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Background: The taxanes docetaxel and cabazitaxel prolong overall survival for men with metastatic castration-resistant prostate cancer (mCRPC), with cabazitaxel approved in the postdocetaxel setting only. Recent data suggest they have similar efficacy but a different safety profile in the first-line mCRPC setting., Objective: To assess patient preference between docetaxel and cabazitaxel among men who received one or more doses of each taxane and did not experience progression after the first taxane., Design, Setting, and Participants: Chemotherapy-naïve patients with mCRPC were randomized 1:1 to receive docetaxel (75 mg/m 2 every 3 wk × 4 cycles) followed by cabazitaxel (25 mg/m 2 every 3 wk × 4 cycles) or the reverse sequence. Randomization was stratified by prior abiraterone or enzalutamide use., Outcome Measurements and Statistical Analysis: The primary endpoint was patient preference, assessed via a dedicated questionnaire after the second taxane. Secondary endpoints included reasons for patient preference, prostate-specific antigen response, radiological progression-free survival, and overall survival. This clinical trial is registered at ClinicalTrials.gov as NCT02044354., Results and Limitations: Of 195 men randomized, 152 met the prespecified modified intent-to-treat criteria for analysis. Overall, 66 patients (43%) preferred cabazitaxel, 40 (27%) preferred docetaxel, and 46 (30%) had no preference (p = 0.004, adjusted for treatment period effect). More patients preferred treatment period 1 (43%, 95% confidence interval [CI] 36-52%) versus period 2 (27%, 95% CI 20-34%). Patient preference for cabazitaxel was mainly related to less fatigue (72%), better quality of life (64%), and other adverse events (hair loss, pain, nail disorders, edema). Adverse events were consistent with the known safety profile of each drug., Conclusions: A significantly higher proportion of chemotherapy-naïve men with mCRPC who received both taxanes preferred cabazitaxel over docetaxel. Less fatigue and better quality of life were the two main reasons driving patient choice., Patient Summary: Men with metastatic castration-resistant prostate cancer preferred cabazitaxel over docetaxel for chemotherapy, mainly because of less fatigue and better quality of life., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: A post-hoc analysis of the phase-3 LATITUDE study assessed the impact of abiraterone acetate plus prednisone (AA+P) on overall survival (OS) and radiographic progression-free survival (rPFS) in men with metastatic castration-sensitive prostate cancer (mCSPC) and visceral metastases (VM)., Methods: Newly diagnosed mCSPC patients were randomized (1:1) to AA+P and androgen deprivation therapy (ADT) or placebo+ADT. Patients with VM in liver or lungs with or without other soft tissue and bone metastases (based on CT/MRI) at baseline were analyzed, after 51.8 months' median follow-up. Co-primary endpoints, OS and rPFS, were analyzed., Results: Among 1199 patients enrolled, 228 (19%) had VM at baseline (114 each in AA+P and placebo groups), of which 53 (23.2%; AA+P = 29, Placebo = 24) had liver metastases and 117 (51.3%; AA+P = 60, Placebo = 57) had lung metastases. In patients with VM, treatment with AA+P versus placebo showed an improvement in OS (median 55.4 vs 33.0 months; HR = 0.582; 95%CI = 0.406-0.835;P = 0.0029) and rPFS (median 30.7 vs 18.3 months; HR = 0.527; 95%CI = 0.366-0.759;P = 0.0005), comparable to that of patients without VM. AA+P versus placebo in lung metastases patients was associated with greater improvement in OS (HR = 0.60; 95%CI = 0.35-1.04;P = 0.0678) than in liver metastases patients (HR = 0.82; 95%CI = 0.41-1.66;P = 0.5814). AA+P versus placebo showed improvement in rPFS in lung metastases patients (HR = 0.50; 95%CI = 0.29-0.89;P = 0.0157), but not in liver metastases patients (HR = 1.05; 95%CI = 0.53-2.09; P = 0.8970)., Conclusion: AA+P treatment improved both rPFS and OS in men with mCSPC and visceral disease, especially those with lung metastases. Men with liver metastases had a poorer prognosis and their optimal treatment remains to be defined., Registration: ClinicalTrials.gov, number NCT01715285., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SM, GL, UR, and PH are employees of Janssen Research & Development and hold company stock. KF has received personal fees from Amgen, Astellas, AstraZeneca, Bayer, Clovis, Curevac, Essa, Genentech, Janssen, Merck Sharp and Dohme (MSD), Orion, and Sanofi. KNC's institution has received funding from Janssen for this study. MÖ received personal fees from Janssen and Sanofi. SF has served on advisory boards for Janssen, Boehringer Ingelheim Pharma, and Aventis, and has received honorarium from Janssen, and travel and accommodation expenses from Aventis. GB and NM declared no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cabazitaxel was shown to improve overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) after abiraterone/enzalutamine and docetaxel failure, though benefit by the presence of DNA damage repair (DDR) defects is unknown. With the advent of poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) in partially overlapping indications with cabazitaxel, we aimed to determine cabazitaxel activity in men with mCRPC according to their DDR status., Methods: This is a retrospective multicenter study that enrolled patients with mCRPC treated with cabazitaxel who had undergone DDR tumour tissue profiling. Patients with at least one deleterious germline or somatic alterations were considered DDR positive (DDR+). Each DDR + patient has been matched with a DDR negative (DDR-) from the same institution who underwent the same test. An exploratory cohort of patients found to be DDR + by liquid biopsy was also included. Prostate specific antigen (PSA) decline≥50% (PSA50), PSA progression-free survival (PFS, PSA-PFS), radiographic PFS (rPFS), clinical PFS or radiographic PFS (c/rPFS) and OS were evaluated., Results: Among 190 men (95 DDR+, 95 DDR-) with tissue sequencing, PSA50 was achieved with cabazitaxel in 29/92 (32%) and 33/92 (36%) in patients with DDR+ and DDR- (P = 0.64). The median rPFS was 5.33 months [95%CI 4.34-7.04] versus 5.75 months [95%CI 4.67-7.27] (P = 0.55). The median OS was 15.4 months [95%CI 12.16-26.6] and 11.5 months [95%CI 9.76-14.4] (P = 0.036), respectively. No PSA50 responses on cabazitaxel were observed in BRCA1/2 patients previously treated with PARPi (n = 10). Similar outcomes with cabazitaxel were observed in the liquid biopsy cohort (n = 63 DDR+)., Conclusions: Our study suggests that cabazitaxel is active in patients with mCRPC regardless of their DDR status, although its activity in men pretreated with a PARPi may be lower., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mihaela Aldea – nothing to disclose. Laurent Lam – nothing to disclose. Emeline Orillard - Honoraria: Astellas, Janssen; Travel, Accommodations, Expenses: Pfizer, Amgen. Casilda Llacer Perez - Travel, Accommodations, Expenses: Astellas Pharma, Angelini Pharma. Mathilde Saint-Ghislain – nothing to disclose. Gwenaelle Gravis - Honoraria (Institution) - Pfizer, BMS, MSD, AstraZeneca, Astellas, Janssen, Bayer; Advisory, Consultancy – BMS, Pfizer, AstraZeneca, Janssen, Sanofi, Ipsen, Bayer; Travel, Accommodations, Expenses: BMS, Pfizer, AstraZeneca, Janssen, Sanofi, Ipsen, MSD. Aude Flechon - Honoraria and Travel, Accommodations, Expenses: AZ Sanofi, Astellas, Janssen AAA. Guilhem Roubaud – Honoraria, travel and advisory: Astellas, Sanofi, Janssen, Astra Zeneca, Ipsen, Pfizer Philippe Barthelemy – Honoraria: Astellas; Advisory, Consultancy: Janssen-Cilag, Sanofi, MSD, BMS, Pfizer, Novartis, Ipsen, Roche; Travel, Accommodations, Expenses: BMS, Amgen, Pfizer, Janssen-Cilag, Roche, Ipsen. Francesco Ricci – nothing to disclose. Frank Priou – nothing to disclose. Zoe Neviere – nothing to disclose. Mathilde Beaufils – nothing to disclose. Brigitte Laguerre – Honoraria and Travel, Accommodations, Expenses: SANOFI, ASTELLAS, BMS, AstraZeneca, Pfizer, JANSSEN. Anne Claire Hardy – Advisory Board: Roche, AstraZeneca, Pfizer, Novartis, GSK, Clovis, Seagen. Carole Helissey - Advisory board: Sanofi, Janssen, Astellas, Roche, Astra Zeneca. Raffaele Ratta – Consulting/Advisory board: AstraZeneca, Astellas, Pfizer, MSD, Bristol-Myers Squibb; Travel, Accommodations, Expenses: Pfizer, Ipsen, Astellas. Delphine Borchiellini - Principal/sub-Investigator of Clinical Trials for: Astellas, AstraZeneca, BMS, Exelixis, Infinity, Janssen, MSD, Novartis, Pfizer, Roche. Honoraria or Advisory/Consultancy: Astellas, AstraZeneca, BMS, Ipsen, MSD, Novartis, Pfizer, Sanofi. Travel, Accommodations, Expenses: BMS, Ipsen, Janssen, Roche. Cedric Pobel – Travel accommodations/Expenses from Amgen and Sandoz. Florence Joly - Expert Board and/or Lectures: Pfizer, GSK, AstraZeneca, Roche, Janssen, Astellas, IPSEN, MSD, BMS, Clovis, Sanofi Bayer. Elena Castro – Consulting/Advisory board: AstraZeneca, Astellas, Bayer, Janssen; Honoraria: Astellas, AstraZeneca, Bayer, Clovis, Janssen, MSD, Pfizer; Research funding (institution): AstraZeneca, Bayer, Janssen; Travel, Accommodations, Expenses: AstraZeneca, Bayer, Janssen. Antoine Thiery-Vuillemin – Honoraria: Pfizer, AstraZeneca, Sanofi, Janssen, Novartis, Ipsen, Roche/Genentech, Bristol-Myers Squibb, MSD, Astellas Pharma; Consulting/Advisory board: Pfizer, AstraZeneca, Sanofi, Janssen, Novartis, Ipsen, Roche, Bristol-Myers Squibb, MSD, Astellas Pharma; Research funding (institution): Pfizer; Travel, Accommodations, Expenses: Roche, MSD, Janssen, Bristol-Myers Squibb. Giulia Baciarello – Honoraria: Janssen, Roche; Consulting or Advisory Role: Amgen, Astellas Oncology, Janssen, Roche; Travel, Accommodations, Expenses: Astellas Oncology, Ipsen, Janssen, Roche. Karim Fizazi - Honoraria - Astellas Pharma, Bayer, Janssen, Sanofi; Consulting or Advisory Role - Amgen (Inst), Astellas Pharma, AstraZeneca (Inst), Bayer, Curevac (Inst), ESSA (Inst), Janssen Oncology, Orion Pharma GmbH, Sanofi; Travel, Accommodations, Expenses – Amgen, Janssen., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Abiraterone acetate (abiraterone) combined with prednisone is a standard of care in metastatic castration-resistant prostate cancer. Recently, benefit in overall survival was reported in metastatic castration-sensitive prostate cancer also, and an extension of indication has been granted. Abiraterone is seldom associated with liver toxicity. The clinical management and the outcome of patients with transaminase increase while on abiraterone have not been described., Patients and Method: We identified 25 men with metastatic prostate cancer and liver function test disorders occurring while on abiraterone treatment from December 2009 to September 2017 in three oncology centres in France., Results: Forty-six liver disorder events occurred in 25 patients while on abiraterone treatment. The median age at liver function test increase was 67 (55-85) years. The incidence of aspartate aminotransférase (AST) (24 events) and that of alanine aminotransférase (ALT) (22 events) increases were similar. Liver toxicity was of grade 1, 2 and 3 (Common Terminology Criteria for Adverse Events. version 4) in 7 (32%), 6 (27%) and 9 (41%) patients for ALT, and in 12 (50%), 6 (25%) and 6 (25%) for AST, respectively. The median time from abiraterone initiation to the detection of liver toxicity was 7.1 (4-95) weeks. The median time from highest ALT/AST increase to normalisation was 6.2 [2-14] weeks. In 13 patients (52%), liver tests spontaneously returned to baseline values, while abiraterone was continued at full dose., Conclusion: Liver function test increase is a rare event that typically occurs within the first two months on abiraterone. Most patients experience normalisation of the tests, either spontaneously or after dose reduction/discontinuation., Competing Interests: Conflict of interest statement E.C. declared having received personal fees from Ipsen, Sanofi, BMS and Pfizer. G.B. declared having received consulting fees from Janssen-Cilag and Sanofi. Y.L. has received honoraria from Sanofi, Janssen, MSD, Roche, BMS, AstraZeneca, Astellas and Seattle Genetics; has received grants from Sanofi, Janssen and MSD and has been an investigator in trials sponsored by MSD, Roche, Astellas, Janssen, Nektar, BMS, Pfizer, Incyte, Clovis, AstraZeneca and Seattle Genetics. L.A. declared serving consulting or advisory role in Novartis, Amgen (Inst), Bristol-Myers Squibb, Bristol-Myers Squibb (Inst), Ipsen (Inst), Roche (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst) and Merck (Inst). C.M. reported receiving grants and personal fees and is a principal investigator/co-principal investigator for Amgen, Astella, AstraZeneca, Bayer, BeiGene, BMS, Genentech, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, Orion and Abbvie. J.A. has received grants and honoraria from AstraZeneca, Roche/Genentech, Novartis, Ipsen and Jansen. O.H. declared having received personal fees from IPSEN, Janssen, Bayer, BMS and Sanofi. S.C. declares serving a consultant role for Janssen, Roche and Merck; that he has received research funding from Astellas and Roche and that he has been beneficiant of travel support from Janssen, Roche and Astellas. K.F. declared having received fees for participation to advisory boards or lectures for Amgen, Astellas, Bayer, Janssen-Cilag, Orion and Sanofi. G.M., P.L. and E.C. declared no disclosure., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: Prostate cancer is the second most common cause of cancer worldwide and is the most frequently detected cancer in the European Union in men over 50 years of age. Androgen deprivation therapy remains the cornerstone of treatment for recurrent or metastatic disease. Unfortunately, nearly all patients will develop resistance to androgen blockade leading to castration-resistant prostate cancer (CRPC). Over the last 10 years, new treatments have dramatically improved overall survival of men with mCRPC. Current therapies are based on AR-axis inhibitors and taxane-based chemotherapies, as well as radiopharmaceuticals and Sipuleucel T., Areas Covered: The authors provide a review of the current field of systemic therapy in metastatic CRPC. This is followed by an in-depth analysis of recent developments in treatment, and the biological rationale behind these therapies., Expert Opinion: Since several trials with docetaxel or novel hormonal agents showed improvement in overall survival in metastatic castration-sensitive prostate cancer, as well as in non-metastatic castration-resistant patients, it is expected that a growing subgroup of patients will be exposed earlier to chemotherapy and to AR targeted agents. It becomes then fundamental to find novel strategies to overcome drug resistance and further improve survival.

Background: Treatment option in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel (DOC), cabazitaxel (CABA) and new hormone therapy (NHT) is limited. Rechallenge with DOC is limited because of cumulative toxicities. This study investigated the activity and safety of CABA rechallenge in mCRPC., Patients and Methods: Clinical data were collected retrospectively in 17 centres in Europe. Eligible patients had undergone rechallenge with cabazitaxel after three previous lines of treatment (DOC, NHT and CABA, in any order). Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Data on toxicities were collected., Results: A total of 69 of 562 patients (Eastern Cooperative Oncology Group performance status 0-1 69%) were rechallenged with CABA (25 mg/m 2 q3w, 58%; 20 mg/m 2 q3w, 27.5%; other, 14.5%) for 1-10 (median 6) cycles; 76.8% received prophylactic granulocyte colony-stimulating factor. Median radiological or clinical PFS with CABA rechallenge was 7.8 months and 11.9 months with initial CABA therapy. OS was 13.7 months (95% confidence interval [CI]: 9.3-15.7) from the first CABA rechallenge cycle, 59.9 months (47.8-67.1) from the first life-extending therapy in mCRPC and 78.3 months (66.4-90.7) from mCRPC diagnosis. Best clinical benefit was improved (34.3%) or stable (47.8%). Lack of response to rechallenge occurred in 17.9% of patients (3.1% with initial CABA). The level of prostate-specific antigen decreased by ≥ 50% in 24% of patients at rechallenge (71% with initial CABA). There was no grade ≥III peripheral neuropathy or nail disorders., Conclusions: CABA rechallenge may be a treatment option without cumulative toxicity in heavily pretreated patients with mCRPC who are still fit and had a progression >3 months after the last CABA injections., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Both docetaxel+androgen deprivation therapy (ADT) and abiraterone acetate 1000mg/d+prednisone/prednisolone 5mg/d+ADT improved survival in patients with metastatic castration-naive prostate cancer. Their use should be offered and guided by patient's own characteristics., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Prostate cancer is one of the most common cancers in men and the fourth leading cause of cancer mortality worldwide. Although major progress has been achieved in the last years for patients with metastatic castrate-resistant prostate cancer (mCRPC), thanks to next-generation androgen receptor axis targeted drugs, taxanes, and bone-targeted agents, immunotherapy has not been widely approved and used for the treatment of prostate cancer. Two large studies with ipilimumab, an anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) antibody reported improved progression-free survival, but not statistically improved overall survival at the primary analysis (CA184 043 and CA184 095)., Case Presentation: Here, we report on two patients who received ipilimumab in these trials and are still in long-term complete remission with a follow-up of 64 and 52 months respectively after the initiation of ipilimumab. Immunohistochemical staining for hMLH1, hMSH2, hMSH6 and PMS2 was performed on archival prostate biopsy samples from one of the two patients; they exhibited normal protein expression. Interestingly for this patient, a high CD3+ and CD8+ T cell infiltration was observed on archival prostate biopsies as well as Treg FoxP3+ T cells., Conclusion: Ipilimumab produces clinical activity in patients with CRPC, including very long responders with no detectable residual disease.

Prostate cancer is initially responsive to androgen deprivation therapy, but most patients eventually develop castration-resistant disease. Enzalutamide is an androgen receptor (AR) inhibitor that targets several steps in the AR signaling pathway and has shown significant efficacy in the treatment of metastatic castration-resistant prostate cancer in patients with or without prior chemotherapy. To provide optimal treatment, it is important to understand the implications of enzalutamide use in the context of other therapies, as recent findings have suggested cross-resistance occurs between and within drug classes. Mutations and splice variants of AR also impact the course of prostate cancer. Future strategies involving enzalutamide should account for previous exposure to taxanes or antiandrogen therapies and the presence of AR variants that could affect efficacy., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The optimal use of new therapies in metastatic castration-resistant prostate cancer (mCRPC) remains to be clarified. Prostate-specific antigen (PSA) response used as a pharmacodynamic end-point may help identify patients with early resistance to new androgen receptor-pathway inhibitors. We aimed to determine the clinical significance of early PSA response (EPR) during therapy with enzalutamide, abiraterone acetate (AA) and orteronel in mCRPC., Methods: Data from patients recruited in clinical trials were studied. PSA values were obtained at baseline and 28 d after treatment initiation. EPR defined as a decline >50% from baseline was calculated according to the Prostate Cancer Working Group 2 criteria. The effects of clinical characteristics on radiographic progression-free survival (rPFS) and overall survival (OS) were examined using the Cox model., Results: EPR was assessed in 118 patients treated in clinical trials and was found to be associated with longer rPFS and OS (P < 0.0001 for both). Median rPFS was 13.9 and 5.6 months (hazard ratio [HR]:0.38, P < 0.001) for patients with and without an EPR, respectively. Median OS was 32.2 months in patients with an EPR and 15.9 months in patients without an EPR (HR: 0.4, P < 0.01). EPR remained prognostic for OS in multivariate analyses (HR: 0.5, p=0.009) that included validated pre-therapeutic prognostic factors for mCRPC. Prognostic values of EPR for rPFS and OS were confirmed in an independent cohort of 95 AA-treated non-trial patients., Conclusions: EPR is an independent prognostic factor in patients with mCRPC treated with next-generation androgen pathway inhibitors and may be useful for the therapeutic management of these patients., (Copyright © 2016 Elsevier Ltd. All rights reserved.)