Docetaxel Extends Enzalutamide Effectiveness

 Enzalutamide (Xtandi) is one of the two second-generation hormonal medications that has been proven to extend survival in men with metastatic castration-resistant prostate cancer (mCRPC). The other is abiraterone (Zytiga). A pilot study suggested that docetaxel can sometimes reverse enzalutamide resistance.

The PRESIDE randomized clinical trial (RCT) treated 687 mCRPC patients in 123 sites throughout Europe. All of them were given enzalutamide along with ADT. 271 started to fail (PSA increase or tumor increase on scans) after 13 weeks. Then they were randomized to receive either:

1. Triplet therapy: Enzalutamide and docetaxel and ADT concurrently, or
2. Docetaxel and ADT and placebo

The triplet therapy extended progression-free survival over docetaxel+ADT, indicating that enzalutamide remained effective. The increase was small, but statistically significant.

Treatment-related adverse events were similar in the two groups, which were mostly attributable to docetaxel.

The triplet group had more serious events - 49% vs 39%

This confirms the earlier Phase II CHEIRON RCT. CHEIRON proved that the combination could delay progression, but it did not improve overall survival.

In a similar RCT, called "ABIDO," a triplet with abiraterone and docetaxel was tried. In early results, toxicity, particularly neutropenia, was significantly worse for the triplet. There was no benefit to this triplet.

This is our first proof that resistance to enzalutamide can be reduced with docetaxel. It also shows that triplet therapy may be beneficial in patients who have already progressed to castration resistance. We would expect a larger effect if used at the first sign of castration resistance.

(Update 8/23) An RCT randomized 81 mCRPC patients to either abiraterone (abi) or abiraterone+cabazitaxel. The combination had superior results:

• Radiographic progression-free survival was 14.8 months for the combination vs 6.4 months for abi alone.
• Overall survival was 24.5 months for the combination vs 18.3 months for abi alone.
• PSA declined more than 50% in 92%  of men using the combination vs 56% using abi alone.

Other combinations with abiraterone that have proved to be useful for patients with mCRPC include apalutamide+abiraterone (ACIS RCT), ipatisertib+abiraterone (IPATential150 RCT), and olaparib+abiraterone (PROpel RCT)-- Results for a PARP inhibitor+abiraterone were not as universally favorable in the MAGNITUDE RCT. Triplet therapy is already standard-of-care in newly diagnosed mHSPC (see this link).