Background Angiotensin II (Ang II) has been shown preclinically to increase VEGF and TGF-β expression through AT1 receptor signaling but to decrease VEGF and TGF-β through AT2. Thus, we hypothesized that the ang II pathway might have a role in carcinogenesis and immune evasion and selectively inhibiting AT1 via angiotensin receptor blockers (ARBs) would enhance responses in combination with PD(L)1 blockade.
Methods We pooled data on 597 patients with advanced solid tumors on 20 prospective anti-PD(L)1 based trials. Fisher’s exact tests were used to compare objective response rates (ORR) and complete response rates (CRR) in patients receiving ARBs or ACE inhibitors (ACEi) to those in patients not receiving ARBs nor ACEi. Log-rank tests and Kaplan-Meier curves were used to compare overall survival (OS) in these same groups. Data were analyzed in tumor types where at least 5 patients were taking ARBs or ACEi. Multiple logistic regression and Cox regression analyses were performed to assess the effect of ARBs on ORR/CR and OS respectively.
Results In total, 597 patients with dozens of tumor types were pooled. Of these, 71 were taking ARBs and 82 were taking ACEi. Three tumor types had at least 5 patients taking ARBs: bladder, ovarian and prostate. ARB use was associated with improvement in ORR (77.8% vs 30.2% ; p=0.019), CRR (55.6% vs 9.3%; p=0.005) and OS (median: not reached vs 14.2 months (95% CI: 7.1–22.0 months; p=0.005) in patients with bladder cancer (n=52), but not ovarian nor prostate cancer. On multivariable analysis, ARB use remained associated with improved ORR, CRR and OS in patients with bladder cancer. Five tumor types had at least 5 patients taking ACEi: prostate, ovarian, colorectal, cervical and bladder. For all five, no benefit was seen in ORR, CRR nor OS with ACEi use (all p>0.10).
Conclusions ARB use was associated with improvement in ORR, CRR and OS in patients with urothelial or bladder cancer receiving anti PD(L)1 based therapy. No benefit was was seen with ARBs in prostate or ovarian cancer nor with ACEi in any tumor type evaluated. The associated benefit seen in bladder cancer with ARBs but not ACEi may be due to selective AT1 blockade by ARBs versus dual AT1/AT2 blockade by ACEi. This data is hypothesis generating and further study is needed to determine if selective AT1 inhibition can improve outcomes when combined with anti PD(L)1 based therapy in bladder cancer and other tumor types.
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