If Xtandi (enzalutamide) and Zytiga (abiraterone acetate) are ineffective, can other drugs in the same class be used?

Sequential Use of Androgen Receptor Pathway Inhibitors After Xtandi and Zytiga Failure

Switching from Xtandi (enzalutamide) to Zytiga (abiraterone), or vice versa, is not recommended due to well-documented cross-resistance, and you should instead move to chemotherapy (cabazitaxel if post-docetaxel, or docetaxel if chemotherapy-naïve) or PSMA-directed therapy. 1

Evidence Against Sequential Novel Hormone Therapy

The St. Gallen Advanced Prostate Cancer Consensus Conference provides the strongest guidance against this practice:

• 55% of the expert panel did not recommend and 42% recommended only in a minority of selected patients switching to the alternate AR pathway inhibitor (abiraterone or enzalutamide) in patients with primary (innate) resistant disease—defined as no PSA decline, no radiological response, and no clinical benefit. 2

• In acquired resistance (initial response followed by progression), 24% did not recommend and 53% recommended only in a minority of selected patients using the other AR pathway inhibitor as immediate next-line treatment. 2

Molecular Basis for Cross-Resistance

The lack of efficacy with sequential therapy is explained by shared resistance mechanisms:

• The AKR1C3/AR-V7 axis confers cross-resistance to all next-generation antiandrogen drugs including enzalutamide, abiraterone, apalutamide, and darolutamide. 3

• Enzalutamide- and abiraterone-resistant prostate cancer cells demonstrate cross-resistance to apalutamide (Erleada) and darolutamide (Nubeqa), meaning other drugs in these classes will not work either. 3

• Chronic treatment with any of these agents activates the steroid hormone biosynthesis pathway and increases AKR1C3 expression, which confers resistance to all other agents in the class. 3

Clinical Evidence of Limited Sequential Benefit

Abiraterone After Enzalutamide

• In a multicenter study of 30 patients treated with abiraterone after enzalutamide progression, only 3 patients (10%) achieved a ≥30% PSA decline, with median time to progression of just 15.4 weeks and no objective radiographic responses. 4

• The median abiraterone treatment duration was only 13 weeks, demonstrating minimal clinical benefit. 4

Enzalutamide After Abiraterone

• The randomized crossover trial (NCT02125357) demonstrated that enzalutamide after abiraterone showed 36% PSA response rate, while abiraterone after enzalutamide showed only 4% PSA response rate (p<0.0001). 5

• Time to second PSA progression was significantly longer with abiraterone-first followed by enzalutamide (19.3 months) versus the reverse sequence (15.2 months; HR 0.66, p=0.036). 5

• If sequential therapy must be attempted, the sequence of abiraterone followed by enzalutamide provides greater clinical benefit than the reverse, though neither is preferred over chemotherapy. 5, 1

Recommended Treatment After Novel Hormone Therapy Failure

Post-Docetaxel and Post-Novel Hormone Therapy

• Cabazitaxel is the category 1 preferred option based on the CARD trial, which demonstrated superior radiographic progression-free survival (8.0 vs 3.7 months; HR 0.54, p<0.0001) and overall survival (13.6 vs 11.0 months; HR 0.64, p=0.008) compared to switching between abiraterone and enzalutamide. 1

• Lutetium-177 PSMA-617 is strongly recommended for patients with PSMA-positive disease confirmed by imaging, with superior PSA response rates (66%) compared to cabazitaxel (37%) and fewer grade 3-4 adverse events (33% vs 53%). 1

Chemotherapy-Naïve Patients

• For patients with good performance status who progressed on abiraterone or enzalutamide without prior chemotherapy, docetaxel-based chemotherapy is the standard recommendation, particularly for symptomatic disease or visceral metastases. 1

Bone-Predominant Disease

• Radium-223 is a category 1 option for patients with good performance status, symptomatic bone-predominant disease, and no visceral metastases, as it improves overall survival. 1, 2

• Do not use radium-223 in patients with visceral metastases—it is contraindicated and ineffective in this setting. 1

Clinical Pitfalls to Avoid

• Do not expect meaningful benefit from sequential abiraterone-enzalutamide therapy due to well-documented cross-resistance mechanisms. 1, 2

• Do not delay chemotherapy in symptomatic patients with good performance status—these patients derive the most benefit from docetaxel or cabazitaxel. 1

• The CARD trial definitively showed cabazitaxel superiority over switching between novel hormone therapies, making sequential use no longer a preferred strategy. 1

• Evidence-based guidance on optimal sequencing remains limited, but switching formulations of abiraterone (original to fine-particle or vice versa) should not be undertaken on disease progression. 2