Bipolar androgen therapy as platform for personalized medicine in castration-resistant prostate cancer

Bipolar androgen therapy as platform for personalized medicine in castration-resistant prostate cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Bipolar androgen therapy as platform for personalized medicine in castration-resistant prostate cancer Wolfgang Lilleby, Hans Geinitz, Samuel Denmeade This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8096472/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background Bipolar androgen therapy (BAT) with supraphysiologic testosterone (SPT) could be a therapeutic platform to keep the “endocrine interference” going in men with castration resistant prostate cancer CRPC (2). This concept, scientifically developed by the Johns Hopkins group, has been tested in several clinical trials (3-4). Case presentation This case report details the diagnosis and novel treatment with BAT during the course of disease of a 68-year-old male patient with primary metastatic prostate cancer identified in November 2019. After treatment failure of standard therapy this patient commenced with SPT given intramuscularly at four weeks intervals and concurrent androgen deprivation throughout treatment with BAT (Figure 1). He responded clinically with stable disease and without serious toxicity. Bipolar androgen therapy castration-resistant prostate cancer personalized medicine Figures Figure 1 Introduction Bipolar Androgen Therapy (BAT) is an emerging treatment strategy for metastatic castration-resistant prostate cancer (mCRPC), based on the paradoxical concept that supraphysiologic testosterone can induce tumor stress and re-sensitize cancer cells to androgen receptor (AR)-targeted therapies. Prior case reports have documented sustained clinical responses to BAT, even in heavily pretreated patients [10]. This case is presented to highlight several notable findings and to underscore the biological plausibility of re-establishing androgen dependence in CRPC. Unlike in the United States, where BAT has been explored in multiple clinical trials [1,4,6], it remains a relatively unknown systemic therapy in Norway. BAT may offer a valuable therapeutic platform to maintain “endocrine interference” in men with mCRPC, a concept originally introduced by Huggins and Hodges and later expanded upon by the Johns Hopkins group [5]. Our patient exhibited a genomic profile characterized by an overrepresented DNA damage repair (DDR) signature and features of BRCAness, making him a strong candidate for BAT. Denmeade and colleagues have proposed that AR activity and BRCAness, identified through Mann-Whitney ranking of gene expression signatures, may predict responsiveness to BAT [7]. This case report details the diagnosis and novel treatment approach using BAT [1] in a 68-year-old male patient diagnosed with primary metastatic prostate cancer (mPCa) in November 2019. The patient had no family history of prostate cancer. Initial pathological analysis revealed a Gleason score of 9 (Grade Group 5) across all 10 biopsy cores. Morphological examination identified intraductal carcinoma (IDC) as the predominant pattern, with focal cribriform architecture and perineural invasion. The pretreatment prostate-specific antigen (PSA) level was 41 ng/mL. Multiparametric MRI (mpMRI) and PSMA-PET/CT imaging revealed tumor spread to pelvic lymph nodes and a solitary metastasis in a thoracic vertebra. The disease was staged as cT3bN1M1a + b. Immunohistochemical analysis of the primary tumor showed intact mismatch repair (MMR) protein expression, negative PD-L1 staining, and focal CD3 positivity. Cell morphology and flow cytometry confirmed concurrent hairy-cell leukemia. AE1/AE3 cytokeratin and NKX3.1 expression supported bone infiltration by prostate cancer cells. Prior to initiating long-term androgen deprivation therapy (ADT), whole-exome sequencing was performed. Clinically relevant genomic alterations were identified in DDR genes including ATM and BARD1 , along with a dominant SBS3 mutational signature, subclonal PTEN mutations, and fusion transcripts involving BRCA2 and PIK3 . Based on tumor board recommendations, the patient received combined ADT and high-energy photon beam radiotherapy to the primary tumor. After four months of ADT, complete testosterone suppression was achieved by adding the second-generation AR inhibitor enzalutamide to goserelin during and after radiotherapy [2]. Due to COVID-19-related delays, fiducial gold markers were placed in April 2020, followed by image-guided conformal radiotherapy (74 Gy) from May to June 2020. At the end of radiotherapy, the patient’s PSA nadir was 0.44 ng/mL. Follow-up MRI scans showed signal changes consistent with a positive response in bone marrow metastases, as well as regression of the prostate tumor and lymph node involvement. By August 2020, PSA had declined to < 0.03 ng/mL, and the patient continued dual androgen blockade with goserelin and enzalutamide. In March 2021, rising PSA levels prompted discontinuation of enzalutamide. Given the patient’s BRCAness profile ( BRCA2 fusion, ATM and BARD1 alterations), olaparib—a PARP inhibitor—was initiated as second-line personalized therapy in April 2021 [3]. The patient experienced a sustained response for 23.8 months, with manageable hematologic toxicity affecting thrombocytes and hemoglobin levels. In February 2023, PSA levels rose again, although the patient remained in good clinical condition. He was enrolled in a basket trial evaluating BAT using superphysiologic testosterone cypionate (SPT) administered intramuscularly [4], alongside continued ADT. The first BAT cycle (March–May 2023) stabilized PSA levels without notable side effects (Fig. 1 ). A PET scan in July showed weak PSMA uptake in retroperitoneal lymph nodes. AR-V7 splice variant analysis, performed before and during enzalutamide treatment, revealed AR-V7 positivity—a marker often associated with resistance to AR-targeted therapies. The second BAT cycle began in September 2023, incorporating the STEP-UP therapy concept (NCT04363164), with ARi added 28 days after each SPT injection. By October 2023, AR-V7 was no longer detectable, suggesting restored AR responsiveness. A third BAT cycle (December 2023–March 2024) included darolutamide in step-up doses, resulting in low PSA levels. A fourth cycle (May–November 2024) combined SPT, ARi, and olaparib, followed by a fifth BAT cycle in December 2024. In January 2025, PET/CT imaging showed increased disease activity and new PSMA uptake in mediastinal lymph nodes. Circulating free DNA analysis via FoundationOne® revealed only a BRAF mutation, likely related to the patient’s hairy-cell leukemia. Olaparib was reintroduced in February 2025, but PSA rose to 37 ng/mL. After discontinuation of PARPi, PSA declined to 29 ng/mL and further to 9.3 ng/mL four weeks later. In May 2025, PSA increased again, and the patient self-administered SPT. PSMA-PET/CT confirmed radiologic disease progression. At last observation, PSA was 54 ng/mL, and in light of diminishing BAT efficacy, a therapy switch was recommended. Discussion The patient’s prolonged disease stability likely reflects a composite therapeutic effect, although the individual contributions of BAT and concurrent agents cannot be definitively separated. Notably, the patient had a durable initial response to enzalutamide, and in the second BAT cycle, AR responsiveness was successfully rechallenged with enzalutamide. In the RESTORE trial, over 50% of patients previously treated with enzalutamide responded to ARi reintroduction following BAT [8]. Similarly, the TRANSFORMER trial demonstrated a 78% response rate to enzalutamide after progression on abiraterone and BAT [1]. Monitoring treatment efficacy using PSA alone is challenging when multiple agents are administered concurrently. In this case, AR-V7—a splice variant associated with resistance to AR-targeted therapies—was used as a biomarker. The variant was initially detected but became undetectable following enzalutamide rechallenge, suggesting a favourable BAT effect. The addition of ARi to ADT resulted in a durable clinical response. This approach is currently being evaluated in the STEP-UP trial (NCT04363164), and was applied in our patient with darolutamide, leading to significant PSA decline and a prolonged progression-free interval. Although the patient initially responded well to olaparib during the fourth BAT cycle, reintroduction of olaparib in the fifth cycle led to rising PSA levels, which subsequently declined after PARPi withdrawal. This pattern may reflect remodeling of DDR pathways and a loss of BRCAness, as previously described in other malignancies [9]. Conclusion Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is paradoxically associated with sustained AR signaling. In this case, the patient exhibited PSA expression in response to supraphysiologic testosterone (SPT), and Bipolar Androgen Therapy (BAT) achieved over two years of clinical benefit with minimal side effects. These findings support the potential of BAT as a promising treatment strategy and warrant its consideration in selected patients with CRPC. Declarations Acknowledgment The authors are deeply obliged to the patient`s willingness to share his case. The graphical assistance by Una Ryg is highly appreciated. Conflict of interest The authors declare no conflicts of interest. Funding No funding involved Author Contribution declaration The listed authors, Wolfgang Lilleby, Hans Geinitz and Samuel Denmeade have substantially contributed to the article and accepted the final version. Ethics statement This work contains genomic findings approved by the institutional tumor board (em professor Eivind Hovig, dr. Kjetil Berner) The study was conducted according to the guidelines of the Declaration of Helsinki (in its most recently amended version). All procedures followed were in accordance with the ethical standards as required by national law. Consent to participate, and Consent to Publish declarations: The patient gave his informed consent to publish his case. Data Availability Statement All processed molecular data of the tumor biopsy and R code for the transcriptome analysis are available through the following DOI: https://doi.org/10.5281/zenodo.4596571 . References Denmeade S, Wang H, Agarwal N, et al. TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men with Castration-Resistant Metastatic Prostate Cancer. J Clin Oncol . 2021;39(12):1371–82. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med . 2019;381(2):121–31. Hussain M, Mateo J, Fizazi K, et al. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med . 2020;383(24):2345–57. Denmeade SR, Isaacs JT. Bipolar androgen therapy: the rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer. Prostate . 2010;70(14):1600–7. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin . 1972;22(4):232–40. Kumar R, Sena LA, Denmeade SR, et al. The testosterone paradox of advanced prostate cancer: mechanistic insights and clinical implications. Nat Rev Urol . 2023;20(5):265–78. Sena LA, Kumar R, Sanin DE, et al. Androgen receptor activity in prostate cancer dictates efficacy of bipolar androgen therapy through MYC. J Clin Invest . 2022;132(23). Markowski MC, Wang H, Sullivan R, et al. Multicohort Open-label Phase II Trial of Bipolar Androgen Therapy in Men with Metastatic Castration-resistant Prostate Cancer (RESTORE): A Comparison of Post-abiraterone Versus Post-enzalutamide Cohorts. Eur Urol . 2021;79(5):692–9. Lin KK, Harrell MI, Oza AM, et al. BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. Cancer Discov . 2019;9(2):210–9. Tran EU, Royz E, Yamamoto K, et al. Bipolar androgen therapy for treatment of metastatic castration-resistant prostate cancer: A case series. Prostate . 2025;85(1):40–47. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 13 Dec, 2025 Reviews received at journal 12 Dec, 2025 Reviewers agreed at journal 05 Dec, 2025 Reviews received at journal 05 Dec, 2025 Reviewers agreed at journal 03 Dec, 2025 Reviewers agreed at journal 03 Dec, 2025 Reviewers invited by journal 03 Dec, 2025 Editor invited by journal 02 Dec, 2025 Editor assigned by journal 28 Nov, 2025 Submission checks completed at journal 28 Nov, 2025 First submitted to journal 28 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8096472","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":554786070,"identity":"286d024a-4abf-433b-b605-7df221e49efe","order_by":0,"name":"Wolfgang 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10:25:47","extension":"html","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":29194,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8096472/v1/ca4c821d8aa2ac8f9e92c2a7.html"},{"id":97687437,"identity":"837247f1-a7fa-47a3-be92-d74cbb57bad1","added_by":"auto","created_at":"2025-12-08 10:25:47","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":122702,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCourse of PSA from diagnosis and during ADT treatment and BAT cycles in blue bars.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBAT-cycle1: SPT+ADT; BAT-cycle2: SPT+ADT+Enzalutamide;\u003c/p\u003e\n\u003cp\u003eBAT-cycle3: SPT+ADT+Darolutamide, BAT-cycle4: SPT+ADT+Olaparib,\u003c/p\u003e\n\u003cp\u003eBAT-cycle5: SPT+ADT+Olaparib,\u003c/p\u003e\n\u003cp\u003eBAT-cycle6: SPT+ADT (self-administered)\u003c/p\u003e","description":"","filename":"BATfigure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8096472/v1/bf380dc5c9e378327395051e.jpg"},{"id":97902396,"identity":"c3eb8671-81c3-4cbd-b401-00b3f4ae8bc5","added_by":"auto","created_at":"2025-12-10 15:52:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":484993,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8096472/v1/774c2f33-d16c-43d8-909a-d0d71d0814eb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Bipolar androgen therapy as platform for personalized medicine in castration-resistant prostate cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBipolar Androgen Therapy (BAT) is an emerging treatment strategy for metastatic castration-resistant prostate cancer (mCRPC), based on the paradoxical concept that supraphysiologic testosterone can induce tumor stress and re-sensitize cancer cells to androgen receptor (AR)-targeted therapies. Prior case reports have documented sustained clinical responses to BAT, even in heavily pretreated patients [10]. This case is presented to highlight several notable findings and to underscore the biological plausibility of re-establishing androgen dependence in CRPC.\u003c/p\u003e\u003cp\u003eUnlike in the United States, where BAT has been explored in multiple clinical trials [1,4,6], it remains a relatively unknown systemic therapy in Norway. BAT may offer a valuable therapeutic platform to maintain \u0026ldquo;endocrine interference\u0026rdquo; in men with mCRPC, a concept originally introduced by Huggins and Hodges and later expanded upon by the Johns Hopkins group [5].\u003c/p\u003e\u003cp\u003eOur patient exhibited a genomic profile characterized by an overrepresented DNA damage repair (DDR) signature and features of BRCAness, making him a strong candidate for BAT. Denmeade and colleagues have proposed that AR activity and BRCAness, identified through Mann-Whitney ranking of gene expression signatures, may predict responsiveness to BAT [7].\u003c/p\u003e\u003cp\u003eThis case report details the diagnosis and novel treatment approach using BAT [1] in a 68-year-old male patient diagnosed with primary metastatic prostate cancer (mPCa) in November 2019.\u003c/p\u003e\u003cp\u003eThe patient had no family history of prostate cancer. Initial pathological analysis revealed a Gleason score of 9 (Grade Group 5) across all 10 biopsy cores. Morphological examination identified intraductal carcinoma (IDC) as the predominant pattern, with focal cribriform architecture and perineural invasion.\u003c/p\u003e\u003cp\u003eThe pretreatment prostate-specific antigen (PSA) level was 41 ng/mL. Multiparametric MRI (mpMRI) and PSMA-PET/CT imaging revealed tumor spread to pelvic lymph nodes and a solitary metastasis in a thoracic vertebra. The disease was staged as cT3bN1M1a\u0026thinsp;+\u0026thinsp;b. Immunohistochemical analysis of the primary tumor showed intact mismatch repair (MMR) protein expression, negative PD-L1 staining, and focal CD3 positivity. Cell morphology and flow cytometry confirmed concurrent hairy-cell leukemia. AE1/AE3 cytokeratin and NKX3.1 expression supported bone infiltration by prostate cancer cells.\u003c/p\u003e\u003cp\u003ePrior to initiating long-term androgen deprivation therapy (ADT), whole-exome sequencing was performed. Clinically relevant genomic alterations were identified in DDR genes including \u003cem\u003eATM\u003c/em\u003e and \u003cem\u003eBARD1\u003c/em\u003e, along with a dominant SBS3 mutational signature, subclonal \u003cem\u003ePTEN\u003c/em\u003e mutations, and fusion transcripts involving \u003cem\u003eBRCA2\u003c/em\u003e and \u003cem\u003ePIK3\u003c/em\u003e. Based on tumor board recommendations, the patient received combined ADT and high-energy photon beam radiotherapy to the primary tumor. After four months of ADT, complete testosterone suppression was achieved by adding the second-generation AR inhibitor enzalutamide to goserelin during and after radiotherapy [2].\u003c/p\u003e\u003cp\u003eDue to COVID-19-related delays, fiducial gold markers were placed in April 2020, followed by image-guided conformal radiotherapy (74 Gy) from May to June 2020. At the end of radiotherapy, the patient\u0026rsquo;s PSA nadir was 0.44 ng/mL. Follow-up MRI scans showed signal changes consistent with a positive response in bone marrow metastases, as well as regression of the prostate tumor and lymph node involvement.\u003c/p\u003e\u003cp\u003eBy August 2020, PSA had declined to \u0026lt;\u0026thinsp;0.03 ng/mL, and the patient continued dual androgen blockade with goserelin and enzalutamide. In March 2021, rising PSA levels prompted discontinuation of enzalutamide. Given the patient\u0026rsquo;s BRCAness profile (\u003cem\u003eBRCA2\u003c/em\u003e fusion, \u003cem\u003eATM\u003c/em\u003e and \u003cem\u003eBARD1\u003c/em\u003e alterations), olaparib\u0026mdash;a PARP inhibitor\u0026mdash;was initiated as second-line personalized therapy in April 2021 [3]. The patient experienced a sustained response for 23.8 months, with manageable hematologic toxicity affecting thrombocytes and hemoglobin levels.\u003c/p\u003e\u003cp\u003eIn February 2023, PSA levels rose again, although the patient remained in good clinical condition. He was enrolled in a basket trial evaluating BAT using superphysiologic testosterone cypionate (SPT) administered intramuscularly [4], alongside continued ADT. The first BAT cycle (March\u0026ndash;May 2023) stabilized PSA levels without notable side effects (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). A PET scan in July showed weak PSMA uptake in retroperitoneal lymph nodes.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAR-V7 splice variant analysis, performed before and during enzalutamide treatment, revealed AR-V7 positivity\u0026mdash;a marker often associated with resistance to AR-targeted therapies.\u003c/p\u003e\u003cp\u003eThe second BAT cycle began in September 2023, incorporating the STEP-UP therapy concept (NCT04363164), with ARi added 28 days after each SPT injection. By October 2023, AR-V7 was no longer detectable, suggesting restored AR responsiveness.\u003c/p\u003e\u003cp\u003eA third BAT cycle (December 2023\u0026ndash;March 2024) included darolutamide in step-up doses, resulting in low PSA levels. A fourth cycle (May\u0026ndash;November 2024) combined SPT, ARi, and olaparib, followed by a fifth BAT cycle in December 2024.\u003c/p\u003e\u003cp\u003eIn January 2025, PET/CT imaging showed increased disease activity and new PSMA uptake in mediastinal lymph nodes. Circulating free DNA analysis via FoundationOne\u0026reg; revealed only a \u003cem\u003eBRAF\u003c/em\u003e mutation, likely related to the patient\u0026rsquo;s hairy-cell leukemia. Olaparib was reintroduced in February 2025, but PSA rose to 37 ng/mL. After discontinuation of PARPi, PSA declined to 29 ng/mL and further to 9.3 ng/mL four weeks later.\u003c/p\u003e\u003cp\u003eIn May 2025, PSA increased again, and the patient self-administered SPT. PSMA-PET/CT confirmed radiologic disease progression. At last observation, PSA was 54 ng/mL, and in light of diminishing BAT efficacy, a therapy switch was recommended.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe patient\u0026rsquo;s prolonged disease stability likely reflects a composite therapeutic effect, although the individual contributions of BAT and concurrent agents cannot be definitively separated. Notably, the patient had a durable initial response to enzalutamide, and in the second BAT cycle, AR responsiveness was successfully rechallenged with enzalutamide. In the RESTORE trial, over 50% of patients previously treated with enzalutamide responded to ARi reintroduction following BAT [8]. Similarly, the TRANSFORMER trial demonstrated a 78% response rate to enzalutamide after progression on abiraterone and BAT [1].\u003c/p\u003e\u003cp\u003eMonitoring treatment efficacy using PSA alone is challenging when multiple agents are administered concurrently. In this case, AR-V7\u0026mdash;a splice variant associated with resistance to AR-targeted therapies\u0026mdash;was used as a biomarker. The variant was initially detected but became undetectable following enzalutamide rechallenge, suggesting a favourable BAT effect.\u003c/p\u003e\u003cp\u003eThe addition of ARi to ADT resulted in a durable clinical response. This approach is currently being evaluated in the STEP-UP trial (NCT04363164), and was applied in our patient with darolutamide, leading to significant PSA decline and a prolonged progression-free interval.\u003c/p\u003e\u003cp\u003eAlthough the patient initially responded well to olaparib during the fourth BAT cycle, reintroduction of olaparib in the fifth cycle led to rising PSA levels, which subsequently declined after PARPi withdrawal. This pattern may reflect remodeling of DDR pathways and a loss of BRCAness, as previously described in other malignancies [9].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eResistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is paradoxically associated with sustained AR signaling. In this case, the patient exhibited PSA expression in response to supraphysiologic testosterone (SPT), and Bipolar Androgen Therapy (BAT) achieved over two years of clinical benefit with minimal side effects. These findings support the potential of BAT as a promising treatment strategy and warrant its consideration in selected patients with CRPC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are deeply obliged to the patient`s willingness to share his case. The graphical assistance by Una Ryg is highly appreciated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding involved\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe listed authors, Wolfgang Lilleby, Hans Geinitz and Samuel Denmeade have substantially contributed to the article and accepted the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work contains genomic findings approved by the institutional tumor board (em professor Eivind Hovig, dr. Kjetil Berner)\u003c/p\u003e\n\u003cp\u003eThe study was conducted according to the guidelines of the Declaration of Helsinki (in its most recently amended version). All procedures followed were in accordance with the ethical standards as required by national law.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate, and Consent to Publish declarations:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient gave his informed consent to publish his case.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll processed molecular data of the tumor biopsy and R code for the transcriptome analysis are available through the following DOI:\u0026nbsp;\u003cstrong\u003ehttps://doi.org/10.5281/zenodo.4596571\u003c/strong\u003e.\u003c/p\u003e"},{"header":"References","content":"\u003col start=\"1\" type=\"1\"\u003e\n\u003cli\u003eDenmeade S, Wang H, Agarwal N, et al. TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men with Castration-Resistant Metastatic Prostate Cancer. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. 2021;39(12):1371\u0026ndash;82.\u003c/li\u003e\n\u003cli\u003eDavis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. \u003cem\u003eN Engl J Med\u003c/em\u003e. 2019;381(2):121\u0026ndash;31.\u003c/li\u003e\n\u003cli\u003eHussain M, Mateo J, Fizazi K, et al. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. \u003cem\u003eN Engl J Med\u003c/em\u003e. 2020;383(24):2345\u0026ndash;57.\u003c/li\u003e\n\u003cli\u003eDenmeade SR, Isaacs JT. Bipolar androgen therapy: the rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer. \u003cem\u003eProstate\u003c/em\u003e. 2010;70(14):1600\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eHuggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. \u003cem\u003eCA Cancer J Clin\u003c/em\u003e. 1972;22(4):232\u0026ndash;40. \u003c/li\u003e\n\u003cli\u003eKumar R, Sena LA, Denmeade SR, et al. The testosterone paradox of advanced prostate cancer: mechanistic insights and clinical implications. \u003cem\u003eNat Rev Urol\u003c/em\u003e. 2023;20(5):265\u0026ndash;78.\u003c/li\u003e\n\u003cli\u003eSena LA, Kumar R, Sanin DE, et al. Androgen receptor activity in prostate cancer dictates efficacy of bipolar androgen therapy through MYC. \u003cem\u003eJ Clin Invest\u003c/em\u003e. 2022;132(23).\u003c/li\u003e\n\u003cli\u003eMarkowski MC, Wang H, Sullivan R, et al. Multicohort Open-label Phase II Trial of Bipolar Androgen Therapy in Men with Metastatic Castration-resistant Prostate Cancer (RESTORE): A Comparison of Post-abiraterone Versus Post-enzalutamide Cohorts. \u003cem\u003eEur Urol\u003c/em\u003e. 2021;79(5):692\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eLin KK, Harrell MI, Oza AM, et al. BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. \u003cem\u003eCancer Discov\u003c/em\u003e. 2019;9(2):210\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eTran EU, Royz E, Yamamoto K, et al. Bipolar androgen therapy for treatment of metastatic castration-resistant prostate cancer: A case series. \u003cem\u003eProstate\u003c/em\u003e. 2025;85(1):40\u0026ndash;47.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"discover-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dion","sideBox":"Learn more about [Discover Oncology](https://www.springer.com/12672)","snPcode":"","submissionUrl":"","title":"Discover Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Bipolar androgen therapy, castration-resistant prostate cancer, personalized medicine","lastPublishedDoi":"10.21203/rs.3.rs-8096472/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8096472/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\n\u003cp\u003eBipolar androgen therapy (BAT) with supraphysiologic testosterone (SPT) could be a therapeutic platform to keep the “endocrine interference” going in men with castration resistant prostate cancer CRPC (2). This concept, scientifically developed by the Johns Hopkins group, has been tested in several clinical trials (3-4).\u003c/p\u003e\n\u003cp\u003eCase presentation\u003c/p\u003e\n\u003cp\u003eThis case report details the diagnosis and novel treatment with BAT during the course of disease of a 68-year-old male patient with primary metastatic prostate cancer identified in November 2019. After treatment failure of standard therapy this patient commenced with SPT given intramuscularly at four weeks intervals and concurrent androgen deprivation throughout treatment with BAT (Figure 1). He responded clinically with stable disease and without serious toxicity.\u003c/p\u003e","manuscriptTitle":"Bipolar androgen therapy as platform for personalized medicine in castration-resistant prostate cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-08 10:25:42","doi":"10.21203/rs.3.rs-8096472/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-13T21:34:35+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-13T03:54:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"220603494621918661205875258287313221012","date":"2025-12-05T16:00:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-05T12:33:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"80730866824870127227857667397225113297","date":"2025-12-03T14:41:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"240245766624671152657291528882230410042","date":"2025-12-03T14:16:05+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-03T14:01:37+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-02T09:31:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-28T16:57:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-28T15:26:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"Discover Oncology","date":"2025-11-28T15:20:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"discover-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dion","sideBox":"Learn more about [Discover Oncology](https://www.springer.com/12672)","snPcode":"","submissionUrl":"","title":"Discover Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"75ba46a1-a3b6-490d-ac8e-fab7ea34f73a","owner":[],"postedDate":"December 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T23:08:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-08 10:25:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8096472","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8096472","identity":"rs-8096472","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}