5 mg. BID) with either MET 850 mg BID (D+M) or placebo (D+P) up to 10 cycles. Prostate-Specific Antigen (PSA) response ≥50% from baseline was the primary end point. Secondary end points included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), toxicity and quality of life (QoL). RESULTS: Out of 99 patients were randomized (D+M = 50; D+P = 49) in 10 French centers. The median follow-up was 86 (IQR 73-88) months. The PSA-response rate reached 66% in the D+M arm, but was not different from that observed in the D+P arm (63%, P = 0,94). In the D+M and D+P arms, the ORR was 28% and 24%, the median PFS was 7.8 and 6.0 months and the median OS was 27 and 20 months (ns), respectively. Diarrhea grade I to II was more frequent in the MET arm (66% vs. 43%). No impairment of QoL was observed. CONCLUSION: MET addition failed to improve the standard DOCE regimen in mCRPC. Further research targeting tumor cell metabolism should be performed.

Chemotherapy for Muscle-invasive Bladder Cancer: Impact of Cisplatin Delivery on Renal Function and Local Control Rate in the Randomized Phase III VESPER (GETUG-AFU V05) Trial.

BACKGROUND: Cisplatin-based combination chemotherapy before surgery is the standard of care for muscle-invasive bladder cancer. However, the optimal chemotherapy modalities have not been precisely defined to date. PATIENTS AND METHODS: In the VESPER trial, patients received after randomization either gemcitabine and cisplatin (GC, 4 cycles) or methotrexate, vinblastine, doxorubicin and cisplatin (dose dense [dd]-MVAC, 6 cycles). Creatinine clearance (CrCl) was calculated before each cycle according to the Cockroft and Gault formula. Definition criteria for local control after neoadjuvant chemotherapy included pathological complete response (ypT0N0), pathological downstaging (

Second-generation hormonotherapy in prostate cancer and bone microenvironment.

Prostate cancer (Pca) is the most commonly diagnosed cancer affecting men in France. Before the age of 75 years old, 1 in 8 French men will have Pca. Androgen deprivation therapies (ADT) remain the standard of care. Such therapies induce significant bone loss. The bone-remodelling cycle depends on the androgen synthesis signalling pathways. Furthermore, age-specific hormonal decline plays a key role in the decrease in bone mass. As a result, the older the patients, the more likely they are to have osteoporosis if they are treated with hormone therapy. Their risk of osteoporotic fracture has an impact on their quality of life and their capacity of independent living. In recent years, newer hormone therapies (acetate abiraterone, enzalutamide, apalutamide and darolutamide) have proved efficient in metastatic castration-resistant Pca (mCRPC) patients as well as in hormone naïve patients, and actually in nonmetastatic diagnosis. The combination of these treatments with ADT highly inhibit androgen production pathways. They are prescribed to aged patients undergoing bone density loss after first-generation antiandrogen treatment. Specific recommendations for bone health management in Pca patients are currently lacking. To date, bone mineral density in patients treated with second-generation hormone therapy has never been assessed in a prospective study. This review aims at reviewing what is known about the impact of second-generation hormonotherapy on bone microenvironment.

Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin With or Without Panitumumab in Patients With Advanced Urothelial Carcinoma: Multicenter, Randomized, French Unicancer GETUG/AFU 19 Study.

This study looked at whether epidermal growth factor receptor inhibition by the monoclonal antibody panitumumab could increase the efficacy of standard chemotherapy in advanced urothelial cancer. Results were disappointing, with higher toxicity and no improvement in efficacy in the combination arm. BACKGROUND: Epidermal growth factor receptor (EGFR) overexpression is frequent and associated with poor outcome in urothelial carcinoma. EGFR inhibition could improve the antitumor activity of chemotherapy. PATIENTS AND METHODS: Patients with advanced, treatment-naïve, histologically confirmed advanced urothelial carcinoma and no HRAS or KRAS mutation in the primary tumor received dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) without or with the anti-EGFR monoclonal antibody panitumumab (Pmab). A randomized (1:2) phase II design was used with progression-free survival (PFS) as the primary endpoint. RESULTS: Ninety-seven eligible patients were randomized; 96 patients were evaluable for toxicity and 87 for efficacy. The median PFS were 6.8 months (95% confidence interval [CI], 6.3-9.2) for dd-MVAC and 5.7 months (95% CI, 4.6-6.4 months) for dd-MVAC+Pmab. For both immunohistochemical and molecular definition of basal/squamous-like (BASQ) tumors, no difference was observed in objective response rates or PFS between the two arms in BASQ and non-BASQ tumors. CONCLUSION: dd-MVAC+Pmab was associated with more serious adverse events and no improvement in efficacy outcomes.

Effectiveness of a nurse-led telephone follow-up in the therapeutic management of patients receiving oral antineoplastic agents: a randomized, multicenter controlled trial (ETICCO study).

PURPOSE: The use of oral cancer drugs (OAD) has increased over the last two decades. The objective of this study was to measure the impact of a nurse-led telephone follow-up in the therapeutic management of patients treated with an OAD regarding toxicity, medication adherence and quality of life. METHODS: A randomized, multicenter, controlled trial was conducted. All consecutive over 18-year-old patients, treated in medical oncology, radiotherapy, or hematology departments, receiving OAD for any cancer were invited to participate to the study. A total of 183 patients treated for solid or hematological cancers with an OAD were randomly assigned to receive a nurse-led telephone follow-up or standard care for 24 weeks. Data were collected between 2015 and 2018. RESULTS: Nurse telephone follow-up did not improve the global score toxicity in the intervention group. However, telephone calls directed by trained nurses induced a significant decrease in number of patients with grade 3 adverse events throughout the follow-up [OR 0.45 (IC à 95%) (0.23, 0.9)](P = 0.03). There was no significant difference in quality of life and medication adherence between groups at any follow-up time point. CONCLUSIONS: In this first French real-life study, the advice provided by qualified nurses via phone calls improved the management of grade 3 toxicities but failed to demonstrate an improvement of all grades of toxicities. More prospective studies are needed to confirm the impact of telephone calls on the toxicities related to OAD. TRIAL REGISTRATION: Clinical trial registration is NCT02459483. Protection committee SUD-ESTI registration is 2015-A00527-42 on 13 April 2015. National Agency for the Safety of Medicines and Health Products registration is 150619-B on the 27 may 2015.

[Docetaxel for octogerian metastatic castration-resistant prostate cancer patient: A multicentric ten years' experience]. / Docétaxel dans le cancer de prostate métastatique résistant à la castration chez l'octogénaire : analyse multicentrique de dix ans de pratique.

INTRODUCTION: There is very few data about the management of elderly patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of this study was to analyze the management of patients aged 80 and over treated with docetaxel for a mCRPC. METHODS AND MATERIALS: Clinical and pathological characteristics of octogerians treated with docetaxel were collected retrospectively from 3 French centers from 2009 to 2019. Patient's outcome, treatments administered before and/or after docetaxel were also analyzed. RESULTS: Data of 89 patients could be analyzed. A total of 20.2 % of patients received the standard regimen and 79.8 % received an adapted one. Patients in the adapted group were significantly older than in standard one. Other patient's characteristics - including the geriatric scales - were similar. Dose reductions for toxicity were more frequent in the standard group (P=0.04). The median overall survival of the total population was 13.3 months. It was longer in the standard group than in the adapted group (26.1 months vs 12.4 months=0.01). In multivariate analysis, the type of docetaxel regimen (standard versus adapted) was an independent predictor of survival. CONCLUSION: This study suggests the benefit of the standard management even in oldest patients. A geriatric evaluation should certainly be processed in patients with poor oncogeriatric scale in order to select the sub-population able to receive the full dose standard docetaxel regimen.

Clinical progression is associated with poor prognosis whatever the treatment line in metastatic castration resistant prostate cancer: The CATS international database.

AIM OF THE STUDY: Our goal was to evaluate the impact of progression type (prostate-specific antigen [PSA] only, radiological or clinical) at initiation of first-, second- and third life-extending therapy (LET) on treatment outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients, by performing a post-hoc analysis using data from the CATS international registry. METHODS: The 669 consecutive mCRPC patients of the CATS registry were classified according to their type of progression at initiation of each LET: PSA only (PSA-p), radiological (±PSA) (Radio-p); or clinical (±PSA, ±radiological) progression (Clin-p). Overall survival (OS), the primary endpoint, was calculated from initiation of the first-, second- and third-LET to death for each sequence. RESULTS: Median OS was shorter in the Clin-p group compared with the PSA-p group (14-month difference in first line; around 7-month difference in second- and third line). Shorter progression-free survival (PFS) was also observed in Clin-p patients, whatever the treatment is. Clinical progression seemed to be associated with a shorter duration of therapy with androgen receptor-targeted therapy (ART) compared with taxanes. CONCLUSIONS: Clinical progression at initiation of a LET is associated with poor outcomes including shorter PFS and OS as well as clinical and biological features of aggressive disease. Stratifying patients in clinical trials according to disease progression type may prevent selection bias and data heterogeneity. In daily practice, first signs of clinical progression may prompt physicians to consider starting a new LET, independently of PSA levels.

Leptomeningeal Metastases in Renal Cell Carcinoma at Initial Diagnosis: 2 Case Reports and Literature Review.

Leptomeningeal metastasis (LM) in solid tumors are rare, even more in renal cell carcinoma (RCC). To date there is a lack of consensual treatment modalities of leptomeningeal metastasis. Furthermore, with the improvement of outcomes and more effective systemic targeted therapies, the management of leptomeningeal metastasis becomes a real challenge. We here report two cases of RCC with leptomeningeal metastasis at initial diagnosis. Both patients had concurrent adjacent skull bone metastasis. Therapeutic management of both patients consisted in surgical resection, followed by radiotherapy in one case. Systemic treatment was delayed according to current recommendations for the management of metastatic RCC. The aim of this work is to report the therapeutic approach and related outcomes and also provide a review of the currently available literature on leptomeningeal disease in renal cell carcinoma. Indeed, local treatment with curative outcome of meningeal location in RCC should be performed specially in LM at initial diagnosis.

Current management of stage I testicular germ cell tumors in a French cancer institute. A practice analysis over the 10 past years.

BACKGROUND: Testicular Germ Cell Tumors (TGCTs) represent the most frequent malignant tumour among young male adults. Orchiectomy alone cure 80% of stage I. Standard options after orchiectomy include radiotherapy (RT), chemotherapy (CT) by 1 cycle of carboplatin AUC 7 or active surveillance (SV) for seminomatous GCTs (SGCT) and retroperitoneal lymphadenectomy (RPLND), CT by 1 or 2 cycles of Bleomycine Etoposide Cisplatine (BEP) or active surveillance for nonseminomatous GCTs (NSGCT). Adjuvant treatments decrease the relapse rate after orchiectomy with substantial toxicities without any benefit on overall survival. Recent guidelines accorded utmost importance on SV rather than adjuvants strategies. The main objective of this study was to describe our current practice over the 10 past years in regard of these recommendations. METHODS: Data of 50 patients with stage I GCT treated in our institute were collected between 2006 and 2016. Demographic and anatomopathologic data were reported. Clinical practice in our center was analyzed during two periods [2006-2011] and [2012-2016] according to the European Association of Urology Guidelines in 2011. RESULTS: Patient's median age was 35.3 years. The analysis of clinical practice during the last 10 years showed that in SGCT, main treatment was RT than SV and CT. This option declined over the years (89% between 2006-2010 versus 53% between 2011-2016) whereas SV was more often employed (27% between 2011-2016 versus none between 2006-2010). Surveillance was used for 64% of NSGCT. CONCLUSIONS: In our center, RT was less used over the years for the benefit of SV which is recommended by guidelines.

Denosumab Toxicity When Combined With Anti-angiogenic Therapies on Patients With Metastatic Renal Cell Carcinoma: A GETUG Study.

BACKGROUND: About one-third of patients with renal cell carcinoma (RCC) have detectable metastases at diagnosis. Among them, bone is the second most frequent metastatic site. Treatment of metastatic RCC mostly relies on anti-angiogenic (AA) therapies and, more recently, immunotherapy. Skeletal-related events (SREs) can be prevented with bone-targeted therapies such as denosumab (Dmab), which has demonstrated superiority when compared with zoledronic acid in solid tumors. However, there is limited available data on Dmab toxicity in combination with AA therapies in patients with kidney cancer. The objective of this study was to retrospectively analyze the toxicity profile (mainly osteonecrosis of the jaw [ONJ] and hypocalcemia) in patients with metastatic renal cell carcinoma (mRCC) treated with Dmab and AA therapy combination. PATIENTS AND METHODS: We conducted a multicenter retrospective study among centers from the French Groupe d'Etudes des Tumeurs Uro Genitales (GETUG). Patients with bone metastases who received concurrently or sequentially AA therapy and Dmab were included in this study. RESULTS: A total of 41 patients with mRCC were enrolled. Although no patient presented with severe hypocalcemia, ONJ occurred in 7 (17%) of 41 patients. Interestingly, all patients with ONJ received the Dmab and AA combination in the first line of treatment; among these patients, 3 patients had no risk factor other than the Dmab and AA combination. CONCLUSION: The incidence of ONJ was high in this real-life population of patients with mRCC treated with AA therapies combined with Dmab. This toxicity signal should warn physicians about this combination in the mRCC population.

Results of the FLAC European Database of Metastatic Castration-Resistant Prostate Cancer Patients Treated With Docetaxel, Cabazitaxel, and Androgen Receptor-Targeted Agents.

BACKGROUND: Several agents have demonstrated an overall survival (OS) benefit in patients with metastatic castration-resistant prostate cancer (mCRPC); however, the optimal sequencing of these therapies is unknown as a result of a lack of prospective randomized controlled trials. This retrospective study aimed to identify clinical factors influencing outcomes and to determine optimal treatment sequencing in patients with mCRPC treated with cabazitaxel (CABA) and/or androgen receptor-targeted agents (ART) after androgen-deprivation therapy (ADT) and docetaxel (DOC). PATIENTS AND METHODS: Records of 574 consecutive patients treated (2012-2016) at 44 centers in 6 countries were retrospectively examined. RESULTS: A total of 267 patients received ADT → DOC → CABA (group 1), 183 patients ADT → DOC → ART → CABA (group 2), and 124 patients ADT → DOC → CABA → ART (group 3), with respective median OS from diagnosis of mCRPC of 38.3, 44.45, and 53.9 months (P = .012 for group 3 vs. group 1). Multivariate analysis showed response to first ADT ≤ 12 months, Gleason score of 8 to 10, clinical progression, and high prostate-specific antigen levels at mCRPC diagnosis were associated with worse OS. Prior receipt of ART did not influence activity of CABA. CONCLUSION: OS appeared to increase with the number of life-extending therapies, with a sequence including DOC, CABA, and an ART providing the greatest OS benefit.

Cancer du rein métastatique : recommandations et perspectives en 1re ligne.

METASTATIC RENAL CELL CARCINOMA: WHICH TREATMENTS IN FIRST-LINE SETTING?: The treatment of metastatic kidney cancer has radically changed during the past decade, notably with the development of tyrosin kinase inhibitors (TKI) and the rise of immunotherapy. Kidney cancer, especially clear cell renal cell carcinoma (CCRC) which regroups 80% of cases, is associated with increased angiogenesis and VEGF (vascular endothelial growth factor) dependent signaling pathways. Targeted therapies have therefore modified therapeutical strategies through direct inhibition of VEGF on its receptor or inhibition of the PI3K/AKT/mTOR pathway. Consequently, new anti-angiogenic molecules are now available as first line treatment and are to be prioritized depending on tumoral histology and prognostic groups. These new molecules have allowed increased patient survival. Immunotherapy is again currently transforming our first line therapeutical approach of metastatic kidney cancer with numerous ongoing therapeutical trials including combination of targeted therapies with immune checkpoint inhibitors or association of various immunotherapies. Beyond these major first line changes, difficulties still remain in the therapeutical sequence which is crucial in the care of these patients. This report aims to underline first line therapeutical recommendations in metastatic kidney cancer and expose results of recent assays.

Sequencing of Taxanes and New Androgen-targeted Therapies in Metastatic Castration-resistant Prostate Cancer: Results of the International Multicentre Retrospective CATS Database.

BACKGROUND: The optimal sequence of life-extending therapies in metastatic castration-resistant prostate cancer (mCRPC) is unknown. OBJECTIVE: To evaluate outcomes among mCRPC patients treated with docetaxel (DOC), cabazitaxel (CABA), and a novel androgen receptor-targeted agent (ART; abiraterone acetate or enzalutamide) according to three different sequences. DESIGN, SETTING, AND PARTICIPANTS: Data from 669 consecutive mCRPC patients were retrospectively collected between November 2012 and October 2016. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the prostate-specific antigen (PSA) response (decrease ≥50% from baseline) to each therapy. Secondary endpoints included best clinical benefit, time to PSA progression, radiological progression-free survival (rPFS), overall survival (OS), and toxicity. RESULTS AND LIMITATIONS: A total of 158 patients received DOC→CABA→ART (group 1), 456 received DOC→ART→CABA (group 2), and 55 received ART→DOC→CABA (group 3). At baseline, PSA progression only and Gleason <8 were more common in group 3. PSA response on DOC was lower in group 3 than in other groups (p=0.02) and PSA response on CABA was higher in the second than in the third line (p=0.001). In Group 3, rPFS on ART (6.6 mo) and DOC (9.2 mo) was also shorter than in the other groups. OS calculated from the first life-extending therapy reached 34.8, 35.8, and 28.9 mo in groups 1, 2 and 3, respectively (p=0.007). Toxicity was comparable between the arms. The main limitations of the trial are its retrospective design and the low number of patients in group 3. CONCLUSIONS: In this retrospective trial, sequencing of DOC, CABA, and one ART, was associated with median OS of up to 35.8 mo. CABA seemed to retain its activity regardless of treatment sequence. DOC activity after ART appeared to be reduced, but the data are insufficient to conclude that cross-resistance occurs. PATIENT SUMMARY: The order of drugs administered to patients with metastatic castration-resistant prostate cancer could impact their efficacy, with cabazitaxel appearing to retain its activity whatever the therapeutic sequence.