039: Retrospective Time to Dose Modification Evaluation of Apalutamide

Statement of Purpose: Erleada® (apalutamide) is an androgen receptor inhibitor indicated for the treatment of metastatic castration sensitive prostate cancer (mCSPC) and non-metastatic castration resistant prostate cancer (nmCRPC). The purpose of this work is to explore if patients with higher exposures of Erleada® (apalutamide) have a higher likelihood of dose modifications due to an adverse event (e.g. rash).

Description of Methods & Materials: Data from two pivotal Phase 3 trials (SPARTAN in patients with nmCRPC and TITAN in patients with mCSPC) were pooled in this analysis. Assuming 240 mg daily dosing, the area under the curve at steady state (AUC_ss), was derived for all patients with evaluable apalutamide plasma concentrations. Time to dose modification was determined based on when subjects had a dose reduction to below 240 mg. Temporary dose interruptions were not considered. An exploratory analysis was conducted, including Kaplan-Meier survival analysis based on the quartiles of exposure levels of apalutamide. A separate sub-analysis was conducted for rash as prior analysis demonstrated that patients with increased apalutamide exposure are more likely to develop skin rash and pruritis [1,2]. Although, dose reductions may overcome these adverse events, based on an individual risk-benefit approach.

Data & Results: The AUC_ss could be derived for 1,299 patients, which is 97.9% of the total population. From the 1,299 PK eligible subjects, 114 patients had a dose reduction due to an adverse event. As only 8 subjects received a dose modification in the first 4 weeks of treatment, AUC_ss was deemed an appropriate predictive exposure marker. No notable difference was identified in the number of [any] dose modifications between quartiles of exposure for the total population (Table 1). In the sub-analysis, 56 patients were identified to have a dose reduction due to rash with no notable difference in dose modifications (Table 1). No clear relationship between exposure and time to dose modification was identified when evaluating all dose modifications (see Figure 1) and dose modifications due to rash only (not shown). The time to dose modification for rash was comparable to non-rash dose modification (p value: 0.71).

Interpretation, Conclusion or Significance: No clear relationship exists between apalutamide exposure and dose modification. In the sub-analysis of patients with rash, there was no increase in dose modifications with higher exposure. This could be due to apalutamide being well tolerated or symptoms being treated early by concomitant agents for rash treatment. Further evaluation is needed to better understand the dichotomy.

Disclosures: AY, SBM, JJL, OA own stock in J&J.