The changing landscape in the management of newly diagnosed castration sensitive metastatic prostate cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Parker DC
PROVIDER: S-EPMC7004830 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
Publications
The changing landscape in the management of newly diagnosed castration sensitive metastatic prostate cancer.
Parker Daniel C DC Cookson Michael S MS
Investigative and clinical urology 20200116 Suppl 1
Metastatic prostate cancer is a heterogeneous disease entity. Men without prior androgen deprivation therapy exposure are termed metastatic castration sensitive prostate cancer (mCSPC). The goal of this article is to update the reader on the rapidly changing landscape of treatment for men with mCSPC. Along with the options available to the clinician for treatment of men with mCSPC, the care of these patients has evolved into a multi-disciplinary field with expanding roles for medical, urologic, ...[more]
Similar Datasets
Project description:The past few years have brought increasing advances in the therapeutic management of metastatic castration-resistant prostate cancer with the approval of several agents, including vaccine therapy with sipuleucel-T, second-line chemotherapy with cabazitaxel, the bone-targeted pharmaceutical denosumab, and the novel antiandrogen therapy abiraterone acetate. There are ongoing developments with other agents in the pipeline such as MDV3100 and alpharadin that have shown promising results. This review describes the clinical trials that brought about the drug approvals of various agents and offers some insights regarding a rational approach to optimal treatment sequencing for these drugs since national guidelines are currently lacking.
| S-EPMC3539272 | biostudies-literature
Project description:BackgroundEmerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current definitions of oligometastasis are solely numerical.ObjectiveTo characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC.Design, setting, and participantsThis was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometastatic), metachronous oligometastatic (≤5 lesions), metachronous polymetastatic (>5 lesions), or de novo metastatic (metastasis at diagnosis) disease.Outcome measurements and statistical analysisWe measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC).Results and limitationsThe frequency of driver mutations in TP53 (p = 0.01), WNT (p = 0.08), and cell cycle (p = 0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p = 0.002), and time to CRPC (95.6 vs 155.8 mo; p = 0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p = 0.01). Mutations in TP53 (incidence rate ratio [IRR] 1.45; p = 0.004) and DNA double-strand break repair (IRR 1.61; p < 0.001) were associated with a higher number of metastases. Mutations in TP53 were also independently associated with shorter rPFS (hazard ratio [HR] 1.59; p = 0.03) and the development of CRPC (HR 1.71; p = 0.01) on multivariable analysis. This study was limited by its retrospective nature, sample size, and the use of commercially available sequencing platforms, resulting in a limited predefined set of genes examined.ConclusionsSomatic mutational profiles reveal a spectrum of metastatic biology that helps in redefining oligometastasis beyond a simple binary state of lesion enumeration.Patient summaryOligometastatic prostate cancer is typically defined as less than three to five metastatic lesions and evidence suggests that using radiation or surgery to treat these sites improves clinical outcomes. As of now, treatment decisions for oligometastasis are solely defined according to the number of lesions. However, this study suggests that tumor mutational profiles can provide a biological definition of oligometastasis and complement currently used numerical definitions.
| S-EPMC10262980 | biostudies-literature
Project description:Prostate cancer (PC) is the leading cause of cancer and the second leading cause of cancer-death among men in the Western world. About 10-20% of men with PC present with metastatic disease at diagnosis, while 20-30% of patients diagnosed with localized disease will eventually develop metastases. Although most respond to initial androgen-deprivation therapy (ADT), progression to castration-resistant PC (CRPC) is universal. In 2004 the docetaxel/prednisone regimen was approved for the management of patients with metastatic CRPC, becoming the standard first-line therapy. Recent advances have now led to an unprecedented number of new drug approvals within the past years, providing many new treatment options for patients with metastatic CRPC. Four new drugs have received U.S. Food and Drug Administration (FDA)-approval in 2010 and 2011: sipuleucel-T, an immunotherapeutic agent; cabazitaxel, a novel microtubule inhibitor; abiraterone acetate, a new androgen biosynthesis inhibitor; and denosumab, a bone-targeting agent. The data supporting the approval of each of these agents are described in this review, as are current approaches in the treatment of metastatic CRPC and ongoing clinical trials of novel treatments and strategies.
| S-EPMC3399094 | biostudies-literature
Project description:Prostate cancer continues to be one of the most commonly diagnosed cancers in men globally and a leading cause of male cancer deaths. The landscape of metastatic hormone-sensitive prostate cancer has significantly changed over the past decade. For many years, androgen deprivation therapy alone through surgical or chemical castration was the mainstay of treatment yielding limited 5-year survival rates. New treatment approaches using Docetaxel chemotherapy or androgen receptor pathway inhibitors to intensify upfront systemic therapy have resulted in significantly improved survival rates compared to androgen deprivation therapy alone. Clinicians are now equipped with an arsenal of drugs capable of prolonging life for metastatic hormone-sensitive prostate cancer patients. Furthermore, new treatment modalities are being tested in clinical trials making treatment of metastatic hormone-sensitive prostate cancer an extremely dynamic space. In this narrative review, we provide an overview of the key systemic treatments for metastatic hormone-sensitive prostate cancer, namely androgen deprivation therapy, novel androgen receptor pathway inhibitors and Docetaxel. We summarise a series of landmark trials that have led to the integration of novel androgen receptor pathway inhibitors and docetaxel into the treatment paradigm for metastatic hormone-sensitive prostate cancer. Lastly, we discuss nursing, financial and side-effect considerations pertaining to the use of these drugs. This article aims to give its readers an understanding of the evidence and clinical aspects of novel therapies in metastatic hormone-sensitive prostate cancer as they become increasingly available for use around the world.
| S-EPMC8575582 | biostudies-literature
Project description:The management of men with metastatic castration-resistant prostate cancer (CRPC) has taken several leaps forward in the last 2 years, with the demonstration of improved overall survival with three novel agents (sipuleucel-T, cabazitaxel, and abiraterone acetate), and a significant delay in skeletal-related events observed with denosumab. The pipeline of systemic therapies in prostate cancer remains strong, as multiple agents with a diverse array of mechanisms of action are demonstrating preliminary signs of clinical benefit, leading to more definitive phase III confirmatory trials. In this review, we will discuss the evolving landscape of treatment options for men with CRPC, with a particular focus on currently approved and emerging treatment options for these patients. Knowledge of these evolving standards will help to optimize delivery of care and long term outcomes in men with advanced CRPC.
| S-EPMC3685202 | biostudies-literature
Project description:Androgen deprivation therapy (ADT) has been conventional treatment of newly diagnosed metastatic prostate cancer for more than 70 years. However, all patients eventually become castration-resistant and a significant proportion of life span is spent in the castration-resistant state. Prospective randomized control trials have incorporated early chemotherapy along with ADT based on the hypothesis that a significant level of resistance to ADT already exists in newly diagnosed metastatic prostate cancer and ADT exhibits synergistic antitumor activity with taxanes. We discuss the changing landscape of management of patients with newly diagnosed metastatic prostate cancer based on recently published landmark randomized trials.
| S-EPMC6402766 | biostudies-literature
Project description:Abiraterone acetate plus prednisone is a standard treatment option for mCRPC. The phase II SWITCH trial showed that further prostate-specific antigen (PSA) responses can be obtained in a subset of patients when prednisone was switched to dexamethasone at progression. Here, we discuss the potential underlying mechanisms, including the activation of glucocorticoid receptors (GR) in progressive mCRPC and the implications for clinical practice.
| S-EPMC6219496 | biostudies-literature
Project description:In a phase II multicenter study, men with castration sensitive metastatic prostate cancer were treated with AT-101, a small molecule Bcl-2 inhibitor, and androgen deprivation therapy. At the end of 7 cycles of therapy in 55 patients, an undetectable PSA was achieved in 31%. However, the combination did not meet the pre-specified level of activity for further development.We conducted a phase II study in men with castration-sensitive metastatic prostate cancer to test the hypothesis that AT-101, a small molecule Bcl-2 inhibitor, has clinical activity in patients initiating androgen deprivation therapy (ADT) for metastatic prostate cancer.Patients with metastatic prostate cancer scheduled to start, or who had recently (within 6 weeks) initiated, ADT were enrolled. ADT with a luteinizing hormone-releasing hormone agonist and bicalutamide was started 6 weeks before initiation of oral AT-101, 20 mg/day for 21 days of a 28-day cycle. The primary endpoint of the study was the percentage of patients with an undetectable prostate-specific antigen (PSA) level (? 0.2 ng/mL) after 7.5 months (1.5 months of ADT alone plus 6 months of combined ADT and AT-101). To assess for an association between chromodomain helicase DNA binding protein 1 (CHD1) and drug sensitivity, fluorescence in situ hybridization with confocal microscopy was assessed in a subgroup of patients.A total of 55 patients were enrolled, with median age of 61 years and a median PSA level of 27.6 ng/dL. Of the 55 patients, 72% had a Gleason score ? 8. Three patients had visceral metastases, and the remaining patients had bone or nodal metastasis. An undetectable PSA level was achieved in 31% of the patients. Of the 31 patients, 12 experienced serious adverse events, 7 of which were considered related to study therapy. Most of the related adverse events were gastrointestinal and nervous system disorders. CHD1 assessment was feasible, with a nonsignificant association with therapeutic sensitivity in a small number of patients.The combination of ADT and AT-101 did not meet the prespecified level of activity for further development of this combination.
| S-EPMC4698193 | biostudies-literature
Project description:IntroductionThe clinical significance of bone marrow (BM) metastasis in prostate cancer as well as impact on oncological prognosis is unclear. We aim to assess the prevalence and clinical outcomes of BM metastasis at initial presentation of metastatic castrate sensitive prostate cancer (CSPC).Patients and methodsRetrospective chart review of newly diagnosed metastatic CSPC patients was performed with collection of clinicopathologic and radiologic characteristics. Descriptive univariate and multivariate analysis was performed as well as survival measures (OS and PFS), which was done using the Kaplan-Meier survival and the Log-rank test.Results189 patients were eligible, of which, eleven patients (6%) had biopsy proven BM involvement at diagnosis. There was a trend to poorer PFS and OS in patients with BM involvement but not statistically significant; however, factors that correlated with inferior PFS and OS in the multivariate analysis included ECOG PS, ALP, and Hb.ConclusionBM metastasis in prostate cancer may lead to poorer survival. Clinical features including poor performance status, anemia, and elevated ALP, could guide bone marrow biopsies in the future to diagnose bone marrow metastasis at an earlier stage.
| S-EPMC9302741 | biostudies-literature
Project description:ImportanceThe adrenal-restrictive HSD3B1(1245A) allele limits extragonadal dihydrotestosterone synthesis, whereas the adrenal-permissive HSD3B1(1245C) allele augments extragonadal dihydrotestosterone synthesis. Retrospective studies have suggested an association between the adrenal-permissive allele, the frequency of which is highest in white men, and early development of castration-resistant prostate cancer (CRPC).ObjectiveTo examine the association between the adrenal-permissive HSD3B1(1245C) allele and early development of CRPC using prospective data.Design, setting, and participantsThe E3805 Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) was a large, multicenter, phase 3 trial of castration with or without docetaxel treatment in men with newly diagnosed metastatic prostate cancer. From July 28, 2006, through December 31, 2012, 790 patients underwent randomization, of whom 527 had available DNA samples. In this study, the HSD3B1 germline genotype was retrospectively determined in 475 white men treated in E3805 CHAARTED, and clinical outcomes were analyzed by genotype. Data analysis was performed from July 28, 2006, to October 17, 2018.InterventionsMen were randomized to castration plus docetaxel, 75 mg/m2, every 3 weeks for 6 cycles or castration alone.Main outcomes and measuresTwo-year freedom from CRPC and 5-year overall survival, with results stratified by disease volume. Patients were combined across study arms according to genotype to assess the overall outcome associated with genotype. Secondary analyses by treatment arm evaluated whether the docetaxel outcome varied with genotype.ResultsOf 475 white men with DNA samples, 270 patients (56.8%) inherited the adrenal-permissive genotype (≥1 HSD3B1[1245C] allele). Mean (SD) age was 63 (8.7) years. Freedom from CRPC at 2 years was diminished in men with low-volume disease with the adrenal-permissive vs adrenal-restrictive genotype: 51.0% (95% CI, 40.9%-61.2%) vs 70.5% (95% CI, 60.0%-80.9%) (P = .01). Overall survival at 5 years was also worse in men with low-volume disease with the adrenal-permissive genotype: 57.5% (95% CI, 47.4%-67.7%) vs 70.8% (95% CI, 60.3%-81.3%) (P = .03). Hazard ratios were 1.89 (95% CI, 1.13-3.14; P = .02) for CRPC and 1.74 (95% CI, 1.01-3.00; P = .045) for death. There was no association between genotype and outcomes in men with high-volume disease. There was no interaction between genotype and benefit from docetaxel.Conclusions and relevanceInheritance of the adrenal-permissive HSD3B1 genotype is associated with earlier castration resistance and shorter overall survival in men with low-volume metastatic prostate cancer and may help identify men more likely to benefit from escalated androgen receptor axis inhibition beyond gonadal testosterone suppression.
| S-EPMC7042830 | biostudies-literature