Dwubiegunowa terapia androgenowa (Bipolar Androgen Therapy)

Dwubiegunowa terapia androgenowa (Bipolar Androgen Therapy)

Nieprzeczytany postautor: Wenus » 09 gru 2016, 15:24

Wklejam artykuł odnośnie raka prostaty, może to będzie przełom w leczeniu zaawansowanego raka prostaty?

http://www.medonet.pl/zdrowie,leczenie- ... 9fff3d3b92
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Re: Dwubiegunowa terapia androgenowa (BAT)

Nieprzeczytany postautor: bela71 » 09 gru 2016, 16:06

Tu artykuł na temat dwubiegunowej terapii androgenowej z większą ilością szczegółów i cytatów niż na onecie:

Bipolar Androgen Therapy Yields Promising Results in Prostate Cancer
https://prostatecancernewstoday.com/201 ... ws-promise

A tu abstrakt samego wystąpienia prof. Denmeade na sympozjum w Monachium:

ORAL PRESENTATION: A phase II study of rapid cycling high dose testosterone (Bipolar Androgen Therapy) in men with metastatic castrate-resistant prostate cancer (mCRPC) resistant to abiraterone and/or enzalutamide
S. Denmeade, E. Antonarakis, C. Paller, H. Wang, T. Benjamin, C. Drake, M. Carducci, M. Eisenberger

Background: Prostate cancer (PC) becomes resistant to chronic castration via an adaptive increase in androgen receptor (AR) axis activity through overexpression, gene amplification, and expression of ligand independent AR variants. AR overexpression, however, is a liability that can be exploited therapeutically. Mechanistically, supraphysiologic T induces PC death through disruption of DNA relicensing due to persistence of AR at origins of replication during the cell cycle. Ligand bound AR can also induce DNA double strand breaks in androgen starved cells re-exposed to androgen.

Methods: In an ongoing study, asymptomatic men (n = 60) with CRPC and progression on A and/or E (30/cohort) receive T cypionate 400 mg IM every 28 days along with ongoing castration to rapidly cycle between polar extremes of supraphysiologic and near-castrate levels of serum T (bipolar androgen therapy, BAT). Men with declining PSA and/or stable radiographic disease can continue BAT after 3 cycles and are rechallenged with A or E at progression. Co-primary endpoints include ≥50% PSA response after 3 cycles of BAT and after re-treatment of E or A after progression to BAT. The study is designed to reject a treatment with <5% PSA response based on prior data with sequential AR targeted treatments. Secondary endpoints include objective response, safety, quality of life, and effect on CTC-based AR-V7 expression.

Results: The study remains open for patient enrollment; 37 have completed at least 3 cycles of BAT and 31/37 (83%) continued on treatment beyond the initial 3 months; 11/37 (30%) had ≥50% PSA decline and 20/37 (54%) had PSAs decline <50%. 4/17 (23%) with measurable disease had RECIST responses and 11/17 (65%) had stable disease after 3 months of BAT. Of 25 men evaluable in the post BAT phase, 8 (32%) and 15 (60%) had ≥50% and <50% PSA declines after 3 months of retreatment with the same pre-study AR targeted treatment (A or E). 21/34 men tested in this group had detectable CTCs with 6/21 testing AR-V7 +. All AR-V7 + men became AR-V7 negative after BAT, and 2/6 of these AR-V7 + men had a ≥50% PSA decline. BAT has generally been well tolerated and no DLT’s have been seen thus far. 1 patient had a self-limited increase in pain and 1 had urinary retention, otherwise there were no bone/soft tissue AE’s with BAT to suggest disease flare.

Conclusions: This preliminary data demonstrates the safety and activity of BAT in patients with CRPC post-A and/or E with PSA and objective responses, including responses in AR-V7 + men. An ongoing multi-center randomized trial is testing BAT vs E in the post-A CRPC population.

http://www.ecco-org.eu/Events/ENA2016/Searchable-Programme#anchorScpr



Oraz linki do wymienionych w tekście badań klinicznych fazy II prowadzonych w Baltimore, USA (oba jeszcze rekrutują):

RE-sensitizing With Supraphysiologic Testosterone to Overcome REsistant (The RESTORE Study) (Restore)
https://clinicaltrials.gov/ct2/show/NCT ... BAT&rank=1




Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance (Transformer)
https://clinicaltrials.gov/ct2/show/NCT02286921?term=transformer+bat&rank=1
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Re: A kuku

Nieprzeczytany postautor: bela71 » 27 sty 2018, 19:12

Pierwsze rezultaty badań fazy II nad terapią psychiatryczną CRCP czyli Bipolar Androgen Therapy dla grupy 30 pacjentów u których enzalutamid przestał już działać.

Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study

Summary


Background
Prostate cancer that progresses after enzalutamide treatment is poorly responsive to further antiandrogen therapy, and paradoxically, rapid cycling between high and low serum testosterone concentrations (bipolar androgen therapy [BAT]) in this setting might induce tumour responses.
We aimed to evaluate BAT in patients with metastatic castration-resistant prostate cancer that progressed after enzalutamide.


Methods
We did this single-centre, open-label, phase 2, multicohort study in the USA.
We included patients aged 18 years or older who had histologically confirmed and radiographically documented metastatic castration-resistant prostate cancer, with no more than two previous second-line hormonal therapies, and a castrate concentration of testosterone.

Patients were asymptomatic, with Eastern Cooperative Oncology Group performance status of 0–2, and did not have high-risk lesions for tumour flare (eg, >5 sites of visceral disease or bone lesions with impending fracture).

For the cohort reported here, we required patients to have had progression on enzalutamide with a continued prostate-specific antigen (PSA) rise after enzalutamide treatment discontinuation.

Patients received BAT, which consisted of intramuscular testosterone cipionate 400 mg every 28 days until progression and continued luteinising hormone-releasing hormone agonist therapy.
Upon progression after BAT, men were rechallenged with oral enzalutamide 160 mg daily
.

The co-primary endpoints were investigator-assessed 50% decline in PSA concentration from baseline (PSA50) for BAT (for all patients who received at least one dose) and for enzalutamide rechallenge (based on intention-to-treat analysis). These data represent the final analysis for the post-enzalutamide cohort, while two additional cohorts (post-abiraterone and newly castration-resistant prostate cancer) are ongoing.
The trial is registered with ClinicalTrials.gov, number NCT02090114.

Findings

Between Aug 28, 2014, and May 18, 2016, we accrued 30 eligible patients and treated them with BAT.
Nine (30%; 95% CI 15–49; p<0·0001) of 30 patients achieved a PSA50 to BAT.
29 patients completed BAT and 21 proceeded to enzalutamide rechallenge, of whom 15 (52%; 95% CI 33–71; p<0·0001) achieved a PSA50 response.
During BAT, the only grade 3–4 adverse event occurring in more than one patient was hypertension (three [10%] patients).
Other grade 3 or worse adverse events occurring during BAT in one [3%] patient each were pulmonary embolism, myocardial infarction, urinary obstruction, gallstone, and sepsis. During enzalutamide retreatment, no grade 3–4 toxicities occurred in more than one patient. No treatment-related deaths were reported during either BAT or enzalutamide retreatment.
Interpretation

BAT is a safe therapy that resulted in responses in asymptomatic men with metastatic castration-resistant prostate cancer and also resensitisation to enzalutamide in most patients undergoing rechallenge.
Further studies with BAT are needed to define the potential clinical role for BAT in the management of metastatic castration-resistant prostate cancer and the optimal strategy for sequencing between androgen and antiandrogen therapies in metastatic castration-resistant prostate cancer to maximise therapeutic benefit to patients.

Funding
National Institutes of Health and National Cancer Institute.


http://www.thelancet.com/journals/lanon ... 70-2045(17)30906-3/fulltext
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Re: Dwubiegunowa terapia androgenowa (Bipolar Androgen Thera

Nieprzeczytany postautor: bela71 » 10 cze 2019, 23:06

Genomic determinants of sensitivity to bipolar androgen therapy (BAT) in castrate-resistant prostate cancer (CRPC).
Michael Thomas Schweizer, Emmanuel S. Antonarakis, Mario A. Eisenberger, Peter Nelson, Jun Luo, Colin Pritchard, ...

Abstract

200

Background: BAT is a promising treatment for CRPC and preclinical work has shown that its effects may be mediated by inducing DNA damage or cell cycle arrest. We sought to evaluate if mutations in DNA damage repair (DDR) genes or cell cycle regulators were associated with improved outcomes. Methods: Biospecimens from CRPC patients enrolled to studies testing BAT underwent germline or somatic next-generation sequencing (NGS). Samples tested included plasma (i.e. cell-free DNA) (N = 79), tumor tissue (N = 21) and saliva (N = 10). A variety of clinical grade NGS platforms were generally used. Given the concern for false negatives, we excluded cases if plasma NGS did not reveal a somatic alteration. Absence of a germline alteration was not assumed to indicate absence of somatic alterations. Comparative analyses to assess candidate biomarkers of BAT efficacy were performed. Results: Most patients received BAT following one or more next generation hormonal therapy, while 6 received BAT as first-line CRPC therapy. Of 65 cases where a germline or somatic pathogenic alteration in any gene was detected, 30 (46%) had evidence of homologous recombination deficiency (HRD), with mutations found in BRCA2 (N = 10), ATM (N = 8), CHEK2 (N = 5), PALB2 (N = 4), CDK12 (N = 3), CHD1 (N = 2), FANCA (N = 1), FANCD2 (N = 1) and BRCA1 (N = 1). TP53 alterations were also common (27/65; 42%). HRD mutations associated with increased PSA50 responses, with a trend toward improved PSA50 responses in TP53 mutated cases too (Table). In a combined analysis, men with HRD and/or TP53 mutations had improved PSA50 responses and near-significant improvement in progression free survival (PFS). Conclusions: These preliminary data suggest that BAT may be most efficacious in cancers harboring mutations in genes involved in DDR and/or cell cycle regulation. These results require prospective confirmation.


https://ascopubs.org/doi/abs/10.1200/JC ... _suppl.200
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