Understanding PSMA-Targeted Radioligand Therapy
- At the 2026 ASCO Genitourinary Cancers Symposium, a major three-day meeting by the American Society of Clinical Oncology (ASCO), researchers shared results from the PSMA Addition trial, which explores how PSMA-targeted radioligand therapy can be used earlier in prostate cancer treatment.
- The study found that adding Pluvicto to standard therapy for metastatic hormone-sensitive prostate cancer can help delay disease progression. While the benefit is modest, it is an important step in offering more treatment options.
- Dr. Stephen J. Freedland, a urologist at Cedars-Sinai Medical Center, told SurvivorNet that the next challenge is figuring out which patients are most likely to benefit from this therapy so treatment can be tailored to each individual.
- For now, PSMA-targeted therapy is a promising option. Its best use will depend on clinical trial results, careful patient selection, open discussions between patients and doctors, and ongoing improvements in personalized care.
For patients whose tumors show high levels of Prostate-Specific Membrane Antigen (PSMA), a protein produced by the cancer cells on their surface, it offers a promising option with mostly manageable side effects.
Read MoreUntil recently, Pluvicto was reserved for heavily pretreated patients with Prostate-Specific Membrane Antigen (PSMA)-positive disease, based on the landmark VISION trial demonstrating improved overall survival (OS) and radiographic progression-free survival (rPFS) in mCRPC.
However, the field is rapidly evolving. A key question now is whether PSMA-targeted radioligand therapy can be moved earlier—into the metastatic hormone-sensitive prostate cancer (mHSPC) setting.
MHSPC is a type of prostate cancer that has spread beyond the prostate but still responds to lowering testosterone. Testosterone is a male hormone (androgen) that fuels prostate cancer growth. When testosterone is reduced, the cancer slows down or even shrinks.
RELATED: Why Men With Advanced Prostate Cancer Should Get the Hugely Important New PSMA PET Scan
At the 2026 ASCO Genitourinary Cancers Symposium, this question was further addressed in the phase III “PSMA Addition” trial.
SurvivorNet spoke with Dr. Stephen J. Freedland, a highly experienced urologist who works at Cedars-Sinai Medical Center, to better understand the implications of these findings for clinical practice.
Radioligand Therapy: Who Is Eligible & How Does It Work?
Established Role: Pluvicto in mCRPC
The approval of Pluvicto in mCRPC was based on robust phase III evidence showing:
Improved overall survival
Improved radiographic progression-free survival
Higher PSA response rates [PSA stands for prostate-specific antigen, which is a protein produced by cells in the prostate gland. Elevated PSA levels may indicate prostate cancer.]
Manageable toxicity profile
Patients eligible for treatment typically have:
Metastatic castration-resistant prostate cancer
Prior exposure to androgen receptor pathway inhibitors and taxane chemotherapy. Per the FDA label, prior taxane is required unless clinically ineligible.
PSMA-positive disease on PET imaging
This established Pluvicto as a standard option in later lines of therapy. However, given its mechanism and activity, there has been strong interest in evaluating its use earlier in the disease course, where tumor burden may be lower and biology potentially more favorable.
The PSMA Addition Trial: Moving Into mHSPC
The phase III PSMA Addition trial represents a major step toward answering whether Lu-177–PSMA can improve outcomes in metastatic hormone-sensitive prostate cancer.
“PSMA Addition was a recently read out phase three clinical trial looking at Pluvicto, a drug that’s been on the market used in advanced metastatic castration resistant prostate cancer, now asking whether we can use it in the castrate sensitive patient population,” Dr. Freedland explained in his discussion with SurvivorNet.
“And so patients got best standard of care versus best standard of care plus Pluvicto all had metastatic hormone sensitive prostate cancer.”
In this study:
All patients had metastatic hormone-sensitive prostate cancer
All patients were required to have PSMA-positive disease on PET imaging
Patients were randomized to:
Best standard of care (SOC), or
SOC plus Pluvicto
Metastatic hormone-sensitive prostate cancer (mHSPC) is when the cancer has spread beyond the prostate but still responds to lowering testosterone, the male hormone that fuels prostate cancer growth.
Metastatic castrate-resistant prostate cancer, or mCRPC, is defined by a combination of factors, including:
RELATED: Understanding Androgen Receptor Pathway Inhibitors For Prostate Cancer
- Low testosterone levels (below 50 ng/mL or 1.7 nmol/L). This confirms that the cancer is truly “castration-resistant,” meaning it’s growing despite low testosterone.
- New or worsening metastatic disease, typically seen on imaging scans that show cancer has either spread to new areas or existing metastatic sites have grown.
- Rising PSA levels
RELATED: When Treatment Stops Working: Managing Metastatic Castration-Resistant Prostate Cancer
Standard of care typically includes androgen deprivation therapy (ADT) with intensification using androgen receptor signaling inhibitors, and in some cases chemotherapy.
Androgen deprivation therapy (ADT) is a type of hormone therapy used to lower the levels of male hormones — called androgens — in the body.
ADT is a type of hormone therapy used to lower the levels of male hormones — called androgens — in the body. The main androgen is testosterone, which is produced mostly by the testicles. It is important because prostate cancer cells need testosterone to grow and survive.By reducing or blocking testosterone, ADT can slow down the growth of cancer or even shrink it. ADT does not cure prostate cancer, but it is very effective at controlling it, especially when the disease is more aggressive or has spread beyond the prostate. In some cases, additional treatments are added to control the disease.
RELATED: Androgen Deprivation Therapy: The Foundation Of Advanced Prostate Cancer Treatment
“We know that androgen deprivation therapy (ADT) alone, or lowering a man’s hormone levels through either shots or pills, are usually not enough to give them a long-term remission,” Dr. Leonard Gomella, Chair of Urology at Thomas Jefferson University’s Sidney Kimmel Comprehensive Cancer Center in Philadelphia, previously told SurvivorNet.
“We’ll usually add something else, such as a pill on top of the androgen deprivation therapy (ADT) to further weaken the cancer and improve a man’s outcome,” he adds.
Study Results: A Measurable Step Forward
The primary endpoint of the study was radiographic progression-free survival (rPFS), defined as time to disease progression or death.
According to data initially reported at ESMO (European Society For Medical Oncology) 2025 and further discussed at the 2026 ASCO Genitourinary Cancers Symposium:
The addition of Pluvicto resulted in a 28% reduction in the risk of progression or death.
Results also show an early positive trend in overall survival (OS) in patients treated with Pluvicto plus SoC
Dr. Freedland highlighted the clinical nuance of these findings:
“It delayed progression… which is super exciting… But a 28% delay… is a little modest.”
He contextualized this by comparing it with prior therapies: “Some of the other therapies… have delayed progression by 60%. So 28%… is a little weaker than we would have liked.”
This distinction is important. While the trial met its primary endpoint, the magnitude of benefit is less than that seen with some existing standard-of-care intensification strategies in mHSPC, such as androgen receptor pathway inhibitors or triplet therapy.
Quality of Life: A Key Consideration
Given the move toward earlier intensification, understanding the impact of treatment on daily functioning is critical. At the 2026 ASCO Genitourinary Cancers Symposium, Dr. Michael J. Morris, head of the Prostate Cancer Section at Memorial Sloan Kettering Cancer Center, presented detailed analyses of patient-reported outcomes (PROs) from the PSMAddition trial.
These analyses were prompted by the efficacy findings, with investigators seeking to determine whether improved disease control could be achieved without compromising quality of life, symptom burden, or functional status.
The latest results from the PSMAddition study found that after approximately 20 months, people who received the treatment and those who did not had similar levels of quality of life and pain. This suggests that Pluvicto may be worth studying further for people with hormone-sensitive prostate cancer.
Dr. Morris explained during his presentation, “These data represent time to worsening quality of life and pain… when the patient has the decline in quality of life, the patient is censored.
“We are presenting today the actual quality-of-life data longitudinally, which is much more illuminating.”
This difference is important for patients. Traditional ways of measuring how long it takes for quality of life to decline—like the analyses shared at ESMO 2025—only look at the first drop and don’t consider that people may feel better afterward. Because of this, these measures can make treatments seem harder on patients than they actually are over time.
The data presented at ESMO 2025 suggested that patients receiving Pluvicto experienced an initial decline in quality of life, with scores later returning to levels comparable to the control arm.
“Quality of life was temporarily worse… and then kind of reverts back… [This] gives us a little bit more confidence… we’re not making people miserable,” Dr. Freedland explains, referring to this patter.
The updated results shared at ASCO GU 2026 give a clearer picture. By looking at patient-reported outcomes over time, researchers found that people’s overall quality of life and pain levels stayed mostly stable when Pluvicto was added to treatment.
Some people experienced a small, temporary drop in day-to-day functioning while receiving the radioligand therapy, but this improved after treatment ended, returning to levels similar to standard therapy alone.
Importantly, overall health and pain stayed stable throughout the study.
These results suggest that starting PSMA-targeted radioligand therapy earlier may cause short-term side effects, but it does not lead to long-lasting declines in quality of life.
For doctors, this highlights the importance of looking at patient-reported outcomes in context. Early drops in well-being may be temporary and improve over time, rather than signaling a lasting effect on quality of life.
Patient Selection: Not All PSMA-Positive Disease Is Equal
One key takeaway from Dr. Freedland’s talk is that PSMA levels can vary from person to person. While the trial only included people whose scans showed PSMA-positive disease, the amount of PSMA can differ.
“There’s someone who lights up like a Christmas tree and there’s one where it’s very faint… Do those patients respond the same? … No, they actually don’t,” says Dr Freedland.
Emerging evidence suggests that:
Patients whose cancer shows higher levels of PSMA tend to respond better to the therapy
Patients with lower or uneven PSMA levels may see less benefit.
It’s important to note that as imaging technology improves, doctors will likely be able to better identify who is most likely to benefit from treatment, helping to achieve the best outcomes.
Moving Toward Personalized Care: Rethinking One-Size-Fits-All Treatment Schedules
In the PSMA Addition trial, most patients had six treatment cycles. In everyday practice, though, doctors may adjust the number of cycles based on each person’s response to treatment.
Dr. Freedland suggested a more adaptive strategy, saying, “Can we do two cycles… repeat imaging… see who’s benefiting… maybe even stop… Some may need more treatment.”
This idea fits with a growing trend in cancer care called “response-adapted therapy,” where treatment is tailored to each patient:
- Doctors use early scans to check if the treatment is working
- Patients who are responding well may need fewer treatments
- Those who need more help can continue or get additional treatment
Although it can be challenging to use this approach in large clinical trials, it may become more common in everyday care as doctors gain more experience.
Where Pluvicto Fits for Men With Metastatic Hormone-Sensitive Prostate Cancer
The PSMAddition trial shows that Pluvicto may help slow the growth of prostate cancer in men whose cancer has spread but still responds to hormone therapy.
That said, it’s not yet a standard treatment for everyone. Doctors are still learning:
- How much it helps: Pluvicto can delay cancer progression, but the benefit is smaller than some other available treatments.
- Impact on survival: More long-term data are needed to know whether it helps men live longer.
- Side effects and daily life: Most patients maintain their routines, but short-term side effects can occur.
- Access: Treatment requires specialized equipment and coordination at certain medical centers.
- Who benefits most: Not every patient responds the same way, so careful testing and discussion with your doctor are important.
Understanding How Radioligand Therapy Works
Radioligand therapy, such as Pluvicto, delivers targeted radiation to prostate cancer cells by binding to PSMA, a protein commonly found on these cells, while minimizing damage to healthy tissue.
A Targeted Strike: How Radioligand Therapy Finds And Fights Advanced Prostate Cancer
“Radioligand therapy is the use of IV treatments that contain a molecule that seeks out a particular target, somewhere in your body, and then once it latches onto that target, releases a dose of radiation,” Dr. Janaki Sharma, a medical oncologist at Sylvester Comprehensive Cancer Center-University of Miami Health System, previously told SurvivorNet.
“In the prostate cancer cases, Lu177-PSMA [lutetium-177 vipivotide tetraxetan PSMA therapy, brand name: Pluvicto] uses the fact that most prostate cancer expresses something called prostate specific membrane antigen (PSMA),” she added, explaining that the therapy goes directly towards the sites in the body that express PSMA and releases radioactivity there.
It is approved for men with metastatic castration-resistant prostate cancer who have already undergone other hormone-based treatments and have PSMA-positive disease confirmed by a PET scan. Pluvicto has been shown to improve survival and reduce symptoms. It can can cause some side effects such as dry mouth, fatigue, and low blood counts.
What Is Radioligand Therapy?
Radioligand therapy is a cutting-edge cancer treatment that merges two powerful concepts: the targeting accuracy of drug therapy and the cell-killing ability of radiation. This innovative approach uses a molecule (called a ligand) that specifically seeks out and binds to cancer cells. This ligand is chemically linked to a radioactive isotope, forming a “radioligand.”
Once injected into the body, the radioligand travels through the bloodstream and binds to receptors found mostly on cancer cells — delivering radiation directly to the tumor site. This allows high doses of radiation to be delivered with precision, limiting damage to surrounding healthy tissue.
This approach is particularly effective in cancers like prostate cancer, where certain surface proteins such as PSMA are heavily expressed. By combining molecular targeting with internal radiation, radioligand therapy offers a promising treatment for advanced cancers that have spread beyond the prostate and are resistant to other treatments.
What Is Pluvicto?
Pluvicto (also known as lutetium Lu 177 vipivotide tetraxetan) is a form of radioligand therapy approved by the FDA for treating certain types of advanced prostate cancer. It is specifically indicated for patients with metastatic castration-resistant prostate cancer (mCRPC) who have already received other treatments like chemotherapy and androgen receptor pathway inhibitors but whose disease has continued to progress.
It can also be used for patients who have been treated with an ARPI as a way to delay chemotherapy.
Pluvicto consists of two parts: a ligand that targets PSMA, and a radioactive isotope called lutetium-177. When injected, this compound hones in on PSMA-expressing cancer cells, delivering localized radiation. Because it works systemically, it can treat not only the main tumor but also metastases — cancerous lesions that have spread throughout the body.
How Does Pluvicto Target Prostate Cancer Cells?
Pluvicto uses the PSMA molecule as a target because the protein is often found on the surface of prostate cells. While normal prostate cells have some PSMA, prostate cancer cells — especially those in advanced or aggressive stages — have a significantly higher concentration of it.
The ligand component of Pluvicto binds tightly to PSMA. Once attached, the radiolabeled component, lutetium-177, emits beta radiation over a short distance — typically a few millimeters. This radiation damages the DNA of the nearby cancer cells, causing them to die. The proximity effect of this therapy is crucial; it ensures that healthy tissues, which either don’t express PSMA or express very little of it, are exposed to far less radiation than the cancer cells.
Who Is Eligible for Pluvicto?
Pluvicto is not intended for all patients with prostate cancer. It is approved for use in men with metastatic castration-resistant prostate cancer (mCRPC) — a form of prostate cancer that no longer responds to traditional hormone therapy and has spread to other parts of the body. Based on the results of the PSMAfore Trial, the FDA recently approved Pluvicto for use after treatment failure with an androgen receptor pathway inhibitor.
To be eligible, patients generally must have:
- Confirmed mCRPC
- Progressed after at least one androgen receptor pathway inhibitor
- Evidence of PSMA-positive disease, confirmed via imaging
Importantly, eligibility hinges on whether the cancer expresses PSMA. That’s where an imaging test known as a PSMA PET scan comes in.
Questions Patients Might Ask About Pluvicto and PSMA-Targeted Therapy
- How do I know if my prostate cancer is PSMA-positive and whether Pluvicto could help me?
- How much can Pluvicto slow my cancer compared to standard treatment alone?
- Is the benefit worth the side effects and extra visits for treatment?
- Should Pluvicto be used early, when my cancer still responds to hormone therapy, or later?
- How will my doctor decide the best time to start it?
- Can the number of treatments be adjusted based on how I respond?
- Will Pluvicto be given alongside hormone therapy, chemotherapy, or other medications?
- Could Pluvicto help me live longer, or just slow the cancer’s growth?
- How much will it cost, and is it covered by insurance?
- What questions are still being researched before Pluvicto becomes a standard treatment for all patients?
Contributing: SurvivorNet Staff
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