Favorable, But Perplexing Results Observed, With Combination for mCRPC

Catherine H. Marshall, MD, MPH

Catherine H. Marshall, MD, MPH

Men with metastatic castration-resistant prostate cancer (mCRPC) had inferior immune responses with the combination of sipuleucel-T (Provenge) and radium-223 (Xofigo) but improved clinical outcomes as compared with sipuleucel-T alone, a small randomized trial showed.

Systemic T-cell proliferation, as measured by PA2024 antigen in blood, increased by 7% at 6 weeks with the combination versus 25.3% with sipuleucel-T monotherapy (P= .0071). Nonetheless, time to radiographic/clinical progression, PSA response, and alkaline phosphatase response all improved significantly with the combination versus sipuleucel-T alone.

The mixed results perplexed investigators but provided enough encouragement to support additional studies, Catherine H. Marshall, MD, MPH, assistant professor of oncology of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, reported at the 2020 Genitourinary Cancers Symposium in San Francisco.¹

“The clinical results provided evidence of synergistic activity with the two drugs,” Marshall toldTargeted Oncology. “The immune response data were the exact opposite of what we had anticipated, and we really don’t have an explanation for that. We intend to continue analyzing the results to try to get some insight into that.”

Discussions for additional studies of the combination have already begun, she added, but details about the study design have yet to be determined.

Through a variety of mechanisms, radiation therapy may enhance immune modulation, including enhanced display of tumor-associated antigens.²Radium-223, an alpha-emitting radioisotope that is a bone-seeking calcium mimetic, targets areas of increased bone turnover and has FDA approval for treatment of mCRPC with symptomatic bone metastases. The autologous cell-based immunotherapeutic agent sipuleucel-T has FDA approval for treatment of minimally symptomatic mCRPC.

Investigators hypothesized that the combination of radium-223 and sipuleucel-T would enhance the latter’s ability to induce immune response, which would lead to better clinical outcomes.

Marshall and colleagues randomized 32 patients with asymptomatic or minimally symptomatic mCRPC to sipuleucel-T alone or with radium-223. Eligible patients had serologic or radiologic disease progression, absolute prostate-specific antigen (PSA) ≥2 ng/mL, and ECOG performance status of 0 to 1. Prior treatment with abiraterone (Zytiga) or enzalutamide (Xtandi) was allowed.

Key exclusion criteria included prior intravenous chemotherapy for mCRPC (except for hormone-sensitive disease), visceral metastases >1.0 cm, adenopathy >3.0 cm, or brain metastases.

The primary end point was PA2024-specific T-cell proliferation in peripheral blood at 6 weeks. Key secondary clinical end points included PSA response (≥50%), alkaline phosphatase response (≥30%), and time to radiographic/clinical progression. Secondary immune end points included prostatic acid phosphatase (PAP)-specific proliferation responses in peripheral blood, PA2024-specific and PAP-specific immune responses by interferon-gamma ELISPOT, and PA2024 and PAP-specific humoral responses.

The study population had a mean age of 70 to 71, about 70% had Gleason score ≥8, four patients in the sipuleucel-T monotherapy arm had exposure to abiraterone, 9 patients total had prior exposure to enzalutamide, median PSA was 25 ng/mL in the combination arm and 33 ng/mL in the monotherapy group, and baseline alkaline phosphatase was about 90 u/L.

PA2024-specific T-cell proliferation remained significantly higher with sipuleucel-T monotherapy out to 14 weeks and decreased thereafter until the proliferation index was similar in the 2 groups at week 26. PAP-specific proliferation remained similar in the 2 groups throughout follow-up. None of the other immune-response measures differed significantly between the 2 groups at any time during follow-up.

With regard to clinical outcomes, the time to radiographic/clinical progression tripled with the combination (9.3 vs 3.1 months), representing a 74% reduction in the hazard ratio (P= .0011). Five patients achieved PSA responses with the combination versus none in the monotherapy arm (P= .04). One patient randomized to single-agent sipuleucel-T had an alkaline phosphatase response compared with 9 in the combination group (P= .01).

Adverse event rates were similar between the 2 groups, including constitutional, hematologic, gastrointestinal, cardiac, and others.

References

1. Marshall CH, Park JC, Fu W, et al. Randomized phase 2 study of sipuleucel-T (Sip-T) with or without radium-223 (Ra-223) in men with bone-metastatic castration resistant prostate cancer. Presented at: 2020 Genitourinary Cancers Symposium; February 13-15, 2020; San Francisco, CA. Abstract 130.
2. 2. Shore ND, Mantz CA, Dosoretz DE, et al. Building on sipuleucel-T for immunologic treatment of castration-resistant prostate cancer.Cancer Control. 2013;20(1):7-16.