RAD001 and zoledronic acid in patients with renal cell carcinoma with bone metastases (RAZOR): A randomized phase II trial.

402 Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common, cause morbidity, and have been identified as an adverse prognostic feature. Previous trials have not assessed the effects of modern therapies on BM from RCC. Randomized data has demonstrated that zoledronic acid (Z) reduces skeletal-related-events (SREs) in RCC patients (pts). Bone turnover markers can identify pts at risk of SREs among those receiving Z. We sought to evaluate the effect on BM of RAD001 (R) (everolimus) alone compared to R+Z in the first-line setting. Methods: 30 treatment naïve pts with RCC and ≥ 1 BM were randomized 1:1 to R 10mg daily vs. R+Z 4mg IV 4-weekly (dose adjusted for creatinine clearance [CrCl]). Key eligibility criteria were ECOG PS ≤ 2, no bisphosphonates, or radiotherapy within 4 wks and CrCl >35ml/min. Bone-specific assessments were performed at baseline, wks-1, 4, 8, and 12. Treatment was continued on allocated arm until progression (RECIST 1.1). The primary objective was to assess the difference in bone turnover markers over the first 12 wks. The primary endpoint was urine N-telopeptide (uNTX) level with secondary endpoints being plasma C-telopeptide (CTX), quality of life (FACT-BP, BPI), progression free survival (PFS), SREs, and safety. Results: Heng prognostic group poor, intermediate, and good risk was 20.0%, 46.7%, 33.3% in R+Z and 40.0%, 46.7%, 13.3% in R. Over first 12 wks, the reduction in mean: uNTX on R+Z relative to R was 68.4% (95% CI (60.1%, 74.9%); p<0.0001); CTX on R+Z relative to R was 77% (95% CI (68%, 83%); p<0.0001). For FACT-BP there was no evidence of a difference (p = 0.5) but addition of Z was favourable for BPI Severity -1.1 (-2.2, 0.23; p = 0.05) and BPI Interference -1.3 (-2.5, 0.03; p = 0.06). Median PFS was 7.5 mo (95% CI 3.4, 14.7) on R+Z and 4.6 mo (95% CI 3.2, 6.3) on R (p = 0.03). Median time to 1st SRE was 9.6 mo (95% CI 4.3, 15.5) on R+Z and 5.2 mo (95% CI 1.6-8.2) on R (p = 0.03). Conclusions: Addition of Z to R significantly reduced bone resorption markers in this RCC population of pts with the adverse prognostic feature of BM. Pts receiving R+Z had prolonged time to 1st SRE and PFS; larger studies are required to further evaluate the addition of bone-specific to targeted therapies in this disease. Clinical trial information: ACTRN12609000980235.