Tyler Cain

Background: Prostate cancer is the most common non-cutaneous malignancy among men in the United States and remains the second leading cause of cancer death in men.¹ Androgen deprivation therapy (ADT) is the first-line treatment for prostate cancer, but ADT resistance often emerges within 2-3 years, resulting in the severe castration-resistant prostate cancer (CRPCa).² This progression is often modulated by androgen receptor (AR) evolution or overactivity through mutation or amplification.³ The novel bipolar androgen therapy (BAT) cyclically alternates between supraphysiologic and near-castrate levels of testosterone and demonstrated potential in re-sensitizing tumors to ADT and reducing disease burden.^4,5

Objective:  In this narrative review, we explored the mechanisms by which bipolar androgen therapy targets castration-resistant prostate cancer, as well as the efficacy of tumor regression. Articles were selected based on relevance to BAT mechanisms and preclinical efficacy.

Search Methods: An online Google scholar search was performed to obtain valid sources from a broad range of journal articles. Search terms: “Castration-resistant prostate cancer”, “bipolar androgen therapy”, and “antiandrogen resistance” were utilized to yield articles published between years 2018 and 2025.

Results: As prostate cancer growth is dependent on androgens, specifically testosterone, the primary ligand for AR, resistance to AR-targeted therapies in CRPCa can be driven by AR amplification or alternative signaling pathways. ^2,3 In patients receiving AR-targeted therapies, AR genotype and expression continued to evolve, with treatment-associated changes manifesting in 50% increase in AR copy numbers, and a 2.5-fold increase in the proportion of patients with AR ligand binding domain truncating rearrangements. Cells within a castrate-like environment of low levels of testosterone often develop hypersensitivity to androgens through amplification of AR gene or AR bypass signaling. Through cross-resistance, many AR inhibitors, which are typically first-line pharmaceuticals, were rendered unproductive in patients, leading to CRPCa.³ In a paradoxical fashion, supraphysiological androgen levels suppressed CRPCa through AR-mediated DNA damage.⁴ BAT exploits this vulnerability by combining high-dose testosterone with antiandrogen therapies to induce cell death and growth inhibition through immunomodulation. The latter triggers ferroptosis and nucleophagy through NF-kB and IRF7 activation.⁵ This environment also promotes infiltration of cytotoxic CD8⁺ T cells and CD57⁺ NK cells.^5,6 In a xenograft CRPCa model, BAT reduced tumor proliferation, demonstrating growth inhibition evidenced by decreased Ki-67 expression, lower mitotic indexes, and an increased cell death index.⁷ Clinically, patients with advanced mCRPCa receiving BAT exhibited a PSA₅₀ response rate of 35.6%, which increased to 40% with the addition of nivolumab.⁸

Conclusion: CRPCa is frequently caused by AR hypersensitivity that undermines conventional ADT or anti-androgen pharmaceuticals. Supraphysiological androgens can induce DNA damage, cell cycle arrest, and other immune activation pathways in CRPCa. Therefore, BAT proposes a safe and effective approach to restore tumor control and sensitivity by cycling supraphysiological and castrate-like levels of testosterone to exploit AR hypersensitivity into promoting tumor regression through nucleophagy, immunomodulation, and ferroptosis.

Works Cited

1. Combes AD, Palma CA, Calopedos R, Wen L, Woo H, Fulham M, Leslie S. PSMA PET-CT in the Diagnosis and Staging of Prostate Cancer. Diagnostics. 2022; 12(11):2594. https://doi.org/10.3390/diagnostics12112594
2. Huang Y, Jiang X, Liang X and Jiang G: Molecular and cellular mechanisms of castration resistant prostate cancer (Review). Oncol Lett 15: 6063-6076, 2018.
3. Annala M, Taavitsainen S, Khalaf DJ, et al. Evolution of Castration-Resistant Prostate Cancer in ctDNA during Sequential Androgen Receptor Pathway Inhibition. Clin Cancer Res. 2021;27(16):4610-4623. doi:10.1158/1078-0432.CCR-21-1625
4. Chatterjee, P. et al. Supraphysiological androgens suppress prostate cancer growth through androgen receptor-mediated DNA damage. J. Clin. Investig. 129, 4245–4260 (2019)
5. Congregado Ruiz B, Rivero Belenchón I, Lendínez Cano G, Medina López RA. Strategies to Re-Sensitize Castration-Resistant Prostate Cancer to Antiandrogen Therapy. Biomedicines. 2023;11(4):1105. Published 2023 Apr 6. doi:10.3390/biomedicines11041105
6. Kumar R, Mendonca J, Owoyemi O, et al. Supraphysiologic Testosterone Induces Ferroptosis and Activates Immune Pathways through Nucleophagy in Prostate Cancer. Cancer Res. 2021;81(23):5948-5962. doi:10.1158/0008-5472.CAN-20-3607
7. Yu J, Lim JE, Song W. Therapeutic Potential of Bipolar Androgen Therapy for Castration-Resistant Prostate Cancer: In Vitro and In Vivo Studies. Biomedicines. 2024; 12(1):181. https://doi.org/10.3390/biomedicines12010181
8. Markowski MC, Taplin ME, Aggarwal R, et al. Bipolar androgen therapy plus nivolumab for patients with metastatic castration-resistant prostate cancer: the COMBAT phase II trial. Nat Commun. 2024;15(1):14. Published 2024 Jan 2.

doi:10.1038/s41467-023-44514-2