Post-Progression Enzalutamide/Abiraterone Not Effective in Metastatic CRPC

Combining continued enzalutamide with abiraterone plus prednisone failed to improve progression-free survival (PFS) in men with metastatic castration-resistant prostate cancer (CRPC) who progressed on enzalutamide, according to results of the phase IV post-marketing PLATO study (abstract 5004).

Enzalutamide and abiraterone are both used to treat chemotherapy-naive metastatic CRPC, generally in sequence. “As several studies have reported a rise in androgens on enzalutamide, we hypothesized that this could drive resistance, and that by inhibiting androgen synthesis by adding abiraterone to enzalutamide, we could reinduce sensitivity and prolong the duration of response,” said Gerhardt Attard, MD, PhD, of the Institute of Cancer Research and the Royal Marsden Hospital in London. He presented the results at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6 in Chicago.

The study utilized a novel design. At baseline, 509 men with chemotherapy-naive metastatic CRPC were enrolled and treated with enzalutamide. Men with no prostate-specific antigen (PSA) level rise at weeks 13 and 21 (251 patients) were then followed until PSA progression, and then randomized to receive either abiraterone plus prednisone plus placebo (125 patients) or abiraterone plus prednisone along with continued enzalutamide (126 patients). The patients were well matched between the groups; most had an ECOG performance status score of 0.

The primary endpoint was PFS, and this was no different between the groups. The continued enzalutamide group had a median PFS of 5.7 months, while the placebo group had a median PFS of 5.6 months, for a hazard ratio (HR) of 0.826 (95% CI, 0.612–1.119; P = .2176).

There was, however, an improvement specifically in radiographic PFS. The median with enzalutamide was 10.0 months, compared with 7.0 months in the placebo group, for an HR of 0.666 (95% CI, 0.470–0.944; P = .0215). Attard said that this finding deserves further scrutiny, but could be subject to multiple biases.

The time to PSA progression did not differ, at 2.8 months in both groups, for an HR of 0.874 (95% CI, 0.617–1.239; P = .04500).

Grade 3 or higher adverse events were more common in the enzalutamide group (44.8% vs 37.1%), though serious adverse events occurred at similar rates (30.4% vs 28.2%). Grade 3 or higher hypertension (9.6% vs 1.6%) and alanine aminotransferase increase (5.6% vs 2.4%) were more common with enzalutamide than with abiraterone plus prednisone alone. Attard said in general, though, that both regimens were reasonably well tolerated.

“Continuing enzalutamide after addition of abiraterone plus prednisone after PSA progression on enzalutamide alone did not result in a statistically significant improvement in PFS,” Attard concluded, adding that exploratory biomarker analyses are ongoing to try and identify distinct patient groups that might benefit from this therapy.

Tanya B. Dorff, MD, of the Keck School of Medicine at the University of Southern California in Los Angeles, was the discussant for the session. She said that these results suggest that if clinicians were using the combination of enzalutamide and abiraterone following progression, “you can consider stopping. This is twice as expensive and it is also more toxic,” she said.