The efficacy and safety of cabazitaxel, as compared with an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who ...were previously treated with docetaxel and had progression within 12 months while receiving the alternative inhibitor (abiraterone or enzalutamide) are unclear.
We randomly assigned, in a 1:1 ratio, patients who had previously received docetaxel and an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide) to receive cabazitaxel (at a dose of 25 mg per square meter of body-surface area intravenously every 3 weeks, plus prednisone daily and granulocyte colony-stimulating factor) or the other androgen-signaling-targeted inhibitor (either 1000 mg of abiraterone plus prednisone daily or 160 mg of enzalutamide daily). The primary end point was imaging-based progression-free survival. Secondary end points of survival, response, and safety were assessed.
A total of 255 patients underwent randomization. After a median follow-up of 9.2 months, imaging-based progression or death was reported in 95 of 129 patients (73.6%) in the cabazitaxel group, as compared with 101 of 126 patients (80.2%) in the group that received an androgen-signaling-targeted inhibitor (hazard ratio, 0.54; 95% confidence interval CI, 0.40 to 0.73; P<0.001). The median imaging-based progression-free survival was 8.0 months with cabazitaxel and 3.7 months with the androgen-signaling-targeted inhibitor. The median overall survival was 13.6 months with cabazitaxel and 11.0 months with the androgen-signaling-targeted inhibitor (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.89; P = 0.008). The median progression-free survival was 4.4 months with cabazitaxel and 2.7 months with an androgen-signaling-targeted inhibitor (hazard ratio for progression or death, 0.52; 95% CI, 0.40 to 0.68; P<0.001), a prostate-specific antigen response occurred in 35.7% and 13.5% of the patients, respectively (P<0.001), and tumor response was noted in 36.5% and 11.5% (P = 0.004). Adverse events of grade 3 or higher occurred in 56.3% of patients receiving cabazitaxel and in 52.4% of those receiving an androgen-signaling-targeted inhibitor. No new safety signals were observed.
Cabazitaxel significantly improved a number of clinical outcomes, as compared with the androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with docetaxel and the alternative androgen-signaling-targeted agent (abiraterone or enzalutamide). (Funded by Sanofi; CARD ClinicalTrials.gov number, NCT02485691.).
Prostate cancer is a major cause of cancer morbidity and mortality. Intra-prostatic inflammation is a risk factor for prostate carcinogenesis, with diet, chemical injury and an altered microbiome ...being causally implicated. Intra-prostatic inflammatory cell recruitment and expansion can ultimately promote DNA double-strand breaks and androgen receptor activation in prostate epithelial cells. The activation of the senescence-associated secretory phenotype fuels further 'inflammatory storms', with free radicals leading to further DNA damage. This drives the overexpression of DNA repair and tumour suppressor genes, rendering these genes susceptible to mutagenic insults, with carcinogenesis accelerated by germline DNA repair gene defects. We provide updates on recent advances in elucidating prostate carcinogenesis and explore novel therapeutic and prevention strategies harnessing these discoveries.
Alternative splicing in prostate cancer Paschalis, Alec; Sharp, Adam; Welti, Jonathan C ...
Nature reviews. Clinical oncology,
11/2018, Letnik:
15, Številka:
11
Journal Article
Recenzirano
Androgen receptor (AR) splice variants (AR-Vs) have been implicated in the development and progression of metastatic prostate cancer. AR-Vs are truncated isoforms of the AR, a subset of which lack a ...ligand-binding domain and remain constitutively active in the absence of circulating androgens, thus promoting cancer cell proliferation. Consequently, AR-Vs have been proposed to contribute not only to resistance to anti-androgen therapies but also to resistance to radiotherapy in patients receiving combination therapy by promoting DNA repair. AR-Vs, such as AR-V7, have been associated with unfavourable clinical outcomes in patients; however, attempts to specifically inhibit or prevent the formation of AR-Vs have, to date, been unsuccessful. Thus, novel therapeutic strategies are desperately needed to address the oncogenic effects of AR-Vs, which can drive lethal forms of prostate cancer. Disruption of alternative splicing through modulation of the spliceosome is one such potential therapeutic avenue; however, our understanding of the biology of the spliceosome and how it contributes to prostate cancer remains incomplete, as reflected in the dearth of spliceosome-targeted therapeutic agents. In this Review, the authors outline the current understanding of the role of the spliceosome in the progression of prostate cancer and explore the therapeutic utility of manipulating alternative splicing to improve patient care.
Introduction of novel agents for the management of advanced prostate cancer provides a range of treatment options with notable benefits for men with metastatic castration-resistant prostate cancer ...(mCRPC). At the same time, understanding of optimal patient selection, effective sequential use, and development of resistance patterns remains incomplete.
To review current systemic therapies and recent advances in drug development for mCRPC and strategies to aid in patient selection and optimal sequencing.
A literature review of PubMed/Medline, Cochrane Library, Current Contents Medicine, Web of Science, Clinical Trial.Gov, WHO-ICTRP (January 2004–November 2017), and the proceedings of major international meetings (2015/2016/2017) was performed in November 2017.
In the last few years, several new options for treatment of mCRPC have shown a survival benefit in phase III trials besides docetaxel:abiraterone, enzalutamide, cabazitaxel, radium-223, and sipuleucel-T. Radium-223 and denosumab have increased options in management of bone metastases. Currently, novel agents such as next-generation androgen receptor (AR) axis-targeting treatments, immunotherapeutics, or therapies targeting other oncogenic and genomic pathways, particularly poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors and PD-1 inhibitors, are under clinical investigation. With increasing treatment options for mCRPC, information on how to personalize management and how to select and sequence existing therapies is beginning to emerge, as are predictive biomarkers (homologous repair mutations, mismatch repair mutations, AR splice variant 7). Finally, early use of active agents in the castration-sensitive state will likely also change the clinical management of the disease when it becomes castrate resistant.
The emergence of new drugs for mCRPC has improved treatment options dramatically. Currently, systemic treatment options for mCRPC include hormonal therapy, chemotherapy, immunotherapy, and radionuclide therapy as well as bone-modifying agents and palliative or supportive measures. Further, new genetically targeted agents (PARP inhibitors and PD-1 inhibitors) are on the horizon for certain subsets of biomarker-selected patients. The best strategies for patient selection and optimal sequential use to achieve the longest cumulative survival improvement and to prevent early resistance remain unclear.
The current literature and proceedings from relevant congresses related to available systemic agents for the treatment of metastatic castration-resistant prostate cancer, including novel genetically targeted therapies, including poly(adenosine diphosphate–ribose) polymerase inhibitors and PD-1 inhibitors, were reviewed. Current therapies and ongoing developments are discussed.
In the last few years, new therapeutics for the treatment of metastatic castration-resistant prostate cancer have increased survival substantially. While promising novel agents are currently under trial, including genetically targeted therapies (poly(adenosine diphosphate–ribose) polymerase inhibitors and PD-1 inhibitors), further clinical and translational research in predictive biomarkers is needed to optimize treatment selection and sequencing strategies for existing drugs.
Signaling networks play key homeostatic processes in living organisms but are commonly hijacked in oncogenesis. Prominent examples include genetically altered receptor tyrosine kinases and ...dysregulated intracellular signaling molecules. The discovery and development of targeted therapies against such oncogenic proteins has imparted clinical benefit. Nevertheless, concerns remain about the limited single-agent efficacy and narrow therapeutic indices of many of these antitumor agents. Moreover, it is apparent that oncogenic proteins comprise complex signaling networks that interact through crosstalk and feedback loops, which modify therapeutic vulnerability. These complexities mandate the study of drug combinations, which will also become necessary to reverse tumor drug resistance. Here, we outline the challenges associated with rational drug codevelopment strategies, with a focus on the importance of analytically validated biomarkers for patient selection and pharmacokinetic-pharmacodynamic (PK-PD) studies. Overall, the most informative clinical studies of novel combinations will have the following characteristics: robust scientific hypotheses leading to their selection; supportive preclinical data from contextually appropriate preclinical model systems; sufficient preclinical PK data to inform on the risk of drug-drug interactions; and detailed PD studies to determine the biologically active dose range for each agent. Toward this end, several novel clinical trial designs may be envisioned to accelerate successful drug combination development while minimizing the risk of late drug combination attrition. Although considerable challenges remain, these efforts may enable important steps to be taken toward more durable therapeutic control of many cancers.
Bromodomain and extra-terminal domain (BET) proteins are reported to be epigenetic anti-cancer drug targets. This first-in-human study evaluated the safety, pharmacokinetics and preliminary ...anti-tumour activity of the BET inhibitor ODM-207 in patients with selected solid tumours.
This was an open-label Phase 1 study comprised of a dose escalation part, and evaluation of the effect of food on pharmacokinetics. ODM-207 was administered orally once daily. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design.
Thirty-five patients were treated with ODM-207, of whom 12 (34%) had castrate-resistant prostate cancer. One dose-limiting toxicity of intolerable fatigue was observed. The highest studied dose achieved was 2 mg/kg due to cumulative toxicity observed beyond the dose-limiting toxicity (DLT) treatment window. Common AEs included thrombocytopenia, asthenia, nausea, anorexia, diarrhoea, fatigue, and vomiting. Platelet count decreased proportionally to exposure with rapid recovery upon treatment discontinuation. No partial or complete responses were observed.
ODM-207 shows increasing exposure in dose escalation and was safe at doses up to 2 mg/kg but had a narrow therapeutic window.
The clinical trial registration number is NCT03035591.
Patient-derived organoids (PDOs) have recently emerged as robust preclinical models; however, their potential to predict clinical outcomes in patients has remained unclear. We report on a living ...biobank of PDOs from metastatic, heavily pretreated colorectal and gastroesophageal cancer patients recruited in phase 1/2 clinical trials. Phenotypic and genotypic profiling of PDOs showed a high degree of similarity to the original patient tumors. Molecular profiling of tumor organoids was matched to drug-screening results, suggesting that PDOs could complement existing approaches in defining cancer vulnerabilities and improving treatment responses. We compared responses to anticancer agents ex vivo in organoids and PDO-based orthotopic mouse tumor xenograft models with the responses of the patients in clinical trials. Our data suggest that PDOs can recapitulate patient responses in the clinic and could be implemented in personalized medicine programs.
Summary Until 2010, docetaxel was the only agent with proven survival benefit for castration-resistant prostate cancer. The development of cabazitaxel, abiraterone acetate, enzalutamide, radium-223, ...and sipuleucel-T has increased the number of treatment options. Because these agents were developed concurrently within a short period of time, prospective data on their sequential use efficacy are scarce. The challenge now is to reach a consensus on the best way to sequence effective treatments, ideally by the use of an approach specific to patient subgroups. However, the absence of robust surrogates of survival and the lack of predictive biomarkers makes data for the sequential use of these agents difficult to obtain and interpret.
Tumor clone dynamics in lethal prostate cancer Carreira, Suzanne; Romanel, Alessandro; Goodall, Jane ...
Science translational medicine,
2014-Sep-17, Letnik:
6, Številka:
254
Journal Article
Recenzirano
Odprti dostop
It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease ...progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers.
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