Cross-Resistance Between Abiraterone and Darolutamide
Cross-resistance between abiraterone and darolutamide occurs primarily through reactivation of androgen receptor (AR) signaling pathways, particularly via AR splice variants like AR-V7 and upregulation of the enzyme AKR1C3, which together restore androgen-dependent tumor growth despite ongoing treatment. 1
Mechanistic Basis of Cross-Resistance
Shared Resistance Pathways
The fundamental mechanism involves the AKR1C3/AR-V7 axis, which confers cross-resistance across all next-generation antiandrogen therapies including abiraterone, enzalutamide, apalutamide, and darolutamide. 1
AR-V7 splice variant expression: This constitutively active androgen receptor variant lacks the ligand-binding domain, making it insensitive to both AR antagonists (like darolutamide) and androgen synthesis inhibitors (like abiraterone). 1, 2
AKR1C3 enzyme upregulation: This enzyme converts weak androgens to more potent forms (converting androstenedione to testosterone and DHEA to androstenediol), effectively bypassing abiraterone's CYP17A1 inhibition. 1
AR full-length overexpression: Resistance to androgen deprivation therapy induces marked overexpression of full-length AR and AR target genes, which then confers cross-resistance to both abiraterone and darolutamide as second-line treatments. 2
Distinct But Convergent Mechanisms
While abiraterone and darolutamide have different primary mechanisms of action, resistance pathways converge:
Abiraterone inhibits CYP17A1 to block androgen synthesis in testes, adrenals, and tumor tissue. 3, 4
Darolutamide competitively inhibits androgen binding to AR, blocks AR nuclear translocation, and prevents AR-mediated transcription. 5, 6
Despite these different targets, chronic treatment with either agent activates the steroid hormone biosynthesis pathway and increases AKR1C3 expression, creating a common resistance mechanism. 1
Clinical Implications from Guidelines
Guideline Recommendations Against Switching
The NCCN explicitly advises against switching from one androgen receptor inhibitor to another (including between abiraterone and darolutamide) after resistance develops, as this approach is rarely effective. 7, 8
The CARD trial demonstrated that cabazitaxel chemotherapy provides superior outcomes compared to switching between AR-targeted agents, with radiographic PFS of 8.0 months versus 3.7 months (HR=0.54, p<0.0001). 8
For patients who have received docetaxel and an AR inhibitor, cabazitaxel is the Category 1 preferred next-line option rather than switching to an alternative AR-targeted therapy. 7
Optimal Sequencing Strategy
When both agents will be used sequentially in treatment-naïve settings:
NCCN recommends starting with abiraterone followed by enzalutamide (if sequential AR-targeted therapy is planned), as this sequence provides superior outcomes compared to the reverse. 8
This principle likely extends to darolutamide, though specific sequencing data between abiraterone and darolutamide are limited in the guidelines provided.
Experimental Evidence of Cross-Resistance
Laboratory Confirmation
Research demonstrates that:
Enzalutamide- and abiraterone-resistant prostate cancer cells exhibit cross-resistance to both apalutamide and darolutamide. 1
Knockdown of AR-V7 in resistant cells resensitizes them to apalutamide and darolutamide treatment, confirming AR-V7's central role. 1
Targeting AKR1C3 resensitizes resistant cells to these agents through AR-V7 inhibition, identifying a potential therapeutic vulnerability. 1
Bidirectional Cross-Resistance
Cells made resistant to abiraterone develop resistance to darolutamide. 1, 2
Conversely, chronic apalutamide treatment activates steroid biosynthesis pathways and confers resistance to enzalutamide, abiraterone, and darolutamide. 1
Critical Clinical Pitfall
The most important pitfall is attempting to switch from abiraterone to darolutamide (or vice versa) after progression, expecting meaningful clinical benefit. 7, 8
This strategy fails because both agents ultimately depend on suppressing AR signaling, and resistance mechanisms restore AR activity through pathways that bypass both drugs' mechanisms. 1, 2
Instead, transition to chemotherapy (cabazitaxel if post-docetaxel, or docetaxel if chemotherapy-naïve) represents the evidence-based approach. 7
Maintaining Androgen Deprivation
Regardless of cross-resistance development: