Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study

Abstract

Background: This phase I/II study in patients with metastatic castration-resistant prostate cancer (mCRPC) explored ipilimumab as monotherapy and in combination with radiotherapy, based on the preclinical evidence of synergistic antitumor activity between anti-CTLA-4 antibody and radiotherapy.

Patients and methods: In dose escalation, 33 patients (≥6/cohort) received ipilimumab every 3 weeks × 4 doses at 3, 5, or 10 mg/kg or at 3 or 10 mg/kg + radiotherapy (8 Gy/lesion). The 10-mg/kg cohorts were expanded to 50 patients (ipilimumab monotherapy, 16; ipilimumab + radiotherapy, 34). Evaluations included adverse events (AEs), prostate-specific antigen (PSA) decline, and tumor response.

Results: Common immune-related AEs (irAEs) among the 50 patients receiving 10 mg/kg ± radiotherapy were diarrhea (54%), colitis (22%), rash (32%), and pruritus (20%); grade 3/4 irAEs included colitis (16%) and hepatitis (10%). One treatment-related death (5 mg/kg group) occurred. Among patients receiving 10 mg/kg ± radiotherapy, eight had PSA declines of ≥50% (duration: 3-13+ months), one had complete response (duration: 11.3+ months), and six had stable disease (duration: 2.8-6.1 months).

Conclusions: In mCRPC patients, ipilimumab 10 mg/kg ± radiotherapy suggested clinical antitumor activity with disease control and manageable AEs. Two phase III trials in mCRPC patients evaluating ipilimumab 10 mg/kg ± radiotherapy are ongoing. ClinicalTrials.gov identifier: NCT00323882.

Keywords: immunotherapy; ipilimumab; metastatic castration-resistant prostate cancer; phase I/II trial; prostate-specific antigen and radiotherapy.

Figure 1.

The study schema. XRT, external-beam radiotherapy; PD, progressive disease; PSA, prostate-specific antigen.

Figure 2.

Waterfall plots of percent change in PSA from baseline. The greatest change at any time up to and including day 85 for patients (n = 65) across all cohorts (A) and for patients (n = 45) in the 10 mg/kg ± XRT group (B). The greatest change at any time during the entire study period for patients (n = 66) across all cohorts (C) and for patients (n = 46) in the 10 mg/kg ± XRT group (D). The number of patients with ≥50% PSA decline is higher in this figure than in Table 4 because the figure includes all declines, regardless of confirmation, and the table includes only confirmed declines.