Overall survival (OS) and biomarker results from combat: A phase 2 study of bipolar androgen therapy (BAT) plus nivolumab for patients with metastatic castrate-resistant prostate cancer (mCRPC).

Abstract

5064 Background: During BAT, intramuscular (IM) administration of testosterone (T) results in rapid cycling of serum T from supraphysiologic to near-castrate levels in men with mCRPC. In a retrospective study, clinical responses to immune checkpoint blockade (ICB) in mCRPC patients (pts) previously treated with BAT were observed. Here, we report the OS and biomarker results of a Phase 2 study in mCRPC pts treated with BAT in combination with nivolumab (COMBAT; NCT03554317). Methods: This was a multi-center, single arm, open label Phase 2 study in mCRPC pts who received T cypionate 400mg IM (BAT) every 28 days plus nivolumab 480mg IV every 28 days. Pts initially received BAT alone for a 12-week period, prior to the addition of nivolumab. Eligible pts were those with asymptomatic mCRPC who had soft tissue metastases amenable to biopsy, and who progressed on at least one prior novel AR targeted therapy (and up to one prior chemo for mCRPC). The primary endpoint was confirmed PSA50 response. OS and radiographic progression free survival (rPFS) were key secondary endpoints. All pts underwent baseline metastatic biopsies, and 24 had a second biopsy after 12 weeks of BAT. Semi-quantitative IHC (for AR, Ki67, MYC, PTEN, TP53, RB1) was performed on 24 paired biopsies, of which 15 pairs were also evaluable for RNA (whole transcriptome) sequencing. Results: 45 pts were enrolled. As previously reported, the PSA50 response was 40% (18/45, 95% CI: 26-56%, P=0.02 against the 25% null hypothesis), and median rPFS was 5.6 (95% CI: 4.4–6.0) months. After a median follow-up of 17.8 months, the median OS was 27.8 (95%% CI: 17.6–NR) months. In 24 pts with paired biopsies prior to administration of nivolumab, BAT significantly decreased median MYC (P=0.046) and Ki-67 (P=0.030) expression by IHC. 71% (17/24) of pts had any decrease in MYC following BAT, with 29% (7/24) having a >50% decrease. A >50% MYC protein decline was associated with longer rPFS (HR 0.33, 95%CI 0.14–0.78, P=0.005) and a nonsignificant association towards longer OS (HR 0.78, 95%CI 0.24–2.48, P=0.679). MYC protein and mRNA levels were tightly intercorrelated (r=0.65, P<0.001). Both rPFS and OS were numerically longer in pts with >50% declines in MYC mRNA levels (P>0.1 for both). Conclusions: BAT combined with nivolumab led to a median overall survival of >2 years in heavily pretreated mCRPC pts. BAT attenuated MYC expression, correlating with better outcomes. Clinical trial information: NCT03554317.