Prevention of Bone Metastases in Patients with High-risk Nonmetastatic Prostate Cancer Treated with Zoledronic Acid: Efficacy and Safety Results of the Zometa European Study (ZEUS)

Wirth, Manfred P.; Tammela, Teuvo L.J.; Cicalese, V.; Veiga, F. Gómez; Delaere, K.P.J.; Miller, Kurt; Tubaro, Andrea; Schulze, Matthias; Debruyne, F.M.J.; Huland, Hartwig; Patel, Anup; Lecouvet, Frédéric; Caris, Christien; Witjes, Wim P.J.

doi:10.1016/j.eururo.2014.02.014

Cited by 117 publications

(73 citation statements)

References 21 publications

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“…ZOL treatment did not alter the number of animals with skeletal tumors in the intact mice -but instead caused a reduction in size of skeletal tumors (Ottewell et al 2014). These observations were in keeping with those of a large-scale human study, in which use of ZOL in men who were at risk for developing metastases failed to prevent the onset of mCaP (Wirth et al 2014). Thus, by itself ZOL is incapable of preventing metastasis caused by factors other than castration.…”

Section: Zoledronic Acid and Castration-induced Bone Metastasissupporting

confidence: 66%

Zoledronic acid at the time of castration prevented castration-induced bone metastasis in mice

Ghosh¹,

Gao²

2014

Endocrine Related Cancer

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Androgen deprivation therapy (ADT) is known to cause bone loss in a majority of patients with castration-resistant prostate cancer (CRPC). A study published in this issue of EndocrineRelated Cancer by Ottewell and colleagues shows that ADT increased bone resorption and triggered growth of disseminated prostate cancer (CaP) cells to form bone metastasis using an in vivo model. However, prevention of bone decay by weekly administration of zoledronic acid (ZOL) at the time of castration prevented ADT-induced tumor growth in bone. Recently, two publications from Japan have demonstrated that ZOL combined with ADT improved outcomes for patients with treatment-naïve CaP with bone metastasis. The mechanistic cause for these patients having an improved overall survival compared with those who were treated with ZOL after ADT initiation or before metastasis development was never explained. Ottewell and colleague's study now suggests that it is the bone loss caused by ADT that promoted bone metastasis, and if ZOL is administered at the time of ADT initiation, it would prevent this bone loss and prolong skeletal-related event-free survival.

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Section: Zoledronic Acid and Castration-induced Bone Metastasissupporting

confidence: 66%

Zoledronic acid at the time of castration prevented castration-induced bone metastasis in mice

Ghosh¹,

Gao²

2014

Endocrine Related Cancer

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“…Four phase III trials were conducted in this population (8)(9)(10)(11). Considering the predominance of bone metastasis in this disease and the ensuing morbidity, 3 of these trials tested bonetargeting agents with a primary objective of delaying time to bone metastasis (8,10,11), whereas the primary endpoint in the study by Nelson and colleagues was PFS or time to disease progression (not including increase in PSA; ref. 9).…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7]. Considering the morbidity of bony metastases, several trials evaluated bonetargeted therapy in this disease population, resulting in no or modest effects and no impact on the totality of the disease (i.e., overall disease progression in bone and non-bone sites) or OS (8)(9)(10)(11). Thus, delaying all site metastasis in patients with nmCRPC remains an unmet medical need (1,(3)(4)(5)12).…”

Section: Introductionmentioning

confidence: 99%

Phase II Study of Single-Agent Orteronel (TAK-700) in Patients with Nonmetastatic Castration-Resistant Prostate Cancer and Rising Prostate-Specific Antigen

Hussain

Corn

Michaelson

et al. 2014

Clinical Cancer Research

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Purpose: Orteronel (TAK-700) is an investigational, nonsteroidal, oral, inhibitor of androgen synthesis with greater specificity for 17,20-lyase than for 17a-hydroxylase. We investigated orteronel without steroids in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC; M 0 ).Experimental Design: Patients with nmCRPC and rising prostate-specific antigen (PSA) received orteronel 300 mg twice daily until PSA progression, metastases, or unacceptable toxicity. The primary endpoint was percentage of patients achieving PSA 0.2 ng/mL (undetectable levels) at 3 months. Secondary endpoints included safety, PSA response, time to metastases, and correlated endpoints.Results: Thirty-nine patients with a median baseline PSA doubling time of 2.4 months (range, 0.9-9.2) received a median of fourteen 28-day treatment cycles. PSA decreased >30% in 35 patients and 6 (16%) achieved PSA 0.2 ng/mL at 3 months. Median times to PSA progression and metastasis were 13.8 and 25.4 months, respectively. Kaplan-Meier estimates of freedom from PSA progression were 57% and 42% at 12 and 24 months, and of freedom from metastasis were 94% and 62% at 12 and 24 months, respectively. At 3 months, median testosterone declined by 89% from baseline. Adverse events led to therapy discontinuation in 12 patients and grade !3/4 adverse events occurred in 22 patients. Most frequent all-cause adverse events included fatigue (64%), hypertension (44%), diarrhea (38%), and nausea (33%), which were primarily grade 1/2.Conclusions: Single-agent orteronel produced marked and durable declines in PSA in patients with nmCRPC. Orteronel has moderate but manageable toxicities and its chronic administration without steroids appears feasible.

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“…Kod pacijenata sa visoko rizičnim nemetastatskim lokalizovanim karcinoma prostate (Gleason score 8-10, node-positive disease, or PSA 20 ng/ ml) nije pokazano da zoledronska kiselina redukuje učestalost razvoja metastaza u odnosu na placebo grupu, ali je u ovoj studiji zoledronska kiselina aplikovana jednom u 3 meseca, tako da ovu studiju možemo da posmatramo sa rezervom (17,1%, sa primenom zoledronske kiseline, nasuprot 17,0%, bez terapije; p = 0,95) 21 . Praktično sve nove studije su ispitivale značaj zolendronske kiseline (ZK) samo kod metastatskog, ali kastraciono rezistentnog CaP.…”

Section: Terapijaunclassified

“…Biohemiski markeri koštanog metabolizma se često koriste u studijama za procenu terapijskog odgovora na antiresorptivne lekove 22 . Nivo ovih markera se meri kako bi se procenile promene u stepenu koštane resorpcije (NTX) i koštane apozicije (BAP) 10,21 . Rezultati ove studije su pokazali značajnu i trajnu supresiju biohemijskih markera koštane resorpcije, ukazujući da ZK smanjuje koštanu resorpciju kod pacijenata sa CaP i koštanim metastazama koji su na ADT.…”

Section: Terapijaunclassified

Benefits of use of zoledronic acid in carcinoma prostate bone metastases (zoledronic acid)

Djordjević¹

2017

Serb J Anes Inten Therap

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SažetakUvod U razvijenim zemljama, karcinom prostate (CaP) je najčešće dijagnostikovan karcinom kod muškaraca, sa preko 1.100.000 novih slučajeva godišnje, širom sveta.Kosti su predilekciono mesto za razvoj metastaza kod ovog karcinoma i pacijenti sa uznapredovalom bolešću imaju veliku učestalost koštanih metastaza. Prema autopsijskim podacima, učestalost sekundarnih depozita u kostima iznosi čak 65-75%. Kod CaP metastaze su osteoblastne, što izaziva pojačanu osteoblastnu aktivnost. Glavna komplikacija koštanih metastaza je razvoj skletnih događaja [1][2][3][4][5] . Prema poslednjoj klasifikaciji, pod skeletnim događajima se podrazumevaju: patološke frakture kostiju (vertebralne i nevertebralne), kompresija kičmene moždine, kao i potreba za hirurgijom ili radioterapijom koštanih metastaza sa ciljem prevencije i lečenja patoloških fraktura i kompresije kičmene moždine, kao i palijacije bola 6 . Prema kliničkim studijama, u periodu posmatranja od 15 meseci, skoro polovina (44,2%) pacijenata sa metastatskim karcinomom prostate (mCaP) će doživeti najmanje jedan skeletni događaj (SREs). SREs mogu imati značajan uticaj na preživljavanje kod pacijenata sa mCaP. Pacijenti koji nemaju SREs-a u prvih 6 meseci imaju duže

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Prevention of Bone Metastases in Patients with High-risk Nonmetastatic Prostate Cancer Treated with Zoledronic Acid: Efficacy and Safety Results of the Zometa European Study (ZEUS)

Cited by 117 publications

References 21 publications

Zoledronic acid at the time of castration prevented castration-induced bone metastasis in mice

Zoledronic acid at the time of castration prevented castration-induced bone metastasis in mice

Phase II Study of Single-Agent Orteronel (TAK-700) in Patients with Nonmetastatic Castration-Resistant Prostate Cancer and Rising Prostate-Specific Antigen

Benefits of use of zoledronic acid in carcinoma prostate bone metastases (zoledronic acid)

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