Addition of Apalutamide to ADT for nmCRPC Particularly Beneficial in Higher-Risk and Luminal Subtypes

For patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), genomic classifier scores and basal-luminal subtype resulting from archived tumor specimens may be biomarkers of response to treatment with apalutamide plus androgen deprivation therapy (ADT), according to research from the phase 3 SPARTAN trial (NCT01946204) published in JAMA Oncology.

The apalutamide-plus-ADT combination produced a median metastasis-free survival (MFS) of 40.5 months compared with 16.2 months for patients receiving ADT alone (HR, 0.28; 95% CI, 0.23-0.35; P <.001). Further, investigation into the biomarker subset of lower-risk patients with a genomic classifier score of 0.6 or less found that MFS was significantly associated with apalutamide plus ADT compared with the ADT alone (HR, 0.46; 95% CI, 0.23-0.95; P = .04). However, patients at higher risk with a genomic classifier score greater than 0.6 saw the greatest treatment effect with apalutamide plus ADT (HR, 0.21; 95% CI, 0.11-0.40; P <.001).

“Our study results suggest that, although all patients with nmCRPC may benefit from the addition of apalutamide to ADT, those with high Decipher genomic classifier scores and those with the luminal subtype of prostate cancer may derive the greatest sustained benefit from apalutamide therapy,” the investigators wrote.

Of the 340 samples collected from individuals, 233 samples passed microarray quality control and were included in the analysis. Specifically, 154 patients in the apalutamide-plus-ADT group and 79 patients in the ADT-alone group were enrolled. The biomarker subset included 233 patients with a median age of 73 years (range, 49-91).

Improvements in both overall survival (OS; HR, 0.52; 95% CI, 0.29-0.94; P = .03) and progression-free survival 2 (PFS2; HR, 0.39; 95% CI, 0.23-0.67; P = .001) were observed for patients in the apalutamide-plus-ADT group who had a higher-risk genomic classifier score. There was no reported association between lower-risk genomic classifier score and apalutamide treatment for OS or PFS2.

Focusing on clinical outcomes among the apalutamide-plus-ADT and ADT-alone groups, patients with higher-risk genomic classifier scores (14.5 months) showed significantly shorter median MFS compared with patients with lower-risk genomic classifier scores (22.1 months) receiving ADT alone (HR, 0.43; 95% CI, 0.22-0.85; P = .01). Patients with both higher- and lower-risk genomic classifier scores had similar outcomes with apalutamide plus ADT (median MFS, not reached; HR, 1.11; 95% CI, 0.58-2.13; P = .75). Overall, adding apalutamide to ADT may help patients overcome the poor prognosis linked with higher genomic classifier scores.

The combination of apalutamide plus ADT was also associated with an improved MFS for both the basal (HR, 0.34; 95% CI, 0.20-0.58; P <.001) and luminal (HR, 0.22; 95% CI, 0.08-0.56; P = .002) tumor subtype cohorts.

The population of patients were randomized 2:1 to receive either apalutamide 240 mg/d plus ADT or placebo plus ADT. Patients were stratified to high- and low-risk categories based on genomic classifier scores as well as into basal and luminal subtypes. The main analyses focused on MFS, OS, and PFS2.

“Further studies to elucidate molecular changes and identify mechanisms of castration resistance and further progression may provide additional insights on factors that regulate higher-risk genomic classifier scores and basal-luminal lineage and differential response to ADT. Although logistically challenging, serial biopsies could provide more accurate real-time reflection of tumor biologic features,” the investigators wrote. “The findings reported herein on the addition of apalutamide to ADT may help in making an informed clinical decision regarding appropriate treatment options for management of advanced prostate cancer.”

Reference

Feng FY, Thomas S, Saad F, et al. Association of molecular subtypes with differential outcome to apalutamide treatment in nonmetastatic castration-resistant prostate cancer. JAMA Oncol. 2021;7(7):1005-1014. doi:10.1001/jamaoncol.2021.1463