Avelumab in Men With Metastatic Castration-Resistant Prostate Cancer, Enriched for Patients Treated Previously With a Therapeutic Cancer Vaccine

Abstract

Therapeutic cancer vaccines including sipuleucel- T , a prostatic acid phosphatase (PAP) targeted vaccine that improves survival in metastatic castration-resistant prostate cancer (mCRPC), can produce immune responses that translate to clinical benefit. The effects of sequential checkpoint inhibitors after therapeutic vaccine on immune responses are unknown. Avelumab is an anti-programmed death ligand-1 monoclonal antibody evaluated in patients with mCRPC in the JAVELIN solid tumor phase 1 trial expansion cohort, enriched for patients with a previous therapeutic prostate cancer-targeted vaccine. mCRPC patients received intravenous avelumab 10 mg/kg every 2 weeks with imaging every 6 weeks. Peripheral blood T-cell responses to PAP and to PA2024, the peptide containing PAP utilized by the vaccine, were evaluated pre and posttreatment. Eighteen patients enrolled, and previous treatments included abiraterone or enzalutamide in 14 (78%), therapeutic cancer vaccine in 14 (78%), and chemotherapy in 4 (22%). Avelumab had a manageable safety profile. There were no sustained prostate specific antigen decreases. Of 17 patients evaluable for best overall response by RECISTv1.1, 12 had stable disease (SD) and 5 had progressive disease. Seven patients had SD for >24 weeks posttreatment. Fourteen patients had previously received therapeutic cancer vaccines. Eleven (79%) had SD as the best overall response. Of these 14 patients, 9 had previously received sipuleucel T . Analysis of antigen-specific T-cell responses pre and postavelumab treatment did not demonstrate changes in interferon-γ production or proliferation in response to PAP or PA2024. This unplanned analysis does not support the use of sequential therapeutic cancer vaccine therapy followed by programmed death ligand-1 inhibition in mCRPC.

Trial registration: ClinicalTrials.gov NCT01772004.

FIGURE 1

Percentage change in PSA from baseline. Spider plot of PSA at baseline and subsequent change on treatment with avelumab. Y-axis represents the percentage change in PSA compared with baseline (% change = 0 at month = 0). X-axis represents time in weeks from the initiation of avelumab, up to 30 weeks. Each line represents the PSA curve for 1 patient post-avelumab. Dashed lines indicate a prior therapeutic vaccine; solid lines indicate no prior therapeutic vaccine. Closed circles indicate the BOR of SD (gray: SD <24 wk and black: SD ≥24 wk); open circles indicate BOR of PD. One patient experienced a decrease in PSA but concurrently developed clinical and radiographic progression. One patient not evaluable for response came off treatment after experiencing an avelumab infusion-related reaction and the PSA curve is not included here. BOR indicates best overall response; PD, progressive disease; SD, stable disease.

FIGURE 2

Cellular responses to PAP and PA2024 decrease. Line plots depict interferon-γ ELISPOT assay and proliferation responses by tritiated thymidine to designated antigens (PAP or PA2024) in PBMC over time. Y-axis represents mean spots per 3×10⁵ PBMC (ELISPOT) or stimulation index (proliferation assay). X-axis represents time in days from the initiation of avelumab. In patients who did not receive sipuleucel-T (right column), solid lines indicate prior PROSTVAC; dashed lines indicate no prior PROSTVAC. Closed circles indicate BOR of SD (gray: SD <24 wk, black: SD ≥24 wk); open circles indicate BOR of PD. BOR indicates best overall response; ELISPOT, enzyme-linked immunosorbent spot; PAP, prostatic acid phosphatase; PBMC, peripheral blood mononuclear cell; SD, stable disease.