Comparison of RNA Marker Panels for Circulating Tumor Cells and Evaluation of Their Prognostic Relevance in Breast Cancer.

Liquid biopsy is a promising tool for therapy monitoring of cancer patients, but a need for further research in this field exists in order to improve sensitivity, specificity, standardization and minimize costs. In our present study, we evaluated two panels of transcripts related with the presence of circulating tumor cells (CTCs) (Panel 1: CK19, EpCAM, SCGB2A2 and Panel 2: EMP2, SLC6A8, HJURP, MAL2, PPIC and CCNE2) in two cohorts of breast cancer patients (metastatic and early). A blood cell fraction possibly containing CTCs was isolated with density gradient centrifugation, followed by RNA isolation and qPCR using TaqMan® or RT-qPCR using hybridization probes. The positivity rates of the investigated panels were similar, albeit higher in metastatic (69.4% Panel 1, 75.0% Panel 2; total 86.1%) compared to early (18.9% Panel 1, 23.3% Panel 2; total 31.1%) breast cancer patients. CK19, SCGB2A2, EMP2, HJURP, MAL2, and CCNE2 individually correlated with shorter overall survival in the metastatic patient cohort. The findings highlight the additional value of Panel 2 markers, which are in contrast to CK19 and EpCAM not solely linked to an epithelial phenotype.

Current Developments in Cellular Therapy for Castration Resistant Prostate Cancer: A Systematic Review of Clinical Studies.

Recently, the development of immunotherapies such as cellular therapy, monoclonal antibodies, vaccines and immunomodulators has revolutionized the treatment of various cancer entities. In order to close the existing gaps in knowledge about cellular immunotherapy, specifically focusing on the chimeric antigen receptors (CAR) T-cells, their benefits and application in clinical settings, we conducted a comprehensive systematic review. Two co-authors independently searched the literature and characterized the results. Out of 183 records, 26 were considered eligible. This review provides an overview of the cellular immunotherapy landscape in treating prostate cancer, honing in on the challenges of employing CAR T-cell therapy. CAR T-cell therapy is a promising avenue for research due to the presence of an array of different tumor specific antigens. In prostate cancer, the complex microenvironment of the tumor vastly contributes to the success or failure of immunotherapies.

Comparison of microfluidic platforms for the enrichment of circulating tumor cells in breast cancer patients.

PURPOSE: Circulating tumor cells (CTCs) hold promise to be a non-invasive measurable biomarker in all cancer stages. Because the analysis of CTCs is still a technical challenge, we compared different types of microfluidic enrichment protocols to isolate these rare cells from the blood. METHODS: Blood samples from patients with early and metastatic breast cancer (BC) were processed using the microfluidic Parsortix® technology employing (i) a single-step cell separation using the standard GEN3D6.5 microfluidic cassette, (ii) a two-step separation with an upfront pre-enrichment, and (iii) a two-step separation with a different type of cassette. In the enriched cells, the gene expression levels of CTC-related transcripts were assessed using quantitative real-time PCR (qPCR) by Taqman® and Lightcycler (LC) technology. RESULTS: 23/60 (38.3%) BC samples were assigned as positive due to the presence of at least one gene marker beyond the threshold level. The prevalence of epithelial markers was significantly higher in metastatic compared to early BC (EpCAM: 31.3% vs. 7.3%; CK19: 21.1% vs. 2.4%). A high level of concordance was observed between CK19 assessed by Taqman® and LC technology, and for detection of the BC-specific gene SCGB2A2. An upfront pre-enrichment resulted in lower leukocyte contamination, at the cost of fewer tumor cells captured. CONCLUSION: The Parsortix® system offers both reasonable recovery of tumor cells and depletion of contaminating leukocytes when the single-step separation using the GEN3D6.5 cassette is employed. Careful selection of suitable markers and cut-off thresholds is an essential point for the subsequent molecular analysis of the enriched cells.

MALAT1 Fusions and Basal Cells Contribute to Primary Resistance against Androgen Receptor Inhibition in TRAMP Mice.

Targeting testosterone signaling through androgen deprivation therapy (ADT) or antiandrogen treatment is the standard of care for advanced prostate cancer (PCa). Although the large majority of patients initially respond to ADT and/or androgen receptor (AR) blockade, most patients suffering from advanced PCa will experience disease progression. We sought to investigate drivers of primary resistance against antiandrogen treatment in the TRAMP mouse model, an SV-40 t-antigen driven model exhibiting aggressive variants of prostate cancer, castration resistance, and neuroendocrine differentiation upon antihormonal treatment. We isolated primary tumor cell suspensions from adult male TRAMP mice and subjected them to organoid culture. Basal and non-basal cell populations were characterized by RNA sequencing, Western blotting, and quantitative real-time PCR. Furthermore, effects of androgen withdrawal and enzalutamide treatment were studied. Basal and luminal TRAMP cells exhibited distinct molecular signatures and gave rise to organoids with distinct phenotypes. TRAMP cells exhibited primary resistance against antiandrogen treatment. This was more pronounced in basal cell-derived TRAMP organoids when compared to luminal cell-derived organoids. Furthermore, we found MALAT1 gene fusions to be drivers of antiandrogen resistance in TRAMP mice through regulation of AR. Summarizing, TRAMP tumor cells exhibited primary resistance towards androgen inhibition enhanced through basal cell function and MALAT1 gene fusions.

The prostate cancer landscape in Europe: Current challenges, future opportunities.

Prostate cancer (PCa) is the most common non-cutaneous cancer in men in Europe and is predicted to exhibit declining mortality in the European Union (EU) due to various recent improvements in treatment. The goal of this short review is to give insight into the European treatment landscape of PCa, while focusing on improvements in care.

A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions.

A synthetic lethal interaction between two genes is given when knock-out of either one of the two genes does not affect cell viability but knock-out of both synthetic lethal interactors leads to loss of cell viability or cell death. The best studied synthetic lethal interaction is between BRCA1/2 and PARP1, with PARP1 inhibitors being used in clinical practice to treat patients with BRCA1/2 mutated tumors. Large genetic screens in model organisms but also in haploid human cell lines have led to the identification of numerous additional synthetic lethal interaction pairs, all being potential targets of interest in the development of novel tumor therapies. One approach is to therapeutically target genes with a synthetic lethal interactor that is mutated or significantly downregulated in the tumor of interest. A second approach is to formulate drug combinations addressing synthetic lethal interactions. In this article, we outline a data integration workflow to evaluate and identify drug combinations targeting synthetic lethal interactions. We make use of available datasets on synthetic lethal interaction pairs, homology mapping resources, drug-target links from dedicated databases, as well as information on drugs being investigated in clinical trials in the disease area of interest. We further highlight key findings of two recent studies of our group on drug combination assessment in the context of ovarian and breast cancer.

Impact of frailty on the management of patients with gynecological cancer aged 80 years and older.

PURPOSE: To assess the impact of frailty on compliance of standard therapy, complication, rate and survival in patients with gynecological malignancy aged 80 years and older. METHODS: In total, 83 women with gynecological malignancy (vulva, endometrial, ovarian or cervical cancer) who underwent primary treatment between 2007 and 2017 were retrospectively analyzed. Frailty index was calculated and its association with compliance of standard treatment, peri- and postoperative mortality and morbidity, and survival was evaluated. RESULTS: Frailty was observed in 24.1% of cases. Both frail and non-frail patients were able to receive standard therapy in most cases - 75.0% and 85.7%, respectively (p = 0.27). Frail patients did not show an increased postoperative complication rate. Frail patients had shorter 3 years overall survival rates (28%) when compared to non-frail patients (55%) (p = 0.02). In multivariable analysis high frailty index (Hazard Ratio [HR] 12.15 [1.39-106.05], p = 0.02) and advanced tumor stage (HR 1.33 [1.00-1.76], p = 0.05) were associated with poor overall survival, but not age, histologic grading, performance status, and compliance of standard therapy. CONCLUSION: Majority of patients was able to receive standard therapy, as suggested by the tumor board, irrespective of age and frailty. Nonetheless, frailty is a common finding in patients with gynecological malignancy aged 80 years and older. Frail patients show shorter progression-free, and overall survival within this cohort.

Loss of HCRP1 leads to upregulation of PD-L1 via STAT3 activation and is of prognostic significance in EGFR-dependent cancer.

Loss of hepatocellular carcinoma-related protein 1 (HCRP1) (alias VPS37A) plays a role in endocytosis of receptor tyrosine kinases as a member of the ESCRT complex and has been linked to poor patient outcome in various types of epithelial cancer. To this date, the molecular and biological mechanisms explaining how its absence would contribute to tumor progression remain unknown. Using genomic editing with CRISPR-Cas9, we generated ovarian and breast cancer cell lines with loss-of-function mutations of HCRP1. We hypothesized that pathways downstream of receptor tyrosine kinases such as epidermal growth factor receptor are affected by HCRP1 loss and looked for deregulated signaling using immunoblotting and classical cancer biology assays. In our study, we show that endogenous deletion of HCRP1 leads to elevated phosphorylation of the transcription factor Signal transducer and activator of transcription 3 (STAT3) and induces upregulation of PD-L1, an important regulator of immune checkpoint inhibition. HCRP1 loss further leads to a mesenchymal phenotype switch in cancer cells, leading to increased proliferation and migration. Concludingly, our data emphasize the role of the tumor microenvironment in tumors with low or absent HCRP1 expression and suggest HCRP1 loss as a potential marker for metastatic potential and immunogenicity of epidermal growth factor receptor-driven cancer.

Thirteen-year analyses of medical oncology outpatient day clinic data: a changing field.

BACKGROUND: Novel treatment modalities like targeted therapy and immunotherapy are currently changing treatment strategies and protocols in the field of medical oncology. METHODS: Numbers of patients and patient contacts admitted to medical oncology day clinics of a large European academic cancer centre in the period from 2006 to 2018 were analysed using our patient administration system. RESULTS: A patient cohort of 9.870 consecutive individual patients with 125.679 patient contacts was descriptively and retrospectively characterised. Mean age was 59.9 years. A substantial increase in both individual patients treated per year (+45.4%; 2006: 1.100; 2018: 1.599) and annual patient contacts (+63.3%; 2006: 8.857; 2018: 14.467) between 2006 and 2018 was detected. Hence and most interestingly, the ratio of visits per patient increased by approximately one visit per patient per year over the last 12 years (+12.4%; 2006: 8.0; 2018: 9.0). Further, a decrease of patient contacts in more prevalent entities like breast cancer was found, while contacts for orphan diseases like myeloma and sarcoma increased substantially. Interestingly, female patients showed more per patient contacts as compared with men (13.5 vs 11.9). Lastly, short-term safety data of outpatient day clinic admissions are reported. CONCLUSIONS: We present a representative and large set of patient contacts over time that indicates an increasing load in routine clinical work of outpatient cancer care. Increases observed were highest for orphan diseases, likely attributed to centralisation effects and increased treatment complexity.

Final Analysis of the Ipilimumab Versus Placebo Following Radiotherapy Phase III Trial in Postdocetaxel Metastatic Castration-resistant Prostate Cancer Identifies an Excess of Long-term Survivors.

BACKGROUND: The phase 3 trial CA184-043 evaluated radiotherapy to bone metastases followed by Ipilimumab or placebo in men with metastatic castrate-resistant prostate cancer (mCRPC) who had received docetaxel previously. In a prior analysis, the trial's primary endpoint (overall survival [OS]) was not improved significantly. OBJECTIVE: To report the final analysis of OS. DESIGN, SETTING, AND PARTICIPANTS: A total of 799 patients were randomized to receive a single dose of radiotherapy to one or more bone metastases followed by either Ipilimumab (n = 399) or placebo (n = 400). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS was analyzed in the intention-to-treat population. Prespecified and exploratory subset analyses based on Kaplan-Meier/Cox methodology were performed. RESULTS AND LIMITATIONS: During an additional follow-up of approximately 2.4 yr since the primary analysis, 721/799 patients have died. Survival analysis showed crossing of the curves at 7-8 mo, followed by persistent separation of the curves beyond that point, favoring the ipilimumab arm. Given the lack of proportional hazards, a piecewise hazard model showed that the hazard ratio (HR) changed over time: the HR was 1.49 (95% confidence interval 1.12, 1.99) for 0-5 mo, 0.66 (0.51, 0.86) for 5-12 mo, and 0.66 (0.52, 0.84) beyond 12 mo. OS rates were higher in the ipilimumab versus placebo arms at 2 yr (25.2% vs 16.6%), 3 yr (15.3% vs 7.9%), 4 yr (10.1% vs 3.3%), and 5 yr (7.9% vs. 2.7%). Disease progression was the most frequent cause of death in both arms. In seven patients (1.8%) in the ipilimumab arm and one (0.3%) in the placebo arm, the primary cause of death was reported as study drug toxicity. No long-term safety signals were identified. CONCLUSIONS: In this preplanned long-term analysis, OS favored ipilimumab plus radiotherapy versus placebo plus radiotherapy for patients with postdocetaxel mCRPC. OS rates at 3, 4, and 5 yr were approximately two to three times higher in the ipilimumab arm. PATIENT SUMMARY: After longer follow-up, survival favored the group of men who received ipilimumab, with overall survival rates being two to three times higher at 3 yr and beyond.

Precision Medicine Tumor Boards: Clinical Applicability of Personalized Treatment Concepts in Ovarian Cancer.

BACKGROUND: Treating cancer according to its molecular alterations (i.e., targeted treatment, TT) is the goal of precision medicine tumor boards (PTBs). Their clinical applicability has been evaluated for ovarian cancer patients in this analysis. METHODS: All consecutive ovarian cancer patients discussed in a PTB at the Medical University of Vienna, Austria, from April 2015 to April 2019 were included (n = 44). RESULTS: In 38/44 (86%) cases, at least one mutation, deletion or amplification was detected. The most frequently altered genes were p53 (64%), PI3K pathway (18%), KRAS (14%), BRCA1 (11%) and BRCA2 (2%). In 31 patients (70%) a TT was recommended. A total of 12/31 patients (39%) received the recommended therapy. Median time from indication for PTB to TT start was 65 days (15-216). Median time to treatment failure was 2.7 months (0.2-13.2). Clinical benefit rate (CBR) was 42%. Reasons for treatment discontinuation were disease progression (42%), poor performance status (PS > 2; 25%), death (17%) or treatment related side effects (8%). In 61% the TT was not administered-mainly due to PS > 2. CONCLUSION: Even though a TT recommendation can be derived frequently, clinical applicability remains limited due to poor patients' general condition after exploitation of standard treatment. However, we observed antitumor activity in a substantial number of heavily pretreated patients.

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.

Assessment of body composition in the advanced stage of castration-resistant prostate cancer: special focus on sarcopenia.

PURPOSE: To assess the prevalence of sarcopenia and whether body composition parameters are associated with disease progression and overall survival (OS) in castration-resistant prostate cancer (CRPC) patients. MATERIALS AND METHODS: This single-centre retrospective study evaluated data of 186 consecutive patients who underwent chemohormonal therapy between 2005 and 2016 as first-line systemic treatment for CRPC. Skeletal muscle and fat indices were determined using computerized tomography data before initiation of chemotherapy. Sarcopenia was defined as SMI of <55 cm2/m2. Visceral-to-subcutaneous fat ratio and skeletal muscle volume were calculated with body composition specific areas. Harrell's concordance index was used for predictive accuracy. RESULTS: A total of 154 (82.8%) patients met the criteria for sarcopenia; 139 (74.7%) individuals completed at least six cycles of docetaxel. Within a median follow-up of 24.1 months, age (HR 1.03, 95% CI 1.01-1.06, p = 0.02), high PSA (1.55, 95% CI 1.07-2.25, p = 0.02) and low skeletal muscle volume (HR 1.61, 95% CI 1.10-2.35, p = 0.02) were the only independent prognostic factor for tumor progression. Overall, 93 (50%) patients died during the follow-up period. The established prognosticator, the prechemotherapy presence of liver metastases (HR 1.32, 95% CI 1.08-1.61, p < 0.01) was associated with shorter OS. Moreover, we noted that patients with an elevated visceral-to-subcutaneous fat ratio tended to have a shorter OS (p = 0.06). CONCLUSION: The large majority of men with CRPC suffers from sarcopenia. In our cohort, low skeletal muscle volume was an independent adverse prognosticator for progression of disease. We could not detect a statistically significant body composition parameter for OS, although patients with a high proportion of visceral fat had a trend for shorter OS. However, we suggest that body composition parameters determined by CT data can provide useful objective prognostic factors that may support tailored treatment decision-making.

Synthetic lethality guiding selection of drug combinations in ovarian cancer.

BACKGROUND: Synthetic lethality describes a relationship between two genes where single loss of either gene does not trigger significant impact on cell viability, but simultaneous loss of both gene functions results in lethality. Targeting synthetic lethal interactions with drug combinations promises increased efficacy in tumor therapy. MATERIALS AND METHODS: We established a set of synthetic lethal interactions using publicly available data from yeast screens which were mapped to their respective human orthologs using information from orthology databases. This set of experimental synthetic lethal interactions was complemented by a set of predicted synthetic lethal interactions based on a set of protein meta-data like e.g. molecular pathway assignment. Based on the combined set, we evaluated drug combinations used in late stage clinical development (clinical phase III and IV trials) or already in clinical use for ovarian cancer with respect to their effect on synthetic lethal interactions. We furthermore identified a set of drug combinations currently not being tested in late stage ovarian cancer clinical trials that however have impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer. RESULTS: Twelve of the tested drug combinations addressed a synthetic lethal interaction with the anti-VEGF inhibitor bevacizumab in combination with paclitaxel being the most studied drug combination addressing the synthetic lethal pair between VEGFA and BCL2. The set of 84 predicted drug combinations for example holds the combination of the PARP inhibitor olaparib and paclitaxel, which showed efficacy in phase II clinical studies. CONCLUSION: A set of drug combinations currently not tested in late stage ovarian cancer clinical trials was identified having impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer.

Synthetic lethal combinations of low-toxicity drugs for breast cancer identified in silico by genetic screens in yeast.

In recent years, the concept of synthetic lethality, describing a cellular state where loss of two genes leads to a non-viable phenotype while loss of one gene can be compensated, has emerged as a novel strategy for cancer therapy. Various compounds targeting synthetic lethal pathways are either under clinical investigation or are already routinely used in multiple cancer entities such as breast cancer. Most of them target the well-described synthetic lethal interplay between PARP1 and BRCA1/2. In our study, we investigated, using an in silico methodological approach, clinically utilized drug combinations for breast cancer treatment, by correlating their known molecular targets with known homologous interaction partners that cause synthetic lethality in yeast. Further, by creating a machine-learning algorithm, we were able to suggest novel synthetic lethal drug combinations of low-toxicity drugs in breast cancer and showed their negative effects on cancer cell viability in vitro. Our findings foster the understanding of evolutionarily conserved synthetic lethality in breast cancer cells and might lead to new drug combinations with favorable toxicity profile in this entity.

LUBAC and ABIN-1 Modulate TRAIL-Based NF-κB Induction in Human Embryonic Kidney 293 Cells.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known to activate the canonical NF-κB pathway similar to TNF. The exact mechanism of the entire signaling cascade is still under investigation. The involvement of linear ubiquitylation as upregulating component has already been shown recently in some cell lines, but not in human embryonic kidney 293 (HEK293) cells. The downregulating function of the ABIN-1 (A20 binding and inhibitor of NF-κB) as linear ubiquitylation antagonist has been shown in combination with some NF-κB-inducing pathways, but not with TRAIL. We performed luciferase and western blot assays using HEK293 cells stimulated with either TRAIL (or TNF as a control) to analyze the involvement of linear ubiquitin chain assembly complex (LUBAC) components and the impact of ABIN-1 and ABIN-1-MAD (truncated form without A20 binding site) on NF-κB signaling. For overexpression experiments, we added plasmids of ABIN-1 and ABIN-1-MAD or LUBAC components HOIP, HOIL-1, or SHARPIN (single and combinations). For downregulation experiments five pairs of either SHARPIN, HOIL-1, or HOIP targeting miRNAs or one miRNA for ABIN-1 were designed and added. ABIN-1 and its truncated form ABIN-1-MAD reduced the NF-κB induction significantly indicating its involvement as antagonist (independent of deubiquitinase A20) of linear ubiquitylation in TRAIL-induced NF-κB signaling. In opposition, knockdown of ABIN-1 using a specific ABIN-1 miRNA led a clear increase of NF-κB signaling. Addition of single LUBAC components or combinations (except for SHARPIN with HOIL-1) resulted in clearly stronger NF-κB inductions. MiRNAs targeting LUBAC components significantly reduced NF-κB activation. Thus, in HEK293 cells linear ubiquitylation by LUBAC critically upregulates and ABIN-1 downregulates TRAIL-induced NF-κB signaling and may be interesting targets for future pathological therapies.

Analysis of hematological parameters as prognostic markers for toxicity and survival of 223Radium treatment.

223Radium (223Ra) has emerged as treatment prolonging survival in patients with metastatic castration-resistant prostate cancer (CRPC). As 223Ra can cause hematotoxicity (HT), pre-existing hematopoiesis might influence the efficacy of 223Ra and the rate of hematotoxicity, but as to our knowledge such data has not been published yet, we retrospectively conducted an analysis on patients receiving 223Ra. 54 patients treated with 223Ra had a median survival of 67 weeks, which was significantly reduced in patients with pre-existing Hb toxicity (Tox) grade 2 (48 weeks P = 0.008) as compared to grade 1 (67 weeks) and normal levels of Hb (not reached); survival in patients with Plt Tox grade 1 was significantly reduced (44 weeks) as compared to normal Plt counts (71 weeks, P = 0.033). Patients with impaired hematopoiesis regarding Hb and Plts developed significantly more grade 3 and 4 HT (Hb < 10 g/dl: 42.9% [3/7] vs 10.6% [5/47], P < 0.001; Plt < 150 G/L: 28.6% [2/7] vs 6.4% [3/47], P = 0.002) and received significantly fewer treatment cycles (Hb <10 g/dl: 5.1 vs 5.8, P = 0.04; Plt < 150 G/L: 3.4 vs 5.6, P < 0.001). These results imply that pre-existing impaired hematopoiesis, in particular thrombocytopenia and anemia, before 223Ra therapy, is an important risk factor for worse outcome of treatment with 223Ra.

Efficacy of cabazitaxel rechallenge in heavily treated patients with metastatic castration-resistant prostate cancer.

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/m2 q3w, 58%; 20 mg/m2 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.