(UroToday.com) At the 2022 American Society of Clinical Oncology Annual Meeting held in Chicago and virtually, the poster session focused on Prostate, Testicular, and Penile cancers on Monday afternoon included a presentation from Dr. Mark C. Markowski discussing bipolar androgen therapy (BAT) in patients with metastatic castrate-resistant prostate cancer (mCRPC).
Treatment approaches in mCRPC have evolved substantially over the past decades, beginning with the introduction of docetaxel and transformed with subsequent data from trials of novel hormonal agents including abiraterone and enzalutamide. However, most patients still progress and die of a disease so further treatment approaches have been sought. One such example is BAT in which patients receive intramuscular (IM) administration of testosterone (T) resulting in rapid cycling of serum T from supraphysiologic to near-castrate levels in men with mCRPC. Building on this treatment paradigm, immune checkpoint blockade (ICB) demonstrated clinical response in patients who had previously received BAT. In this phase 2 trial (COMBAT; NCT03554317), patients received BAT in combination with nivolumab.
COMBAT is a multi-center, single arm, open label Phase 2 study in asymptomatic patients with 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) (NCT03554317). These men received T cypionate 400mg IM (BAT) every 28 days plus nivolumab 480mg IV every 28 days. Patients received an initial 12-weeks run in period with BAT alone, prior to the addition of nivolumab.
The primary endpoint was confirmed PSA50 response. OS and radiographic progression free survival (rPFS) were key secondary endpoints. All patients underwent baseline metastatic biopsies, and 24 had a second biopsy after 12 weeks of BAT. The authors further performed semi-quantitative IHC (for AR, Ki67, MYC, PTEN, TP53, RB1) on 24 paired biopsies, of which 15 pairs were also evaluable for RNA (whole transcriptome) sequencing.
The authors included 45 patients who were treated with the combination of BAT and nivolumab. In terms of the primary outcome, the PSA50 response was 40% (18/45, 95% CI: 26-56%, P=0.02 against the null hypothesis of 25%).
Further, the median rPFS was 5.6 (95% CI: 4.4–6.0) months and median overall survival was 27.8 (95% CI: 17.6-NR) months.
After a median follow-up of 17.8 months, the median OS was 27.8 (95%% CI: 17.6–NR) months.
Among the 24 patients who had paired biopsies prior to administration of nivolumab, BAT significantly decreased median MYC (P=0.046) and Ki-67 (P=0.030) expression by IHC. 17 (71%) patients had any decrease in MYC following BAT, with 29% (7/24) having a >50% decrease. The MYC response to treatment appeared to be prognostic: 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 those patients with >50% declines in MYC mRNA levels.
Thus, the authors conclude that there are favourable outcomes of the combination of BAT and nivolumab in heavily pretreated patients with mCRPC, with a median overall survival of exceeding 2 years and durable responses in a subset of patients.
Presented by: Mark Christopher Markowski, MD., Ph.D., medical oncologist at the Kimmel Cancer Center at Sibley Memorial Hospital, Johns Hopkins Medicine