Pembrolizumab + 177Lu-PSMA-617 for Prostate Cancer

Overseen By UCSF Genitourinary Medical Oncology Recruitment

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: University of California, San Francisco

Must be taking: LHRH analogues

Must not be taking: Anti-PD-1, Anti-PD-L1

Disqualifiers: Autoimmune disease, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 11

Duration: Up to 36 weeks

48 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment option for men with prostate cancer that has spread and is unresponsive to standard hormone treatments. The study combines two therapies: pembrolizumab, an immune-boosting drug, and 177Lu-PSMA-617 (also known as Pluvicto), a targeted radiation treatment. It targets those who have tried at least one androgen blocker, such as abiraterone or enzalutamide, but continue to experience disease progression. Participants must have a prostate cancer diagnosis that has spread and is resistant to hormone therapy, with a PSMA-positive lesion, indicating a specific marker detectable on a scan. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to the development of potentially effective therapies.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not have received other systemic anti-cancer therapies within 14 days before starting the study treatment. LHRH analogues are an exception and must be continued if you haven't had a bilateral orchiectomy (surgical removal of both testicles).

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that combining 177Lu-PSMA-617 and pembrolizumab is generally safe. Earlier studies found that taking one dose of 177Lu-PSMA-617 followed by pembrolizumab did not raise major safety concerns. Patients experienced manageable side effects, indicating a positive safety profile.

One study examined 177Lu-PSMA-617 with standard care and found it safe for people with advanced prostate cancer. Adding pembrolizumab did not cause unexpected problems, suggesting reasonable safety. While every treatment carries potential risks, the evidence so far reassures those considering joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Pembrolizumab combined with 177Lu-PSMA-617 for prostate cancer because it offers a novel approach compared to current treatments. Most traditional therapies for prostate cancer involve hormone therapy or chemotherapy, but this combination utilizes a targeted form of radiation therapy. 177Lu-PSMA-617 is a radioligand therapy that specifically targets prostate-specific membrane antigen (PSMA) found on prostate cancer cells, delivering radiation directly to the tumor. Meanwhile, Pembrolizumab is an immunotherapy that helps the immune system recognize and attack cancer cells. Together, they offer a promising way to enhance precision in treatment and potentially improve outcomes by combining targeted radiation with immune system activation.

What evidence suggests that this trial's treatments could be effective for metastatic castrate-resistant prostate cancer?

Research shows that combining 177Lu-PSMA-617 and pembrolizumab may help treat advanced prostate cancer that no longer responds to hormone therapy. In this trial, participants will receive both 177Lu-PSMA-617 and pembrolizumab. Studies have found that 177Lu-PSMA-617 can help patients live longer and slow cancer growth when used with standard treatments. Early trials have shown promising results when combined with pembrolizumab. Patients generally tolerated the combination well, experiencing side effects similar to those expected from each treatment alone. These findings suggest that this treatment could be effective for patients whose cancer has progressed despite previous treatments. ^{1 2 3 6 7}

Who Is on the Research Team?

Rahul Aggarwal, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

Men over 18 with advanced prostate cancer that's resistant to hormone therapy and has spread, who've had prior treatment fail. They must understand the trial and agree in writing, have a low testosterone level, recovered from past treatments' side effects, no recent vaccines or major surgeries, no severe allergies to pembrolizumab or its ingredients, not on high-dose steroids or immunosuppressants, and be willing to follow safety guidelines.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document

My organs are functioning well.

My testosterone levels are very low (< 50 ng/dL) as required.

Exclusion Criteria

Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment on C1D1. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent

I have been treated with specific immune therapy for cancer.

I have brain metastases that have not been treated.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive two doses of 177Lu-PSMA-617 and pembrolizumab, with the possibility of up to six total doses in the absence of clinical progression or unacceptable toxicity.

Up to 36 weeks

Every 6 weeks for up to 6 doses

Safety Follow-up

Participants undergo safety follow-up visits approximately 30 days and 90 days following the end of treatment visit.

3 months

2 visits (in-person)

Long-term Follow-up

Participants are contacted every 3 months to assess survival, disease status, and anti-cancer therapy status until death, withdrawal of consent, or study closure.

Up to 5 years

Every 3 months (in-person or telephone)

What Are the Treatments Tested in This Trial?

Interventions

• 177Lu-PSMA-617
• Pembrolizumab

Trial Overview The study is testing a combination of Pembrolizumab (an immune system booster) with a radioactive drug called 177Lu-PSMA-617 targeting prostate cancer cells. It's for patients whose cancer worsened after treatments like abiraterone. The goal is to see if this combo helps when standard therapies don't work anymore.

How Is the Trial Designed?

Group I: Pembrolizumab, 177Lu-PSMA-617 Experimental Treatment 2 Interventions

Participants will receive 400 mg of Pembrolizumab every 6 weeks and an infusion of 7.4 gigabequerel (GBq) (+/- 10%) of 177Lu-PSMA-617 on Cycle 1 Day 1 (of a 28 day cycle), and 6 weeks later, then at the first subsequent rise in PSA for up to six total doses, in the absence of unequivocal clinical progression, radiographic progression, or unacceptable toxicity, with a minimum interval of 6 weeks between doses.

177Lu-PSMA-617 is already approved in United States, European Union for the following indications:

Approved in United States as Pluvicto for:

• Metastatic castration-resistant prostate cancer

Approved in European Union as Pluvicto for:

• Metastatic castration-resistant prostate cancer

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Prostate Cancer Foundation

Collaborator

Trials

52

Recruited

3,000+

Published Research Related to This Trial

[177Lu]Lu-PSMA-617 (PluvictoTM) is an FDA-approved treatment for prostate cancer specifically for patients with PSMA-positive metastatic castration-resistant prostate cancer who have already undergone other therapies.

This treatment uses a targeted radioligand therapy that delivers radiation directly to tumor cells, effectively killing them while minimizing damage to healthy tissue, as shown in multiple clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[177Lu]Lu-PSMA-617 (PluvictoTM): The First FDA-Approved Radiotherapeutical for Treatment of Prostate Cancer. Hennrich, U., Eder, M.[2022]

In a phase 3 trial involving 831 patients with metastatic castration-resistant prostate cancer, the addition of 177Lu-PSMA-617 to standard care significantly improved both imaging-based progression-free survival (8.7 months vs. 3.4 months) and overall survival (15.3 months vs. 11.3 months).

While 177Lu-PSMA-617 was associated with a higher incidence of grade 3 or above adverse events (52.7% vs. 38.0%), it did not negatively impact the patients' quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. Sartor, O., de Bono, J., Chi, KN., et al.[2023]

The newly developed radionuclide therapy agent [177Lu]Lu-P17-079 ([177Lu]Lu-1) shows high uptake in PSMA-positive tumors and significantly increased bone uptake compared to other agents, indicating its potential effectiveness in targeting both prostate cancer and bone metastases.

PET imaging with [68Ga]Ga-P17-079 confirms the dual-targeting capability of [177Lu]Lu-1, making it a promising candidate for further development in treating prostate cancer with bone metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lu-177-Labeled Hetero-Bivalent Agents Targeting PSMA and Bone Metastases for Radionuclide Therapy. Zha, Z., Ploessl, K., Choi, SR., et al.[2023]

In a study of 168 patients undergoing 177Lu-PSMA therapy for metastatic castration-resistant prostate cancer, a higher PD-L2 signature was linked to significantly longer overall survival (OS), suggesting it may enhance treatment response.

Conversely, PD-L1 levels did not show a significant association with patient outcomes, indicating that PD-L2 may be a more relevant biomarker for predicting the efficacy of 177Lu-PSMA therapy, particularly in patients with lower LDH levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysing the tumor transcriptome of prostate cancer to predict efficacy of Lu-PSMA therapy. Handke, A., Kesch, C., Fendler, WP., et al.[2023]

In a phase 2 trial involving 30 men with metastatic castration-resistant prostate cancer, 57% achieved a significant PSA decline of 50% or more after treatment with Lutetium-177 [177Lu]-PSMA-617, indicating its efficacy in this patient population.

The treatment was associated with low toxicity, with the most common side effects being mild dry mouth and transient nausea, and it also led to clinically meaningful improvements in pain and quality of life for many patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Hofman, MS., Violet, J., Hicks, RJ., et al.[2021]

In a study involving 43 men with metastatic castration-resistant prostate cancer, a single dose of lutetium-177-PSMA-617 followed by pembrolizumab maintenance was found to be safe, with only 5% of patients experiencing serious treatment-related adverse events.

The treatment showed promising efficacy, with 56% of patients in the second part of the study achieving a confirmed objective response, indicating potential for durable clinical benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial. Aggarwal, R., Starzinski, S., de Kouchkovsky, I., et al.[2023]

[177Lu]Lu-PSMA-617 is effective in targeting prostate cancer, but some patients do not respond well; ongoing research is exploring combination therapies to improve outcomes for both treatment-naïve and resistant patients.

Combining [177Lu]Lu-PSMA-617 with other treatments, such as alpha radiation emitters and immune checkpoint inhibitors, shows promise in enhancing therapeutic responses, particularly for patients who have developed resistance to initial therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Towards Improving the Efficacy of PSMA-Targeting Radionuclide Therapy for Late-Stage Prostate Cancer-Combination Strategies. Arbuznikova, D., Eder, M., Grosu, AL., et al.[2023]

177Lu-PSMA-617 therapy has shown promising efficacy in treating metastatic prostate cancer, with a majority of patients experiencing a decline in prostate-specific antigen (PSA) levels, which is associated with longer survival rates.

The analysis of 17 studies indicated that while significant toxicities were infrequent, cytopenias were noted, and factors like performance status and tumor grade were important predictors of treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of 177Lu-PSMA-617 in Patients With Metastatic Castration-Resistant Prostate Cancer. Sun, M., Niaz, MO., Nelson, A., et al.[2020]

PSMA-targeted imaging and therapy have significantly improved the management of prostate cancer, particularly in advanced stages like metastasized castration-resistant prostate cancer.

Lutetium-177-conjugated PSMA-617 or PSMA-I&T (Lu-PSMA) has shown promising results in both multicenter retrospective and monocenter prospective trials, indicating its potential as an effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prostate Cancer Theranostics: PSMA Targeted Therapy. Seifert, R., Alberts, IL., Afshar-Oromieh, A., et al.[2021]

Citations

1. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00451-5/fulltext

Single-dose 177Lu-PSMA-617 followed by maintenance ... A single priming dose of 177Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2107322

Lutetium-177–PSMA-617 for Metastatic Castration ... The PSMA-targeted radioligand 177Lu-PSMA-617 prolonged overall survival and delayed imaging-based progression when added to standard care in patients with PSMA- ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03805594

NCT03805594 | 177Lu-PSMA-617 and Pembrolizumab in ... This phase Ib trial studies the dose and schedule of 177Lu-PSMA-617 and pembrolizumab in treating persons with castration-resistant prostate cancer

4. jnm.snmjournals.org jnm.snmjournals.org/content/early/2025/09/25/jnumed.125.270704

First-Line [177Lu]Lu-PSMA-617 Therapy Without ADT ... Quantitative 68Ga-PSMA-11 PET and clinical outcomes in metastatic castration-resistant prostate cancer following 177Lu-PSMA-617 (VISION Trial).

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.5017

PRINCE: Phase I trial of 177Lu-PSMA-617 in combination ... The combination of 177 Lu-PSMA-617 and pembrolizumab had promising activity. Toxicities were generally consistent with those of single-agent 177 Lu-PSMA-617 ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37922930/

Single-dose 177 Lu-PSMA-617 followed by maintenance ... A single priming dose of 177 Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic ...

7. annalsofoncology.org annalsofoncology.org/article/S0923-7534(25)00852-X/fulltext

Final overall survival and safety analyses of the phase III ... At the time of the final OS analysis, 299 deaths were reported in 142/234 participants (60.7%) in the 177Lu-PSMA-617 arm and 157/234 (67.1%) in ...