Can I Combine Lu-177 PSMA with Checkpoint Inhibitors or Other Immunotherapies — What the Evidence Says About Dual-Therapy Options

Why Researchers Are Excited About This Combination

If you have metastatic castration-resistant prostate cancer (mCRPC) and have already been through hormone therapy and chemotherapy, you may have heard about two treatments: Lu-177 PSMA radioligand therapy and immunotherapy. Now, scientists are asking whether these might work better together than either alone.

The short answer is yes—there is scientific reason to think they might. Here's the honest part: most of what we know comes from small, early-stage trials. This article covers the science, the key studies, and what it could mean for you and your care team.

For background on Lu-177 PSMA therapy and what clinical trials have already shown, see our article on what the latest clinical trial results tell us about Lu-177 PSMA for stage 4 prostate cancer.

What Is a Checkpoint Inhibitor — and Why Has It Struggled in Prostate Cancer Alone?

Your immune system has natural "brakes" that stop it from attacking your own healthy tissue. Cancer cells can hijack those brakes to hide from immune cells. Checkpoint inhibitors are drugs that release those brakes, allowing your immune system to recognize and attack cancer cells again.

Two major types of checkpoint inhibitors are studied in prostate cancer:

• PD-1 and PD-L1 inhibitors — drugs like pembrolizumab block a signal that cancer cells use to hide from immune cells. These are approved in many cancer types and in certain prostate cancers with specific genetic changes (such as MSI-H or mismatch repair deficiency).
• CTLA-4 inhibitors — drugs like ipilimumab block a different immune brake and are sometimes used alongside PD-1 inhibitors in what is called a "dual checkpoint" approach.

Here's the challenge: in most men with mCRPC, checkpoint inhibitors used alone have not shown strong results. Prostate cancer is often described as "immunologically cold," meaning the immune system does not naturally recognize and attack it well. The environment inside and around the tumor keeps immune cells out or inactive.

This is where Lu-177 PSMA may help.

How Lu-177 PSMA Radiation May Activate the Immune System

When radiation damages cancer cells, it can do more than kill them. It can trigger a process called immunogenic cell death. Dying cancer cells release signals called damage-associated molecular patterns (DAMPs) that act like an alarm for the immune system.

According to a peer-reviewed review published through the National Institutes of Health's PubMed Central, this process may draw more T cells (immune fighter cells) into the tumor, broaden the range of cancer targets the immune system recognizes, and increase PD-L1 expression on tumor cells. This makes those cells more visible to checkpoint inhibitors.

In simpler terms: radiation may help turn a cold tumor into a hot one—a tumor the immune system is ready to attack. Checkpoint inhibitors can then keep that immune response going and prevent cancer cells from suppressing it again.

Researchers also discuss what is called the abscopal effect, a rare but documented phenomenon where radiation at one site triggers immune responses against cancer at distant, unirradiated sites. Lu-177 PSMA, because it delivers radiation to every PSMA-expressing cancer cell throughout the body, may be uniquely positioned to trigger a broader systemic immune response. This remains an active area of research and is not reliably observed in every patient.

The PRINCE Trial: The Most Studied Combination So Far

The main early study of this approach is the PRINCE trial (NCT03658447). This Phase Ib/II study tested Lu-177 PSMA-617 combined with pembrolizumab in men with mCRPC who had already received at least one androgen receptor pathway inhibitor.

Early results presented at the American Society of Clinical Oncology (ASCO) showed that in an initial group of 18 patients, approximately 44% had an objective response (meaning the cancer shrank or stabilized on imaging). Median radiographic progression-free survival—the time before imaging showed cancer growing again—was 6.5 months in this group. About 28% of patients had a PSA decline of 50% or more from baseline, a common marker of treatment response. No dose-limiting toxicities occurred, and serious side effects were uncommon.

A related dose-expansion Phase 1 study, published through The Lancet Oncology (via NIH PubMed Central), tested a single dose of Lu-177 PSMA-617 followed by maintenance pembrolizumab. In the dose-expansion part of that study (Part B), the study enrolled 43 patients with a median follow-up of 16.5 months. Of 25 patients in Part B, 14 (56%) had a confirmed objective response.

These are encouraging early findings. It's important to understand their limits. These studies are small and were designed mainly to test safety and look for early benefits, not to prove the combination is better than either treatment alone. Larger randomized trials are the next step.

The EVOLUTION Trial: A Randomized Study Adds Important Data

The EVOLUTION trial (NCT05150236) used a randomized Phase II design to compare:

• Lu-177 PSMA-617 alone
• Lu-177 PSMA-617 combined with ipilimumab (a CTLA-4 inhibitor) and nivolumab (a PD-1 inhibitor)

The trial enrolled approximately 110 patients and measured PSA progression-free survival as its primary outcome. According to reporting from the Prostate Cancer Foundation's 2025 Scientific Retreat, the EVOLUTION trial showed that the combination of Lu-177 PSMA-617 with ipilimumab and nivolumab extended radiographic progression-free survival compared to Lu-177 PSMA-617 alone.

This is meaningful progress. Unlike the earlier single-arm studies, this trial had a comparison group, so the improvement is more directly tied to the dual checkpoint therapy. However, the full published data from this trial, including overall survival outcomes, were still being collected and reviewed at the time of writing. Check the published data with your oncologist.

Other Combination Approaches Under Investigation

The checkpoint inhibitor combinations above are the most advanced, but researchers are also testing other immunotherapy pairings alongside Lu-177 PSMA:

• Triple therapy (PARP inhibitor plus checkpoint inhibitor plus Lu-177 PSMA): A Phase Ib trial (NCT07090369, the LumOnate trial) is studying the combination of Lu-177 PSMA-I&T with olaparib and pembrolizumab. This targets DNA repair defects and the immune system at the same time. It is in very early stages.
• Sipuleucel-T plus Lu-177 PSMA: Sipuleucel-T is a therapeutic cancer vaccine that trains a patient's own immune cells to attack prostate cancer. A Phase I trial (NCT07219147) is evaluating whether pairing it with Lu-177 PSMA-617 offers added benefit.

A broader review of how PSMA-targeted therapies interact with immune pathways, published through NIH PubMed Central, notes that researchers are combining targeted radionuclide therapies with immune modulation to address each approach's limits when used alone.

What Adding Immunotherapy May Mean for Side Effects

Adding a checkpoint inhibitor carries risks. Checkpoint inhibitors can sometimes cause the immune system to become overactive, attacking healthy tissues alongside or instead of cancer cells. These are called immune-related adverse events (irAEs). They can affect the lungs, liver, colon, skin, thyroid, kidneys, and joints.

In the combination trials conducted so far, the safety picture has been relatively manageable. In the initial PRINCE group of 18 patients, only one Grade 3 or higher adverse event was reported: inflammatory arthritis. However, researchers are still collecting safety data from larger and longer trials, and individual responses vary.

For men who have already experienced bone marrow suppression, kidney effects, or dry mouth from Lu-177 PSMA alone, adding an immunotherapy agent requires careful discussion with your oncology team. Your kidney function, liver function, and immune history all affect your eligibility and risk level.

For a deeper look at the known side effects of Lu-177 PSMA therapy on its own, our article on real-world side effects of Lu-177 PSMA therapy and how doctors manage them may be a helpful starting point before your next consultation.

Who May Be Most Likely to Respond

Researchers are working to identify which patients are most likely to benefit from a combined radioligand and immunotherapy combination. Some early signals suggest that certain tumor characteristics matter:

• Tumors that show some degree of immune cell presence even before treatment (sometimes called a partially warm tumor).
• Tumors with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H). These already respond better to checkpoint inhibitors and are worth testing for if you have not had tumor genomic profiling done.
• Tumors with a high mutation burden, which may generate more targets for the immune system to recognize.
• Patients whose PSMA PET scan shows widespread, highly-positive PSMA expression across multiple sites. This means more cells receive radiation, potentially triggering more immunogenic cell death at more locations.

No standard biomarker test currently exists that can reliably predict who will respond to this specific combination. Comprehensive genomic profiling of your tumor may reveal relevant features, and your oncologist can advise whether that testing makes sense in your situation.

What This Means for Patients Right Now

As of mid-2026, combining Lu-177 PSMA with checkpoint inhibitors or other immunotherapies is not a standard, approved treatment. It is an area of active clinical research. The data is early but scientifically grounded, and multiple trials are ongoing.

Here is what this means practically:

• If you are currently on Lu-177 PSMA, your doctor will not typically add a checkpoint inhibitor outside of a clinical trial.
• If you have already received Lu-177 PSMA and your disease has progressed, asking about combination trials is worth discussing with your oncologist.
• If your tumor genomic profile shows MSI-H or mismatch repair deficiency, your oncologist may already be discussing checkpoint inhibitors as part of your care plan, separately from the combination research discussed here.
• Asking your treatment center whether any trials like the EVOLUTION follow-on studies or the LumOnate trial are currently enrolling is a good question to ask.

For a broader look at the lifestyle and integrative approaches that may support your care during Lu-177 PSMA treatment, see our article on integrative therapies and lifestyle changes that can support Lu-177 PSMA treatment.

When to Talk to Your Doctor

Bring this topic up with your oncologist if any of the following apply to you:

• You are on Lu-177 PSMA and want to know whether a combination approach or clinical trial is available to you.
• You have progressed on Lu-177 PSMA alone and are looking for what comes next.
• Your tumor has not been tested for MSI-H status, mismatch repair deficiency, or tumor mutational burden. These results can open different treatment pathways.
• You want to understand the specific risks of adding immunotherapy given your current kidney, liver, and bone marrow health.
• You are open to enrolling in a clinical trial and want to understand your options.

This article is for general information and is not a substitute for medical advice. Always consult your oncologist or care team about your specific situation.