Androgen deprivation therapy and side effects:are GnRH antagonists safer?

Androgen deprivation therapy(ADT)with gonadotropin-releasing hormone(GnRH)agonists and antagonists is the mainstay of advanced prostate cancer treatment.Both drug classes decrease levels of luteinizing hormone and follicle-stimulating hormones(FSH),thereby lowering testosterone to castrate levels.This is associated with adverse events(AEs),including cardiovascular(CV)disorders,bone fractures,metabolic dysfunction,and impaired cognitive function.This literature review discusses these AEs,with a focus on CV and bone-related events.A hypothesis-generating meta-analysis of six clinical trials showed a potentially increased risk for CV disorders with GnRH agonists versus the GnRH antagonist degarelix.While no study has directly compared GnRH agonists versus antagonists with a primary CV outcome,one hypothesis for this observation is that GnRH agonists lead to initial surges in FSH that may negatively impact CV health,whereas antagonists do not.GnRH agonists are associated with metabolic and cognitive AEs and while data are lacking for GnRH antagonists,no differences in risk are predicted.Other common AEs with ADT include injection site reactions,which are much more common with degarelix than with GnRH agonists,which may reflect differing administration and injection techniques.Future studies are needed to further evaluate and compare the safety profiles of GnRH agonists and antagonists,especially in patients with pre-existing CV disease and other co-morbidities.Physicians should carefully evaluate benefits and risks when prescribing ADT and ensure that side effects are well managed.

Evolving landscape and novel treatments in, metastatic castrate-resistant prostate cancer

Treatment options for castrate-resistant prostate cancer （CRPC） have advanced in recent years and significantly improved the Outlook for patients with this aggressive and lethal disease. Further understanding of the biology＇of CRPC has led to several new targeted therapies and continues to emphasize the importance of androgen receptor （AR） directed therapy. The treatment landscape is rapidly changing and further biologically rationale, biomarker-based ongoing clinical trials are needed. We review the recent results of major clinical trials in CRPC. New and investigational agents now in clinical evaluation are reviewed including inhibitors of angiogenesis, microtubules, chaperones, AR and intracellular kinases, as well as immunotherapy, radiopharmaceuticals and bone-targeted agents. The recent improvement in prognosis for CRPC brings continued optimism for further improvements. Thoughtful planning of clinical trials and further understanding of the mechanisms of resistance to therapies will allow for continued progress in patient care.

Network meta-analysis of combination strategies in metastatic hormone-sensitive prostate cancer

This study compared different doublet and triplet therapies for efficacy and safety in metastatic hormone-sensitive prostate cancer(mHSPC).PubMed,EMBASE,and the Cochrane Library were comprehensively searched for eligible randomized controlled trials(RCTs)published from inception to October 2023.Interventions included abiraterone,apalutamide,enzalutamide,docetaxel,darolutamide,and androgen deprivation therapy(ADT),either as doublet or triplet therapies.The outcomes examined were overall survival(OS),progression-free survival(PFS),castration-resistant prostate cancer(CRPC)-free survival,time to symptomatic skeletal event(SSE),and toxicity.The surface under the cumulative ranking curve(SUCRA)was determined to identify the preferred treatments.Ten RCTs were included.The combination of darolutamide,docetaxel,and ADT had the highest SUCRA of 84.3 for OS,followed by combined abiraterone,docetaxel,and ADT(SUCRA=71.6).The highest SUCRAs for PFS were observed for triplet therapies(abiraterone,docetaxel,and ADT[SUCRA=74.9],followed by enzalutamide,docetaxel,and ADT[SUCRA=74.3])and other androgen receptor axis-targeted therapy-based doublet therapies(SUCRAs:26.5–59.3).Darolutamide,docetaxel,and ADT had the highest SUCRAs,i.e.,80.8 and 84.0 regarding CRPC-free survival and time to SSE,respectively.Regarding Grade>3 adverse events(AEs),the SUCRAs of triplet therapies(SUCRAs:14.8–31.5)were similar to that of docetaxel and ADT(SUCRA=39.5).Three studies had a low risk of bias in all categories;the remaining studies had at least an unclear risk of bias in at least one category.Triplet therapy demonstrated potentially enhanced effectiveness than doublet therapy in mHSPC,with acceptable safety concerns.Darolutamide might be the optimal option for triplet therapy in combination with docetaxel and ADT.

Intermittent, low-dose, antiandrogen monotherapy as an alternative therapeutic option for patients with positive surgical margins after radical prostatectomy

The aim of the present study was to determine whether oncologic outcomes and adverse events associated with active on/off intermittent antiandrogen monotherapy （daily bicalutamide, 50 mg per day） are comparable with those of standard external beam radiation therapy （EBRT） or combined androgen blockade （CAB） therapy in prostate cancers with positive surgical margins after radical prostatectomy. Two hundred twenty-three patients with positive surgical margins post-radical prostatectomy who underwent active surveillance （AS, n = 32）, EBRT without hormone therapy （n = 55）, intermittent antiandrogen monotherapy without EBRT （IAAM, n= 50）, or CAB without EBRT （n = 86）, between 2007 and 2014, were reviewed retrospectively. Pathologic outcomes, biochemical recurrence rates, radiological disease progression, and adverse events were collected from medical records. Biochemical recurrence rates, biochemical recurrence-free survival rates, and radiological recurrence were not different between the groups （P = 0.225, 0.896, and 0.284, respectively）. Adverse event rates and severities were lower for IAAM compared with EBRT or CAB （both P 〈 0.05）, but were comparable to those for AS （P = 0.591 and 0.990, respectively）. Grade ：〉3 adverse events were not reported in the IAAM or AS groups. Erectile dysfunction and loss of libido rates were lower in the IAAM group compared with the EBRT and CAB groups （P = 0.032）. Gastrointestinal complications were more frequently reported in the EBRT group （P = 0.008）. Active on/off IAAM treatment might be an appropriate treatment option for patients with positive surgical margins after radical prostatectomy. Furthermore, regarding oncologic outcomes, IAAM was comparable to standard EBRT but had a milder adverse event profile.

Simulating androgen receptor selection in designer yeast

Androgen receptor(AR)mutation is closely associated with prostate cancer(PCa)and is one of the mechanisms of resistance to PCa therapies such as AR antagonists.Although sequencing technologies like next-generation sequencing(NGS)contributes to the high-throughput and precise detection of AR mutations carried by PCa patients,the lack of interpretations of these clinical genetic variants has still been a roadblock for PCa-targeted precision medicine.Here,we established a designer yeast reporter assay to simulate natural androgen receptor(AR)selection using AR antagonists.Yeast HIS3 gene transactivation was associated with the ligand-induced recruitment of steroid receptor coactivator-1(SRC-1)by AR mutants,where yeast growth in histidine-free medium was determined as the outcome.This assay is applicable to determine a wide range of clinical AR mutants including those with loss of function relating to androgen insensitivity syndrome(AIS),and those associated with PCa conferring resistance to AR antagonists such as enzalutamide(ENZ),bicalutamide(BIC),and cyproterone acetate(CPA).One clinical AR mutant previously reported to confer ENZ-resistance,F877L,was found to confer partial resistance to CPA as well using designer yeast.Our simple and efficient assay can enable precise one-pot screening of AR mutants,providing a reference for tailored medicine.