Apalutamide added on to abiraterone acetate, prednisone extends rPFS in mCRPC

Adding apalutamide (APA) to abiraterone acetate and prednisone (AAP) significantly extends radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) compared with AAP only, according to the final analysis of the ACIS* trial presented at ASCO GU 2021.

This phase III, double-blind, placebo-controlled trial involved 982 patients (median age 71.0 years) with chemotherapy-naive mCRPC who were randomized to receive either APA 240 mg once daily + AAP 1,000 mg once daily + 5 mg twice daily (APA + AAP; n=492) or placebo + AAP (AAP alone; n=490). Patients continued treatment until disease progression, occurrence of intolerable toxicity, or consent of study withdrawal. All patients remained on continuous androgen deprivation therapy. [ASCO GU 2021, abstract 9]

At a median follow-up of 54.8 months, patients treated with APA + AAP achieved an extended median rPFS by 7.4 months (p<0.0001), with a consistent 30 percent reduction in risk of radiographic progression or death (24.0 vs 16.6 months; hazard ratio [HR], 0.70) compared with AAP alone.

The overall survival (OS) was similar between the APA + AAP and AAP alone arms (36.2 vs 33.7 months; HR, 0.95; p=0.498), which did not reach statistical significance.

On the other hand, significantly more patients treated with APA + AAP than AAP alone achieved a 50 percent confirmed decline in prostate-specific antigen (PSA) level from baseline to 12 weeks (79.5 percent vs 72.9 percent; relative response [RR], 1.09; p=0.015). “However, this PSA decline favouring the combination arm [of APA + AAP] translated into only a marginal delay in time to PSA progression [(median 13.8 vs 12.0 months)],” said lead author Dr Dana Rathkopf from Memorial Sloan Kettering Cancer Center in New York, New York, US.

A significantly higher percentage of patients on APA + AAP also demonstrated an undetectable PSA (<0.2 ng/mL) at any time during treatment than those on AAP alone (24.6 percent vs 19.2 percent; RR, 1.28; p=0.040).

In a subgroup of patients with specific biomarker signatures, such as PAM50 luminal subtype tumour and average or high androgen receptor activity, the rPFS (HR, 0.70 and 0.71, respectively) and OS (HR, 0.84 and 0.91) benefits with APA + AAP were greater compared with AAP alone, but “future studies will be needed to confirm these observations,” Rathkopf noted.

However, grade 3–4 serious and treatment-emergent adverse events (AEs) leading to discontinuation occurred at a slightly higher rate in the APA + AAP arm than the AAP alone arm (37.3 percent vs 31.1 percent and 9.4 percent vs 6.3 percent, respectively). Despite this, there were no new safety signals identified, and “the safety profile of the combination was consistent with the previously reported safety of the individual drugs,” Rathkopf said.

“In conclusion, ACIS met its primary endpoint, [the] rPFS, as assessed by investigator review, was extended by … 7.4 months in [this] updated final analysis with APA + AAP vs the active comparator, AAP alone,” said Rathkopf.

“[Of note,] clinical and biomarker subgroups identified in this analysis will need further exploration to better delineate who might benefit most from the addition of apalutamide to abiraterone in [patients with] mCRPC,” she added.

*ACIS: An efficacy and safety study of apalutamide (JNJ-56021927) in combination with abiraterone acetate and prednisone versus abiraterone acetate and prednisone in participants with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC)