These results suggest that pTVG-HP may have had a single-agent benefit that could not be appreciated using an MFS endpoint. This is consistent with results from other trials of anticancer vaccines, which suggest that these may have more impact on longer-term endpoints such as survival.

Metabolic changes in tumors and immune organs may provide insights into treatment-associated biological effects. Larger studies are warranted to validate these findings.

P1, N=15, Active, not recruiting, University of Oklahoma | Recruiting --> Active, not recruiting | Trial completion date: Dec 2026 --> May 2028

Treatment with DNA vaccines and pembrolizumab demonstrated anti-tumor activity in terms of PSA declines and objective responses. The addition of pTVG-AR did not significantly increase measures of clinical efficacy; however, it was associated with a slight increase in toxicity to tissues that also express AR.

P2, N=26, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Dec 2025 --> Oct 2026

These results suggest that pTVG-HP may have had single-agent benefit that could not be appreciated using a MFS endpoint, challenging the notion that MFS can uniformly serve as a surrogate endpoint for overall survival in this stage of disease.

In mCRPC, docetaxel remains foundational, while cabazitaxel is preferred over ARPI switching after prior docetaxel and one ARPI, supporting mechanism-based sequencing. Immunotherapy has a limited but important niche: sipuleucel-T may benefit selected patients with low symptom burden, whereas immune checkpoint inhibitors are best reserved for biomarker-defined subsets such as microsatellite instability-high or mismatch repair-deficient tumors; tumor mutational burden should be interpreted cautiously in prostate cancer. Ongoing trials and emerging antigen-directed platforms will clarify whether chemotherapy can act as an immune-enabling partner in defined settings.

P1, N=30, Recruiting, City of Hope Medical Center | Not yet recruiting --> Recruiting | Trial completion date: Jun 2027 --> Jul 2028 | Initiation date: Dec 2025 --> Mar 2026 | Trial primary completion date: Jun 2027 --> Jul 2028

Despite the addition of multiple life-prolonging therapeutic modalities now available to treat patients with mCRPC, the mechanism of action of sipuleucel-T remains unique for patients with advanced prostate cancer. Therefore, maximizing the appropriate clinical utilization of sipuleucel-T in patients with mCRPC within current treatment paradigms is essential.

We previously reported a clinical trial (NCT02499835) evaluating PD-1 blockade combined with an anti-tumor DNA vaccine, pTVG-HP (encoding prostatic acid phosphatase), in patients with metastatic castration-resistant prostate cancer...These findings suggest that patients experiencing irAEs can have immune responses to tumor irrespective of obvious anti-tumor efficacy, at least with these treatments, and underscore the importance of tumor-infiltrating professional antigen presenting cells and T-cell activation for successful immunotherapy. Moreover, our findings suggest that combining vaccines and PD-1 blockade with MDSC-targeting therapies, anti-VISTA, and/or anti-PARP therapies might be further explored.

Given the use of sipuleucel-T as a standard of care backbone, there is emerging interest in combining it with other immunotherapies, hormonal therapies, or chemotherapies to improve its clinical efficacy. This review summarizes past experiences and current knowledge of combining sipuleucel-T with other treatments and explores future approaches to enhance such combinatorial strategies.

P1, N=14, Recruiting, University of Wisconsin, Madison | Not yet recruiting --> Recruiting