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Bone-targeting radiopharmaceuticals for the treatment of bone-metastatic castration-resistant prostate cancer: exploring the implications of new data.

ABSTRACT: BACKGROUND:Clinical features of patients with castration-resistant prostate cancer (CRPC) are characterized by a high incidence of bone metastases, which are associated with impairment of quality of life, pain, skeletal-related events (SREs), and a negative impact on prognosis. Advances in the understanding of cancer cell-bone stroma interactions and molecular mechanisms have recently permitted the development of new agents. PURPOSE:We review the merits, applications, and limitations of emerging data sets on bone-metastatic CRPC with a focus on radium-223, an ?-emitting radiopharmaceutical, and its use in therapy for this disease. METHODS:References for this review were identified through searches of PubMed and Medline databases, and only papers published in English were considered. Related links in the databases were reviewed, along with relevant published guidelines, recently published abstracts from major medical meetings, and transcripts from a recent round table of clinical investigators. RESULTS:Prior to radium-223, available bone-targeted therapies demonstrated the ability to delay SREs and palliate bone pain in patients with metastatic CRPC but without evidence of improvement in overall survival (OS). In a randomized controlled phase III trial, radium-223 demonstrated the ability to improve OS and delay SREs in docetaxel-pretreated or docetaxel-unfit men with symptomatic bone-metastatic CRPC and was not associated with significantly more grade 3 or 4 adverse events than placebo. CONCLUSION:Radium-223 has a targeted effect on bone metastases in CRPC and has an important role in docetaxel-pretreated or docetaxel-unfit men with symptomatic bone-metastatic CRPC.

SUBMITTER: Ryan CJ

PROVIDER: S-EPMC4200991 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Bone-targeting radiopharmaceuticals for the treatment of bone-metastatic castration-resistant prostate cancer: exploring the implications of new data.

Ryan Charles J CJ Saylor Philip J PJ Everly Jason J JJ Sartor Oliver O

The oncologist 20140917 10

<h4>Background</h4>Clinical features of patients with castration-resistant prostate cancer (CRPC) are characterized by a high incidence of bone metastases, which are associated with impairment of quality of life, pain, skeletal-related events (SREs), and a negative impact on prognosis. Advances in the understanding of cancer cell-bone stroma interactions and molecular mechanisms have recently permitted the development of new agents.<h4>Purpose</h4>We review the merits, applications, and limitati ...[more]

PMID: 25232039

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Project description:Enzalutamide is a novel antiandrogen with proven efficacy in metastatic castration-resistant prostate cancer (mCRPC).To evaluate enzalutamide's effects on cancer and on androgens in blood and bone marrow, and associate these with clinical observations.In this prospective phase 2 study, 60 patients with bone mCRPC received enzalutamide 160mg orally daily and had transilial bone marrow biopsies before treatment and at 8 wk of treatment.Androgen signaling components (androgen receptor [AR], AR splice variant 7 (ARV7), v-ets avian erythroblastosis virus E26 oncogene homolog [ERG], cytochrome P450, family 17, subfamily A, polypeptide 1 [CYP17]) and molecules implicated in mCRPC progression (phospho-Met, phospho-Src, glucocorticoid receptor, Ki67) were assessed by immunohistochemistry; testosterone, cortisol, and androstenedione concentrations were assessed by liquid chromatography-tandem mass spectrometry; AR copy number was assessed by real-time polymerase chain reaction. Descriptive statistics were applied.Median time to treatment discontinuation was 22 wk (95% confidence interval, 19.9-29.6). Twenty-two (37%) patients exhibited primary resistance to enzalutamide, discontinuing treatment within 4 mo. Maximal prostate-specific antigen (PSA) decline ? 50% and ? 90% occurred in 27 (45%) and 13 (22%) patients, respectively. Following 8 wk of treatment, bone marrow and circulating testosterone levels increased. Pretreatment tumor nuclear AR overexpression (> 75%) and CYP17 (> 10%) expression were associated with benefit (p = 0.018). AR subcellular localization shift from the nucleus was confirmed in eight paired samples (with PSA decline) of 23 evaluable paired samples. Presence of an ARV7 variant was associated with primary resistance to enzalutamide (p = 0.018). Limited patient numbers warrant further validation.The observed subcellular shift of AR from the nucleus and increased testosterone concentration provide the first evidence in humans that enzalutamide suppresses AR signaling while inducing an adaptive feedback. Persistent androgen signaling in mCRPC was predictive of benefit and ARV7 was associated with primary resistance.We report a first bone biopsy study in metastatic prostate cancer in humans that searched for predictors of outcome of enzalutamide therapy. Benefit is linked to a pretreatment androgen-signaling signature.ClinicalTrials.gov identifier NCT01091103.

Dataset Information

Bone-targeting radiopharmaceuticals for the treatment of bone-metastatic castration-resistant prostate cancer: exploring the implications of new data.

Publications

Bone-targeting radiopharmaceuticals for the treatment of bone-metastatic castration-resistant prostate cancer: exploring the implications of new data.

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