HSD3B1 and overall survival (OS) in men with low-volume (LV) metastatic prostate cancer (PCa) treated with androgen deprivation therapy (ADT) or chemohormonal therapy in the CHAARTED Randomized trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5020-5020 ◽  
Author(s):  
Jason W.D. Hearn ◽  
Christopher Sweeney ◽  
Nima Almassi ◽  
Chad A. Reichard ◽  
Chandana A. Reddy ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Randomized Trial ◽  
High Volume ◽  
Variant Allele ◽  
Castration Resistant Prostate Cancer ◽  
Chemohormonal Therapy ◽  
Androgen Ablation ◽  
Androgen Synthesis ◽  
Kaplan Meier ◽  
Visceral Metastases

5020 Background: The HSD3B1(1245A > C) variant allele, whose frequency varies by race, encodes a missense sequence that stabilizes the rate-limiting enzyme responsible for extragonadal androgen synthesis, thus enhancing intratumoral dihydrotestosterone (DHT) synthesis. Multiple retrospective studies have found that men inheriting the HSD3B1(1245C) variant allele exhibit early resistance to ADT. We sought to validate these findings with prospective data from the Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED). Methods: Men with newly metastatic PCa were randomized to receive either ADT plus docetaxel at a dose of 75 mg/m2 every 3 weeks for 6 cycles (arm A) or ADT alone (arm B). We determined germline HSD3B1 genotype in the subset of men with LV disease ( < 4 bone metastases, no visceral metastases). We analyzed freedom from castration-resistant prostate cancer (CRPC) and OS according to HSD3B1 genotype using Cox and Kaplan-Meier methods. Results: 197 patients with LV disease had blood samples available and were genotyped, including 97 in arm A and 100 in arm B. Docetaxel did not improve OS of LV men. Of the 197 men, 47% were homozygous wild-type (WT), 43% were heterozygous, and 10% were homozygous variant. When all 197 men were analyzed as one goup, the median time to CRPC was 39.7 mos. in homozygous WT men vs. 25.0 mos. in men with one or more copies of the variant allele (HR 1.27, 95% CI 0.89 to 1.82; p = 0.187). Although OS data are still maturing, at 52 months OS was 83% (95% CI 75% to 91%) in homozygous WT men vs. 64% (95% CI 55% to 74%) in men with one or more variant alleles. There was a suggestion that docetaxel delayed development of CRPC among men with at least 1 variant allele (20.3 vs. 40.7 mos.; HR 0.66, 95% CI 0.40 to 1.04; p = 0.08). Benefit for men with high-volume disease was not evident. Conclusions: Inheritance of the HSD3B1(1245C) allele that augments DHT synthesis may be associated with lower OS in men treated with ADT with or without docetaxel for LV newly metastatic PCa. Additional study is warranted in patients with LV disease. Clinical trial information: NCT00309985.

scholarly journals Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial

2018 ◽  
Vol 36 (11) ◽  
pp. 1080-1087 ◽  
Author(s):  
Christos E. Kyriakopoulos ◽  
Yu-Hui Chen ◽  
Michael A. Carducci ◽  
Glenn Liu ◽  
David F. Jarrard ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Volume ◽  
Phase Iii ◽  
Cancer Trial ◽  
Term Survival ◽  
Chemohormonal Therapy ◽  
Androgen Ablation ◽  
Hormone Sensitive ◽  
Low Volume

Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m2 for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio [HR], 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.

Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer

2021 ◽  
pp. 89-94
Author(s):  
Philipp Dahm
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Adverse Events ◽  
Randomized Trial ◽  
Median Time ◽  
Androgen Deprivation Therapy ◽  
Androgen Deprivation ◽  
Chemohormonal Therapy ◽  
Androgen Ablation ◽  
Hormone Sensitive

This chapter summarizes the findings of the landmark Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) trial conducted in men with metastatic, hormone-sensitive prostate cancer comparing docetaxel therapy plus systemic androgen-deprivation therapy to androgen-deprivation therapy alone. It demonstrated improved median overall survival and median time to progression in the chemotherapy arm at the price of some increased severe adverse events.

scholarly journals Titration of Androgen Signaling: How Basic Studies Have Informed Clinical Trials Using High-Dose Testosterone Therapy in Castrate-Resistant Prostate Cancer

Life ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 884
Author(s):  
Steven K. Nordeen ◽  
Lih-Jen Su ◽  
Gregory A. Osborne ◽  
Perry M. Hayman ◽  
David J. Orlicky ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Dose ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Ablation ◽  
Clinical Observations ◽  
Clinical Benefits ◽  
Castrate Resistant Prostate Cancer ◽  
Prostate Cancers ◽  
Castrate Resistant ◽  
Basic Studies

Since the Nobel Prize-winning work of Huggins, androgen ablation has been a mainstay for treatment of recurrent prostate cancer. While initially effective for most patients, prostate cancers inevitably develop the ability to survive, grow, and metastasize further, despite ongoing androgen suppression. Here, we briefly review key preclinical studies over decades and include illustrative examples from our own laboratories that suggest prostate cancer cells titrate androgen signaling to optimize growth. Such laboratory-based studies argue that adaptations that allow growth in a low-androgen environment render prostate cancer sensitive to restoration of androgens, especially at supraphysiologic doses. Based on preclinical data as well as clinical observations, trials employing high-dose testosterone (HDT) therapy have now been conducted. These trials suggest a clinical benefit in cancer response and quality of life in a subset of castration-resistant prostate cancer patients. Laboratory studies also suggest that HDT may yet be optimized further to improve efficacy or durability of response. However, laboratory observations suggest that the cancer will inevitably adapt to HDT, and, as with prior androgen deprivation, disease progression follows. Nonetheless, the adaptations made to render tumors resistant to hormonal manipulations may reveal vulnerabilities that can be exploited to prolong survival and provide other clinical benefits.

Long-Term Androgen Ablation and Docetaxel Up-Regulate Phosphorylated Akt in Castration Resistant Prostate Cancer

2011 ◽  
Vol 185 (6) ◽  
pp. 2376-2381 ◽  
Author(s):  
Takeo Kosaka ◽  
Akira Miyajima ◽  
Suguru Shirotake ◽  
Eriko Suzuki ◽  
Eiji Kikuchi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Ablation ◽  
Castration Resistant ◽  
Phosphorylated Akt

May non-metastatic clinically localized castration-resistant prostate cancer after primary androgen ablation benefit from salvage prostate radiotherapy?

2013 ◽  
Vol 139 (11) ◽  
pp. 1955-1960 ◽  
Author(s):  
Angela Botticella ◽  
Alessia Guarneri ◽  
Andrea Riccardo Filippi ◽  
Niccolò Giaj Levra ◽  
Fernando Munoz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Radiotherapy ◽  
Androgen Ablation ◽  
Castration Resistant

scholarly journals Crosstalk Between Nuclear MET and SOX9/β-Catenin Correlates with Castration-Resistant Prostate Cancer

2014 ◽  
Vol 28 (10) ◽  
pp. 1629-1639 ◽  
Author(s):  
Yingqiu Xie ◽  
Wenfu Lu ◽  
Shenji Liu ◽  
Qing Yang ◽  
Brett S. Carver ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Combined Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Ablation Therapy ◽  
Androgen Ablation ◽  
Castration Resistant ◽  
Activate Cell ◽  
Androgen Ablation Therapy

Castration-resistant prostate cancer (PCa) (CRPC) is relapse after various forms of androgen ablation therapy and causes a major mortality in PCa patients, yet the mechanism remains poorly understood. Here, we report the nuclear form of mesenchymal epithelial transition factor (nMET) is essential for CRPC. Specifically, nMET is remarkably increased in human CRPC samples compared with naïve samples. Androgen deprivation induces endogenous nMET and promotes cell proliferation and stem-like cell self-renewal in androgen-nonresponsive PCa cells. Mechanistically, nMET activates SRY (sex determining region Y)-box9, β-catenin, and Nanog homeobox and promotes sphere formation in the absence of androgen stimulus. Combined treatment of MET and β-catenin enhances the inhibition of PCa cell growth. Importantly, MET accumulation is detected in nucleus of recurrent prostate tumors of castrated Pten/Trp53 null mice, whereas MET elevation is predominantly found in membrane of naïve tumors. Our findings reveal for the first time an essential role of nMET association with SOX9/β-catenin in CRPC in vitro and in vivo, highlighting that nuclear RTK activate cell reprogramming to drive recurrence, and targeting nMET would be a new avenue to treat recurrent cancers.

Anaplastic features (AnaF) and DNA-damage repair pathway (DDR) mutations in metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 92-92
Author(s):  
Vincent Chau ◽  
Ravi Amrit Madan ◽  
Marijo Bilusic ◽  
Lisa M. Cordes ◽  
Jennifer L. Marte ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastases ◽  
Mutational Analysis ◽  
Short Interval ◽  
Elevated Serum ◽  
High Volume ◽  
Small Cell ◽  
Castration Resistant Prostate Cancer ◽  
Damage Repair ◽  
Serum Cea

92 Background: Anaplastic prostate cancer displays features of small-cell carcinoma, a type of neuroendocrine tumor. Treatments for anaplastic prostate cancer are based on small cell lung cancer regimens. Both AnaF and mutations in DDR pathways, including BRCA2 confer an aggressive phenotype. For patients (pts) with certain DDR mutations, olaparib (O) was recently FDA approved, and an ongoing study is evaluating whether the addition of durvalumab (D) confers additional benefit in mCRPC (NCT02484404). We evaluate a potential preliminary relationship between DDR mutations, treatment with D and O, and AnaF. Methods: This is a phase II study of O plus D in pts with mCRPC with disease that is amenable to biopsy. On-study core biopsies undergo mutational analysis. Prior treatment with enzalutamide (enza) and/or abiraterone (abi) is required. D is given at 1500 mg iv q28 days + O 300 mg tablets po q12 hours. The primary endpoint is PFS. Pts were categorized into those with and without AnaF as defined by Aparicio et al. (2013). AnaF include small-cell histology; exclusively visceral metastases; predominantly lytic bone metastases; bulky lymphadenopathy (≥5 cm) or high-grade (Gleason ≥8) mass in prostate/pelvis; low PSA (≤10 ng/mL) at initial presentation with high volume (≥20) bone metastases; neuroendocrine markers in histology or serum plus elevated LDH, malignant hypercalcemia, or elevated serum CEA; or short interval (≤6 months) to androgen-independent progression. Results: Of 55 pts accrued, 24 had prior abi and enza; 19 pts had prior taxane. Common adverse events include anemia, fatigue, and nausea. Also, 11 pts (20.0%) displayed clear AnaF (Table) and 43 pts lacked AnaF, including 8 (14.5%) with partial AnaF that did not meet the full criteria, 4 (7.3%) who likely did not have AnaF due to difficulty in quantifying disease burden, 29 (52.7%) who did not have AnaF, and 2 (3.6%) had unknown status. Four pts (36.4%) with clear AnaF had DDR aberrations, including 3 (27.3%) with BRCA2, 1 (9.1%) with both BRCA2 and CHEK2, and 1 (9.1%) with ATM. Conclusions: Pts with mCRPC with DDR mutations can also have AnaF. This preliminary data demonstrates that pts with anaplastic prostate cancer and pts with DDR mutations are two distinct populations with some degree of overlap. O+D is well-tolerated, and future studies should focus on finding optimal treatments for pts with AnaF without and without DDR mutations. Clinical trial information: NCT02484404. [Table: see text]

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