LETTER TO THE EDITOR
Ahead of print publication  

Response of prostate cancer to addition of dutasteride after progression on abiraterone


1 Department of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
2 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai 200031, China

Date of Submission08-May-2020
Date of Acceptance09-Jun-2020
Date of Web Publication08-Sep-2020

Correspondence Address:
Sheng-Song Huang,
Department of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065
China
Zhen-Fei Li,
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai 200031
China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aja.aja_45_20

PMID: 32896838


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How to cite this URL:
Lian JP, Gao YY, Tang JJ, Chen X, Liu Y, Wu DL, Li ZF, Huang SS. Response of prostate cancer to addition of dutasteride after progression on abiraterone. Asian J Androl [Epub ahead of print] [cited 2020 Sep 22]. Available from: http://www.ajandrology.com/preprintarticle.asp?id=294531

Dear Editor,

Abiraterone has achieved great success in clinic by targeting cytochrome P450 17A1 (CYP17A) for prostate cancer therapy.[1],[2] However, drug resistance is inevitable and novel strategy is urgently required. Our previous work unveils a steroidal metabolic pathway for abiraterone in patients.[3],[4] Steroidogenic enzyme 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) catalyzes abiraterone to Δ[4]-abiraterone (D4A), which is further catalyzed to 5α-abiraterone (5α-Abi) by steroid-5α-reductase (SRD5A). The metabolite 5α-Abi binds to androgen receptor (AR) directly and activates AR signaling.[4] This metabolic pathway not only reduces plasma concentration of abiraterone, but also generates a mild AR agonist, which might cause drug resistance. Dutasteride, as a potent SRD5A inhibitor, suppresses the conversion from D4A to 5α-Abi and might be used to enhance abiraterone efficiency [Figure 1]a.[4] However, this function of dutasteride has not been proved in clinic. Here, we report the effect of dutasteride plus abiraterone treatment in two abiraterone-resistant patients.
Figure 1: Dutasteride enhances the efficacy of abiraterone in two abiraterone-resistant patients. (a) Schema of dutasteride function in abiraterone metabolism. (b) Alteration of PSA and plasma abiraterone metabolites in patient #W7546. 5α-Abis, 5α-Abi + 3α-OH-5α-Abi + 3β-OH-5α-Abi; 5β-Abis, 5β-Abi + 3α-OH-5β-Abi + 3β-OH-5β-Abi. (c) Maximum PSA reduction of patient #W7546 when treated with abiraterone alone or together with dutasteride. (d) Alteration of PSA, plasma abiraterone metabolites in patient #D3459. PSA: prostate-specific antigen; D4A: Δ[4]-abiraterone; 3βHSD1: steroidogenic enzyme 3β-hydroxysteroid dehydrogenase 1; Abi: abiraterone; Abi/P: abiraterone plus prednisone treatment; APD: abiraterone/prednisone and dutasteride taken at the same time; AP+D: abiraterone/prednisone and dutasteride taken separately.

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Two metastatic castration-resistant prostate cancer (mCRPC) patients after abiraterone resistance were recruited in a clinical research for the combination therapy (dutasteride and abiraterone plus prednisone) at Tongji Hospital (Shanghai, China) with signed informed consent, following a protocol approved by the Ethics Committee of Tongji Hospital (ChiCTR1800015510). The clinical characteristics of patients at diagnosis are listed in [Supplementary Table 1[Additional file 1] ]. They progressed to mCRPC in 20 months (#W7546) and 12 months (#D3459), respectively. The serum testosterone level was consistently lower than 20 ng dl−1 even after abiraterone resistance. Considering of the dynamics of abiraterone metabolism, plasma samples were collected approximately 3 h after abiraterone administration.[5] A liquid chromatography-mass spectrometry (LC-MS) method was established with minor modification of our previous protocol to detect all 8 abiraterone metabolites at the same time (Supplementary Method [Additional file 2] for details).[6]

The patient #W7546 received abiraterone (1000 mg once daily), prednisone (5 mg twice daily), and dutasteride (0.5 mg once daily), at the same time in the morning, which we short named as APD, according to the clinic protocol. Previously, he responded to abiraterone for more than 3 months with maximum prostate-specific antigen (PSA) reduction of 80% [Figure 1]b and [Figure 1]c. However, his PSA increased dramatically after abiraterone resistance (day 102–161). He received the combination therapy since day 188 and the increase of PSA was halted. The addition of dutasteride led to a maximum PSA reduction of 23.0% and extended the response to abiraterone for 2–3 months [Figure 1]b and [Figure 1]c. The effect of dutasteride on abiraterone metabolism was confirmed by the increase of plasma abiraterone and the reduction to 0 of plasma 5α-Abi and its downstream metabolites. These data together indicate that dutasteride enhances abiraterone efficacy in this patient.

Dutasteride was administered to the patient #D3459 since day 243. He received abiraterone and prednisone in the morning but dutasteride in the afternoon (AP+D) for the first 4 months due to gastrointestinal irritation and then changed to the standard protocol (APD) as the patient #W7546. The patient #D3459 responded to abiraterone for more than 5 months with a maximum PSA reduction of 95.8% [Figure 1]d. The AP+D therapy showed no effect on PSA until 63 days later. The effect of dutasteride on abiraterone metabolism in this patient was gradually achieved as indicated by the increase of plasma Abi and reduction to 0 of 5α-Abis 63 days after the addition of dutasteride. Although no significant PSA reduction after the combination therapy, the addition of dutasteride held PSA increase for approximately 130 days.

Currently, there is no efficient therapy for abiraterone-resistant mCRPC. Dutasteride itself shows mild effect for prostate cancer therapy but might be used together with other drugs.[7],[8] Here, we show that dutasteride enhances abiraterone clinical efficacy in two abiraterone-resistant patients. The addition of dutasteride extended PSA doubling time and led to PSA reduction. The increase of plasma abiraterone and reduction of 5α-Abis might be clinical indicators for the efficiency of dutasteride. Notably, the patient #W7546 responded to the combination therapy more quickly than the patient #D3459 as indicated by the alteration of PSA. It might result from patient heterogeneity. The differences in drug administration (APD vs AP+D) might also contribute to the clinical divergence. Previous investigation on abiraterone pharmacokinetics indicates that plasma abiraterone has decreased significantly and the major metabolites have been generated already 6 h after drug administration. Thus, dutasteride might not be able to effectively affect abiraterone metabolism when taking separately (AP+D). However, dutasteride has a long half-life in patients (10 days to 5 weeks), which is helpful for abiraterone metabolism regulation after enough accumulation.[9]

Together, these data demonstrate that dutasteride is capable to regulate abiraterone metabolism to benefit some abiraterone-resistant patients. The main limitation of the present case report is the limited number of patients. Future clinical research with more patients to confirm the clinical effect of the combination therapy after abiraterone resistance is in progress.


  Author Contributions Top


SSH and ZFL conceived and designed the study. JPL, XC, YL, and DLW collected the clinical data. YYG and JJT detected plasma abiraterone metabolites. SSH and ZFL wrote the manuscript. All authors have read and approved the final manuscript.


  Competing Interests Top


All authors declared no competing interests.


  Acknowledgments Top


This research was partially funded by the National Key R&D program of China (2018YFA0508200 to ZFL), Clinical Innovations of Shanghai SHENKANG (SHDC12019112 to DLW), the Strategic Priority Research Program of Chinese Academy of Sciences (XDB19000000 and XDA12010318 to ZFL), the National Natural Science Foundation of China (81672526 to DLW and 81872075 to JJT), and the Prostate Cancer Foundation Young Investigator Award (#15YOUN11 to ZFL).

Supplementary Information is linked to the online version of the paper on the Asian Journal of Andrology website.

 
  References Top

1.
Barrie SE, Potter GA, Goddard PM, Haynes BP, Dowsett M, et al. Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alpha-hydroxylase/C17-20 lyase). J Steroid Biochem Mol Biol 1994; 50: 267–73.  Back to cited text no. 1
    
2.
de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995–2005.  Back to cited text no. 2
    
3.
Li Z, Bishop AC, Alyamani M, Garcia JA, Dreicer R, et al. Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature 2015; 523: 347–51.  Back to cited text no. 3
    
4.
Li Z, Alyamani M, Li J, Rogacki K, Abazeed M, et al. Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy. Nature 2016; 533: 547–51.  Back to cited text no. 4
    
5.
Alyamani M, Emamekhoo H, Park S, Taylor J, Almassi N, et al. HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer. J Clin Invest 2018; 128: 3333–40.  Back to cited text no. 5
    
6.
Alyamani M, Li Z, Upadhyay SK, Anderson DJ, Auchus RJ, et al. Development and validation of a novel LC-MS/MS method for simultaneous determination of abiraterone and its seven steroidal metabolites in human serum: innovation in separation of diastereoisomers without use of a chiral column. J Steroid Biochem Mol Biol 2017; 172: 231–9.  Back to cited text no. 6
    
7.
Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med 2010; 362: 1192–202.  Back to cited text no. 7
    
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Thompson IM Jr., Goodman PJ, Tangen CM, Parnes HL, Minasian LM, et al. Long-term survival of participants in the prostate cancer prevention trial. N Engl J Med 2013; 369: 603–10.  Back to cited text no. 8
    
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Azzouni F, Godoy A, Li Y, Mohler J. The 5 alpha-reductase isozyme family: a review of basic biology and their role in human diseases. Adv Urol 2012; 2012: 530121.  Back to cited text no. 9
    


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