Targeting IGF-1/2 with xentuzumab (Xe) plus enzalutamide (En) in metastatic castration-resistant prostate cancer (mCRPC) after progression on docetaxel chemotherapy (DCt) and abiraterone (Abi): Randomized phase II trial results.

Abstract

5030 Background: Insulin-like growth factor receptor-1 (IGF-1R) signaling activates the PI3K/AKT pathway and may lead to androgen receptor (AR) transactivation and progression to endocrine treatment resistance. Xe, an IGF-ligand-neutralizing antibody, binds to IGF-1 and IGF-2 and inhibits IGF-1R signaling. This multi-center randomized phase II trial (NCT02204072) evaluated anti-tumor activity of Xe plus En in mCRPC. Methods: Men with histologically/cytologically confirmed mCRPC and progression after DCt+Abi were randomized to receive Xe 1000mg IV QW + En 160mg/day oral, or En alone (28-day cycles until progression or intolerable adverse events [AEs]). Primary endpoint: progression-free survival by investigator assessment (PFS-IA); secondary: PFS by central review (PFS-CR), overall survival (OS), AEs. Results: Overall, 43 patients were randomized per arm; 70% Caucasian and 29% Asian (median age 70 y; range 46–88). At baseline (BL) the two arms were generally well balanced, although 33% v 47% were ECOG PS O, and 72% v 56% had a Gleason total score ≥8. By data cut-off (23 October 2017), 39/43 (Xe+En) and 38/43 patients (En) had discontinued, most due to disease progression. The median PFS-IA was 7.4 m for Xe+En (95% CI: 3.5–8.7) and 6.2 m for En (3.5–11.1) [HR = 0.99 (0.56–1.73); p = 0.96]. The results were similar after adjusting for BL ECOG PS and Gleason score. The median PFS-CR was 3.6 m for Xe+En (3.5–8.1) and 6.2 m for En (3.6–8.3) (HR = 1.22 [0.70–2.13]; p = 0.48). OS data are immature. For the two arms, prostate-specific antigen (PSA) response rates were 21% and 19%; maximum decline in PSA: -20 v -9 μg/L; PSA change at week 12: 19% v 18%; maximum decline in circulating tumor cells (CTC): -52% v -35%; and CTC response: 16% v 11%. The most frequently reported AEs were: fatigue 67% v 49%; decreased appetite 56% v 54%; weight reduction 37% v 12%; anemia 33% v 44%; back pain 30% v 37%. Nine patients discontinued Xe due to AEs. Conclusions: Addition of Xe to En did not prolong PFS in mCRPC compared with En alone. There were no notable differences in PSA-related endpoints and CTC between arms. Clinical trial information: NCT02204072.

Therapeutic Targeting of the IGF Axis

“…Xentuzumab is being tested clinically with afatinib in EGFR-mutant lung cancer (NCT02191891), in prostate cancer with enzalutamide (NCT02204072) and in HR+ breast cancer with everolimus and exemestane (NCT02123823). In advanced prostate cancer, the addition of xentuzumab to enzalutamide did not improve outcomes overall, although there was evidence of PFS prolongation in patients with high tumor IGF1 mRNA, albeit in a small sample [204]. In breast cancer, there was evidence of activity in patients with non-visceral disease [205].…”

“…Although no useful biomarker has yet been identified, this information could yet be generated by preclinical research e.g., [237,238,239], and ongoing trials. Support for this statement comes from the preliminary evidence of benefit from xentuzumab in breast cancer patients with predominant bone metastases, and prostate cancer patients whose tumors express high IGF1 mRNA [204,205].…”

A phase 1 trial of xentuzumab, an IGF‐neutralizing antibody, in Japanese patients with advanced solid tumors

“…The combination of xentuzumab and enzalutamide vs enzalutamide alone was also evaluated in a phase 2 trial in patients with metastatic castration‐resistant prostate cancer that had progressed after docetaxel and abiraterone. Although the safety profile was generally similar between treatment arms, addition of xentuzumab to enzalutamide did not prolong progression‐free survival vs enzalutamide alone 9 …”

Important players in carcinogenesis as potential targets in cancer therapy: an update

“…Moreover xentuzumab + enzalutamide inhibited the growth of castration-resistant LuCaP 96CR PDX with acquired resistance to enzalutamide, and improved survival in vivo [194]. Nevertheless the addition of xentuzumab to enzalutamide did not prolong progressionfree survival in patients with metastatic castration-resistant prostate cancer compared with enzalutamide alone [195].…”