Circulating and Intratumoral Adrenal Androgens Correlate with Response to Abiraterone in Men with Castration-Resistant Prostate Cancer

Mostaghel, Elahe A.; Marck, Brett T.; Kolokythas, Orpheus; Chew, Felix S.; Yu, Evan Y.; Schweizer, Michael T.; Cheng, Heather H.; Kantoff, P.; Balk, Steven P.; Taplin, Mary‐Ellen; Sharifi, Nima; Matsumoto, Alvin M.; Nelson, Peter S.; Montgomery, Robert B.

doi:10.1158/1078-0432.ccr-21-1819

Cited by 18 publications

(13 citation statements)

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“…The current study showed that high serum 3‐keto‐5α‐abiraterone concentrations were associated with short treatment duration, although the serum concentrations were decreased after adding the 5α‐reductase inhibitor dutasteride 17,29 . Consistently, Mostaghel et al 30 have reported that high serum 3‐keto‐5α‐abiraterone concentrations on abiraterone was associated with short time to progression in abiraterone monotherapy. In addition, higher serum abiraterone concentrations were previously shown to be associated with a better PSA response and longer progression‐free survival with abiraterone monotherapy 31,32 .…”

Section: Discussionsupporting

confidence: 83%

A Phase II Trial of Abiraterone With Dutasteride for Second‐Generation Antiandrogen‐ and Chemotherapy‐Naïve Patients With Castration‐Resistant Prostate Cancer

Shiota

Inoue

Tashiro

et al. 2023

The Journal of Clinical Pharma

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The development of a novel therapy to overcome primary and acquired resistance to abiraterone is an unmet need. This study aimed to evaluate the efficacy and safety of adding 5α-reductase inhibitor dutasteride to abiraterone, explore proof of concept, and identify candidates suitable for combination therapy. This phase II, single-arm, and open-label study enrolled second-generation antiandrogen-and chemotherapy-naïve patients with castration-resistant prostate cancer. Patients received abiraterone and prednisolone for 4 weeks, followed by adding dutasteride. The primary end point was a 50% prostate-specific antigen response rate. Serum concentrations of abiraterone and its metabolites as well as HSD3B1 and SRD5A2 genotypes were measured. The association between drug metabolism and genotypes and their impact on the efficacy of combination therapy were assessed. Among 21 patients, 18 (85.7%) achieved ≥50% PSA reduction. Median time to treatment failure was not reached during the median followup of 15.4 months. No patients experienced grade ≥3 adverse events. Although dutasteride reduced serum 3-keto-5α-abiraterone concentrations, higher serum 3-keto-5α-abiraterone concentrations on combination therapy were associated with a shorter time to treatment failure. HSD3B1 and SRD5A2 genotypes were associated with serum 4-abiraterone and 3-keto-5α-abiraterone concentrations before adding dutasteride, respectively. Time to treatment failure was longer in patients with homozygous wild-type HSD3B1, but comparable between those with the SRD5A2 genotype. The promising outcomes of this study warrant further investigation of combination therapy in a randomized trial. Stratification by HSD3B1 and SRD5A2 genetic profiles might identify patients suitable for combination therapy.

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Section: Discussionsupporting

confidence: 83%

A Phase II Trial of Abiraterone With Dutasteride for Second‐Generation Antiandrogen‐ and Chemotherapy‐Naïve Patients With Castration‐Resistant Prostate Cancer

Shiota

Inoue

Tashiro

et al. 2023

The Journal of Clinical Pharma

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“…Nearly all prostate cancer deaths are due to CRPC ( 1 , 2 ). Intratumoral androgen biosynthesis is required to drive CRPC progression ( 3 – 6 ). The enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which catalyzes the initial, irreversible, and rate-limiting step in the conversion of the adrenal-derived steroid dehydroepiandrosterone (DHEA) to dihydrotestosterone (DHT) — the most potent natural stimulus of the AR — is a critical enzymatic gatekeeper that confers tumors with the ability to harness adrenal androgens ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

BMX controls 3βHSD1 and sex steroid biosynthesis in cancer

Li¹,

Berk²,

Goins³

et al. 2023

Journal of Clinical Investigation

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Prostate cancer is highly dependent on androgens and the androgen receptor (AR). Hormonal therapies inhibit gonadal testosterone production, block extragonadal androgen biosynthesis, or directly antagonize AR. Resistance to medical castration occurs as castration-resistant prostate cancer (CRPC) and is driven by reactivation of the androgen-AR axis. 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) serves as the rate-limiting step for potent androgen synthesis from extragonadal precursors, thereby stimulating CRPC. Genetic evidence in men demonstrates the role of 3βHSD1 in driving CRPC. In postmenopausal women, 3βHSD1 is required for synthesis of aromatase substrates and plays an essential role in breast cancer. Therefore, 3βHSD1 lies at a critical junction for the synthesis of androgens and estrogens, and this metabolic flux is regulated through germline-inherited mechanisms. We show that phosphorylation of tyrosine 344 (Y344) occurs and is required for 3βHSD1 cellular activity and generation of Δ 4 , 3-keto-substrates of 5α-reductase and aromatase, including in patient tissues. BMX directly interacts with 3βHSD1 and is necessary for enzyme phosphorylation and androgen biosynthesis. In vivo blockade of 3βHSD1 Y344 phosphorylation inhibits CRPC. These findings identify what we believe to be new hormonal therapy pharmacologic vulnerabilities for sex-steroid dependent cancers.

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“…Additionally, a method for the intratumoral quantification of DHEAS concentrations was recently reported (Mostaghel et al, 2021). A more in-depth analysis of tissue steroid profiling methods was provided in a recent review (Šimková et al, 2021).…”

Section: -Oxygenated Androgen Quantificationmentioning

confidence: 99%

The role of 11-oxygenated androgens in prostate cancer

2023

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11-oxygenated androgens are a class of steroids capable of activating the androgen receptor (AR) at physiologically relevant concentrations. In view of the AR as a key driver of prostate cancer (PC), these steroids are potential drivers of disease and progression. The 11-oxygenated androgens are adrenal-derived, and persist after androgen deprivation therapy (ADT), the mainstay treatment for advanced PC. Consequently, these steroids are of particular interest in the castration-resistant prostate cancer (CRPC) setting. The principal androgen of the pathway, 11-ketotestosterone (11KT), is a potent AR agonist and the predominant circulating active androgen in CRPC patients. Additionally, several precursor steroids are present in the circulation which can be converted into active androgens by steroidogenic enzymes present in PC cells. In vitro evidence suggests that adaptations frequently observed in CRPC favour the intratumoral accumulation of 11-oxygenated androgens in particular. Still, apparent gaps in our understanding of the physiology and role of the 11-oxygenated androgens remain. In particular, in vivo and clinical evidence supporting these in vitro findings is limited. Despite recent advances, a comprehensive assessment of intratumoral concentrations has not yet been performed. The exact contribution of the 11-oxygenated androgens to CRPC progression therefore remains unclear. This review will focus on the current evidence linking the 11-oxygenated androgens to PC, will highlight current gaps in our knowledge, and will provide insight into the potential clinical importance of the 11-oxygenated androgens in the CRPC setting based on the current evidence.

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Circulating and Intratumoral Adrenal Androgens Correlate with Response to Abiraterone in Men with Castration-Resistant Prostate Cancer

Cited by 18 publications

References 50 publications

A Phase II Trial of Abiraterone With Dutasteride for Second‐Generation Antiandrogen‐ and Chemotherapy‐Naïve Patients With Castration‐Resistant Prostate Cancer

A Phase II Trial of Abiraterone With Dutasteride for Second‐Generation Antiandrogen‐ and Chemotherapy‐Naïve Patients With Castration‐Resistant Prostate Cancer

BMX controls 3βHSD1 and sex steroid biosynthesis in cancer

The role of 11-oxygenated androgens in prostate cancer

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