Immunotherapy is rapidly expanding across the spectrum of prostate cancer—moving from late-stage mCRPC into neoadjuvant, perioperative, and localized treatment settings. New trials are testing CAR-T cells, IL-15–based immune activators, DNA vaccines, PARP-sensitized immunoradiation, and intraoperative immune-stimulating agents to strengthen tumor control and prevent recurrence.
Across leading centers worldwide, early-phase studies are exploring strategies that boost local immune activation, reshape the tumor microenvironment, and enhance responses to surgery or radiation. Together, these innovations signal a shift toward using immunotherapy at earlier disease stages, aiming for deeper remissions and long-term cure in high-risk prostate cancer.
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Clinical Study of PSMA-Targeted CAR-T Cells in Castration-Resistant Prostate Cancer
This Phase I/II study, conducted at The Affiliated Hospital of Xuzhou Medical University, evaluates the safety and early efficacy of PSMA-targeted CAR-T cells in patients with castration-resistant prostate cancer (CRPC). The trial is designed in two sequential parts. The first phase follows a dose-escalation approach in which nine patients are divided into three cohorts, each receiving an increasing dose of CAR-T cells. Before infusion, all patients undergo lymphodepleting chemotherapy with cyclophosphamide given on days −8 and −7 and fludarabine administered from days −6 to −2. On day 0, participants receive a single infusion of PSMA-CAR-T cells at one of three dose levels (1×10⁸, 1×10⁹, or 1×10¹⁰ cells). To support CAR-T cell expansion, subcutaneous IL-2 at 75,000 IU/kg is given daily during the first 14 days and then three times weekly from days 15 to 28. This phase focuses on determining the maximum tolerated dose and characterizing acute safety.
Once the optimal dose is identified, the study proceeds to phase II, enrolling eleven additional patients treated with the same lymphodepleting regimen and the selected therapeutic CAR-T dose. Participants undergo regular monitoring every four weeks, including PSA measurements, blood tests, and clinical assessments. Imaging follow-up includes bone scans, prostate and pelvic MRI, and PET-CT when necessary. After six months of intensive monitoring, patients continue with visits every three months for two years, followed by annual follow-up for up to five years to evaluate long-term safety, recurrence risk, and overall survival.
Overall, the study aims to define the safety profile, establish the recommended therapeutic dose, and explore the antitumor activity of PSMA-targeted CAR-T therapy in men with advanced, treatment-resistant prostate cancer.
Neoadjuvant ADT + Darolutamide + Pembrolizumab, Followed by Adjuvant Pembrolizumab in Molecularly Stratified High-Risk Prostate Cancer
This Phase II, single-arm study at Mount Sinai evaluates an intensified neoadjuvant regimen—androgen deprivation therapy (leuprolide), darolutamide, and pembrolizumab—for men with NCCN high-risk, localized prostate cancer. After radical prostatectomy, all patients continue adjuvant pembrolizumab for 12 additional cycles.
What makes this study unique is its molecular selection: only tumors with all three aggressive genomic features are eligible:
- Decipher Genomic Classifier > 0.6
- High AR activity score (ARoS > 11)
- Luminal B subtype (PAM50)
This design enriches for patients who are at the highest risk of recurrence and may benefit most from intensified neoadjuvant therapy.
The treatment strategy in this study consists of an intensified neoadjuvant regimen delivered before surgery, combining androgen deprivation with targeted androgen receptor inhibition and immune checkpoint blockade. Patients first begin leuprolide-based ADT, administered every 12 weeks, together with daily darolutamide at a total dose of 1200 mg for a 16-week period. During this same window, they also receive pembrolizumab at 200 mg intravenously every three weeks for a total of five cycles. After completing the neoadjuvant phase and undergoing radical prostatectomy, participants continue with adjuvant pembrolizumab for an additional 12 cycles to sustain immune activation and potentially eliminate micrometastatic disease.
The primary objective of the trial is to determine the proportion of patients who achieve minimal residual disease at the time of surgery, defined as a residual cancer burden of 0.25 cm³ or less on final pathology. Secondary objectives include evaluating the rate of pathologic complete response, assessing MRI- and pathology-based tumor downstaging, characterizing the safety and tolerability of the regimen according to CTCAE v5.0, and measuring biochemical progression-free and metastasis-free survival during follow-up. Additional analyses will quantify changes in tumor volume during treatment, explore immune responses through detailed blood-based immunophenotyping and cytokine profiling, and investigate genomic and transcriptomic alterations using whole-exome sequencing and RNA sequencing of tumor samples.
This study addresses a critical unmet need in high-risk localized prostate cancer, a population with substantial recurrence risk despite definitive local therapy. By combining potent androgen suppression with pembrolizumab, the investigators aim to induce deeper preoperative tumor regression, enhance antitumor immunity, and ultimately reduce long-term recurrence rates in a genomically defined high-risk cohort.
Immunotherapy With N-803, ETBX-071, and M-CENK Combined With Radiation for High-Risk Prostate Cancer
This Phase II trial is testing an intensive immunotherapy-radiation approach for men with high-risk prostate cancer who cannot undergo surgery. The goal is to boost the immune system before and after radiation to improve tumor control.
The treatment combines three experimental immunotherapies with standard external beam radiation therapy (EBRT):
- N-803 — an IL-15 superagonist that activates NK cells and T cells.
- ETBX-071 — a PSA-targeted adenoviral vaccine designed to stimulate an immune attack against prostate cancer cells.
- M-CENK — autologous “memory-like” NK cells expanded outside the body to increase their anti-cancer activity.
Treatment Plan
Participants first undergo screening tests and apheresis to collect blood cells for NK-cell preparation.
The treatment is delivered in stages:
- Pre-radiation phase (6 weeks):
Patients receive N-803, ETBX-071, and a dose of M-CENK. A biopsy is then performed to evaluate early immune response. - Radiation therapy:
EBRT is given either over 2 weeks (hypofractionated) or 9 weeks (standard), depending on the physician’s choice. - Post-radiation phase:
After radiation, patients continue with four more cycles of N-803, ETBX-071, and M-CENK.
Androgen deprivation therapy may begin 6 months after radiation if needed.
Objectives
The primary aim of this trial is to determine whether the immunotherapy regimen given before radiation can trigger a complete pathologic response in high-risk prostate cancer. Researchers are also evaluating the degree of PSA reduction at the end of treatment, specifically looking for a PSA30 response.
Secondary objectives focus on understanding how patients respond both clinically and pathologically after radiation, as well as assessing the overall safety of this multi-component approach and measuring the time until disease recurrence.
Exploratory goals extend beyond tumor response to include broader aspects of patient health and biology. These include evaluating changes in quality of life and sexual function during and after treatment, characterizing immune activation and alterations within the tumor microenvironment, and monitoring circulating tumor DNA as a marker of minimal residual disease.
Sipuleucel-T–Based Autologous Cellular Immunotherapy for Advanced Prostate Cancer (OU-SCC-EXCITE)
This pilot, open-label phase I study from the University of Oklahoma evaluates whether extending the course of Sipuleucel-T immunotherapy can enhance immune activation and anti-tumor activity in men with metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T (Provenge) is an FDA-approved autologous cellular vaccine that stimulates an immune response against prostatic acid phosphatase (PAP). Traditionally, it is administered in three doses over one month. This trial tests whether spacing the third dose later—at 12–14 weeks—may produce a stronger and more durable immune response.
Treatment Approach
Participants receive three infusions of Sipuleucel-T, each containing at least 50 million autologous CD54⁺ cells activated with PAP–GM-CSF. Doses are administered at:
- Week 0
- Week 2
- Week 12–14
The extended schedule allows investigators to measure how immune responses evolve over a longer interval and whether boosting at week 12–14 improves immunologic memory.
Primary Objectives
The study has two main goals:
- Feasibility: Determine whether ≥85% of enrolled patients can successfully complete all three planned infusions.
- Immune Response: Measure increases in IgG levels and T-cell proliferation against prostate cancer–associated antigens from baseline to week 12–14.
Secondary Objectives
Key secondary assessments include:
- Evaluating differences in immune responses among racial groups.
- Assessing preliminary anti-tumor activity through changes in PSA from baseline to 30 days after the final Sipuleucel-T dose.
Study Population
Eligible participants are men ≥18 years with asymptomatic or minimally symptomatic mCRPC, ECOG 0–1, and life expectancy ≥6 months. Exclusion criteria include prior Sipuleucel-T treatment, active infections requiring antibiotics, significant immunosuppression, or allergies to components of the therapy.
Study Duration
The study aims to enroll 13 patients, with treatment and follow-up lasting up to 12 months for immune monitoring. Full study completion is expected by 2026, with feasibility, safety, and immunologic endpoints guiding future trials of extended-schedule autologous cellular therapy.
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Radium-223, Peposertib, and Avelumab for Advanced mCRPC
This phase I/II trial, led by the National Cancer Institute, is testing whether strengthening targeted radiation with a DNA-damage repair inhibitor—and adding immunotherapy—can improve outcomes in men with metastatic castration-resistant prostate cancer (mCRPC) that has spread to the bones.
What the Study Is Testing
The trial compares three approaches:
- Radium-223 alone – a bone-targeted alpha-radiation treatment already used for mCRPC.
- Radium-223 + Peposertib (M3814) – peposertib blocks DNA-PK, preventing cancer cells from repairing radiation-induced DNA damage.
- Radium-223 + Peposertib + Avelumab – adds a PD-L1 inhibitor to boost immune recognition and killing of tumor cells.
The goal is to see whether combining these treatments delays disease progression more effectively than radium-223 alone.
This phase I/II study tests whether combining radium-223 with the DNA-PK inhibitor peposertib, with or without the immunotherapy avelumab, can improve treatment for men with metastatic castration-resistant prostate cancer involving the bones. The early phase identifies the safest dose of peposertib, and the later phase measures how long patients stay free from radiographic progression. Researchers also track skeletal events, survival, side effects, patient symptoms, and biomarker changes.
Patients are randomly placed into one of three groups: radium-223 alone, radium-223 plus peposertib, or the triple combination with avelumab. Treatment lasts up to six monthly cycles, followed by monitoring for two years.
Eligible men must have bone-metastatic CRPC, remain on ADT, and have previously progressed on AR-targeted therapy or taxanes. The study aims to see whether combining targeted bone radiation, DNA-repair inhibition, and immunotherapy can produce stronger and longer-lasting disease control.
Study of Cabozantinib and Nivolumab in Metastatic Castration-Resistant Prostate Cancer (CANOPY)
This multicenter phase II trial evaluates the combination of cabozantinib and nivolumab in men with metastatic castration-resistant prostate cancer (mCRPC). All participants begin with a baseline tumor biopsy, start cabozantinib (40 mg orally daily) together with nivolumab (480 mg IV every 4 weeks), and undergo a second biopsy during Cycle 2 to assess early biological changes.
Treatment continues in 28-day cycles until radiographic progression, unacceptable toxicity, or patient withdrawal. PSA levels are checked every cycle, and imaging is performed every two cycles during the first year and then every three cycles.
The primary endpoint is 6-month radiographic progression-free survival (rPFS), assessed using RECIST 1.1 for soft tissue disease and PCWG3 criteria for bone metastases. Secondary endpoints include PSA responses (≥50% decline), overall response rate in measurable disease, overall survival, time to PSA progression, symptomatic skeletal events, circulating tumor cell conversion, and safety (CTCAE v5.0).
Eligible men must have mCRPC with documented progression, prior exposure to at least one AR-targeted agent and one taxane (unless ineligible), and ECOG performance status ≤2. Up to 47 patients will be enrolled.
This study explores whether dual targeting of the VEGF/MET/TAM pathways (cabozantinib) together with PD-1 blockade (nivolumab) can produce stronger tumor control in advanced prostate cancer.
Immunotherapy Before and After Surgery for High-Risk Prostate Cancer
This Phase II study tests a novel combination of three immunotherapies—N-803, ETBX-071, and M-CENK—given both before and after prostatectomy in men with high-risk prostate cancer. The goal is to boost the immune system’s ability to attack the tumor, reduce the chance of recurrence, and determine whether the approach is safe and effective.
The regimen includes N-803, an IL-15–based immune activator that stimulates NK and T cells; ETBX-071, a PSA-targeted adenoviral vaccine designed to trigger anti-tumor immune responses; and M-CENK, autologous cytokine-enhanced NK cells collected by apheresis and expanded ex vivo. All three components are administered over a six-week period before surgery, followed by radical prostatectomy. After surgery, patients receive four additional cycles of the same immunotherapy, and some may also undergo external-beam radiation if indicated.
The main outcomes assessed are event-free survival and biochemical recurrence-free survival. Secondary measures include early PSA changes and overall safety. Exploratory analyses will evaluate quality of life, sexual function, immune activation, and changes in the tumor microenvironment.
Men with high-risk prostate cancer who have not yet undergone prostatectomy may be eligible. Participants are monitored for up to five years to understand long-term disease control and recovery.
Trial of pTVG-HP DNA Vaccine + Nivolumab + Targeted Ablation in Non-Castrate Recurrent Oligometastatic Prostate Cancer
This Phase 1 pilot study is testing whether a DNA vaccine (pTVG-HP), combined with the PD-1 inhibitor nivolumab and targeted radiation to resistant lesions, can eliminate metastatic deposits in men with non-castrate, recurrent oligometastatic prostate cancer (OMPC). The trial focuses on activating the immune system early in the recurrence phase—before the disease becomes castration resistant—to improve long-term control and delay systemic therapy.
pTVG-HP is a DNA vaccine encoding prostatic acid phosphatase (PAP), designed to stimulate PAP-specific T-cell responses. Participants receive the vaccine as intradermal injections alongside nivolumab, aiming to enhance T-cell activity by blocking PD-1–mediated suppression. If some metastases fail to respond, targeted ablation (such as SBRT) is added to eliminate resistant lesions and potentially boost systemic immunity.
The study enrolls men who previously underwent prostatectomy and any needed radiation, and now show biochemical recurrence with a rising PSA and a PSA doubling time > 0, along with ≤3 metastatic lesions on PSMA PET/CT or conventional imaging. Patients must be non-castrate, with testosterone ≥50 ng/dL, and fit for immunotherapy.
The primary goal is to determine how many participants reach a complete PSA response (PSA <0.2 ng/mL) one year after prostatectomy. Safety and adverse-event rates are also key outcomes. Secondary endpoints include metastasis-free survival at one and two years, long-term PSA control over five years, and changes in PSA doubling time.
Because this is an early-phase study, only about 14 patients will be enrolled. Participants are followed for up to five years to assess PSA kinetics, recurrence patterns, immune effects, and long-term tolerability.
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Pembrolizumab With Radiation ± Olaparib for High-Risk Localized Prostate Cancer
This randomized Phase II study is testing whether adding the PARP inhibitor olaparib to pembrolizumab and standard radiation + ADT can enhance anti-tumor immunity in men with high-risk localized prostate cancer. Both pembrolizumab and PARP inhibition are known to make tumor cells more sensitive to radiation. PARP inhibition may also boost immune recognition by increasing neoantigen load and promoting T-cell infiltration, suggesting potential synergy with checkpoint blockade.
All patients begin pembrolizumab approximately three weeks before radiation. Those in Arm 1 also receive olaparib for three cycles, starting at the same time. Standard-of-care radiation and ADT are delivered per NCCN guidelines. After radiation, all patients continue pembrolizumab for one year as adjuvant immunotherapy.
The trial is designed to determine whether the combination can prolong cancer control after radiation. The primary outcomes are biochemical recurrence–free survival and metastasis-free survival at three years. Secondary analyses assess testosterone recovery, alterations in homologous recombination repair genes, and correlative immune biomarkers including PD-L1 expression, T-cell subsets, cytokines, TCR clonotypes, and circulating tumor DNA.
Eligible participants must have high-risk or very-high-risk localized prostate cancer, ECOG 0–1, and no prior prostate radiation or prolonged ADT. The study aims to enroll 64 men, with follow-up extending through 2029.
Neoadjuvant Xaluritamig Before Radical Prostatectomy in Localized Prostate Cancer
This Phase 1b study is evaluating xaluritamig (AMG 509)—a bispecific T-cell engager targeting STEAP1—as a neoadjuvant therapy for men with newly diagnosed, localized intermediate- or high-risk prostate cancer. The goal is to understand how well patients tolerate xaluritamig before prostate surgery and whether radical prostatectomy remains safe and feasible after treatment.
Study Approach
Participants are assigned to one of two cohorts:
- Cohort A: Xaluritamig monotherapy given intravenously before surgery.
- Cohort B: Xaluritamig combined with an oral GnRH antagonist, providing short-term androgen suppression up to the time of prostatectomy.
After approximately 8 weeks of neoadjuvant therapy, all patients undergo radical prostatectomy. The study closely monitors perioperative safety, surgical complication rates, and the ability to complete surgery as planned.
Main Objectives
The primary focus is on safety and tolerability—evaluating treatment-emergent and treatment-related adverse events, changes in lab parameters, and complications categorized by Clavien–Dindo classification. Another key goal is to confirm whether radical prostatectomy can be performed safely after neoadjuvant STEAP1-targeted immune therapy.
Key Secondary Measures
To explore early biological activity, the trial also measures:
- Changes in PSA levels from baseline
- MRI-based PI-RADS scores
- Pathologic complete response (pCR) rates
- Minimal residual disease (MRD) at surgery
- Time to postoperative PSA rise (≥0.2 ng/mL)
- PSA progression-free survival
- Presence of undetectable PSA after surgery
- Full pharmacokinetic profile of xaluritamig (Cmax, Tmax, AUC, half-life, accumulation)
Who Is Enrolled
The study includes 40 men with localized, intermediate- or high-risk prostate cancer who have not yet undergone prostatectomy and meet standard safety and organ-function criteria.
Intraoperative STM-416p in Radical Prostatectomy
This early-phase study is testing STM-416p, an investigational immune-stimulating therapy, given directly during radical prostatectomy for men with localized prostate cancer. STM-416p is delivered intraoperatively into the surgical bed, with the goal of boosting local and systemic anti-tumor immunity immediately after the tumor is removed.
Purpose of the Trial
The main aim is to understand whether STM-416p is safe and tolerable when applied during surgery. Researchers are specifically watching for:
- Dose-limiting toxicities in the first 21 days
- Treatment-emergent adverse events over 90 days
- Any serious complications related to the surgical wound
- Effects on wound healing using the ASEPSIS scoring system
As a Phase 1 dose-escalation study, it is designed only to determine safety, not treatment effectiveness.
How the Treatment Works
STM-416p contains resiquimod (R848), a TLR7/8 agonist that activates innate immunity. It is formulated in a gel-like matrix that is applied directly to tissues during prostate removal. After surgery, blood and urine samples are collected to measure:
- Pharmacokinetics (how much drug reaches the bloodstream and how fast)
- Pharmacodynamic effects, including changes in circulating cytokines (immune signaling proteins)
Who Can Join
Men ≥18 years old with:
- Histologically confirmed prostate cancer (Grade Group 2–5)
- Planned radical prostatectomy within 28 days of screening
- ECOG performance status ≤2
- Adequate organ and bone marrow function
- Patients needing postoperative drains or with recent anticancer treatment are excluded.
Study Size and Timeline
The trial plans to enroll 18 participants.
Primary safety data will be collected within the first 12 weeks, and full study completion is expected in 2026.