Expanding the Role of PSMA-Targeted Radioligand Therapy in Prostate Cancer: Early Insights From PSMA Addition and the Evolving Use of Lutetium-177–PSMA (Pluvicto)

Prostate cancer treatment has undergone a remarkable transformation over the past decade, with the integration of androgen receptor pathway inhibitors, chemotherapy, and—more recently—targeted radioligand therapies. Among these, lutetium-177–labeled prostate-specific membrane antigen (PSMA) therapy (Lu-177–PSMA-617, commercially known as Pluvicto) has emerged as a significant advance for patients with metastatic castration-resistant prostate cancer (mCRPC).

Until recently, Pluvicto was reserved for heavily pretreated patients with 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.

At the 2026 ASCO Genitourinary Cancers Symposium, this question was further addressed in the phase III “PSMA Addition” trial. SurvivorNet attended the meeting and 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.

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

• 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.

As Dr. Freedland explained in his discussion with SurvivorNet:

“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. 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

Standard of care typically includes androgen deprivation therapy (ADT) with intensification using androgen receptor signaling inhibitors, and in some cases chemotherapy.

Efficacy Results: A Statistically Significant but Modest Benefit

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 2025 and further discussed at ASCO GU 2026:

• The addition of Pluvicto resulted in a 28% reduction in the risk of progression or death – (HR 0.72; 95% CI: 0.58, 0.90)

• Results also show an early positive trend in overall survival (OS) in patients treated with Pluvicto plus SoC (HR 0.84; 95% CI: 0.63, 1.13)

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 most recent results from PSMAddition show that after a median of 20.6 months in the treatment arm and 19.9 months in the control arm, hazard ratios for health-related quality of life (HRQOL) and pain hovered around 1.0, suggesting potential value in evaluating Pluvicto for hormone-sensitive disease.

As 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 distinction is clinically meaningful. Traditional time-to-deterioration analyses (such as those initially presented at ESMO 2025) capture the first decline in quality of life, but do not account for subsequent recovery. As a result, they may overestimate the sustained burden of treatment.

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.

Dr. Freedland described this pattern: “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.”

However, the updated analyses presented at ASCO GU 2026 provide a more nuanced understanding. Using longitudinal PRO assessments investigators demonstrated that overall health-related quality of life and pain were largely maintained over time with the addition of Pluvicto.

While a modest, transient decline in functional well-being was observed during active radioligand therapy, these changes resolved after completion of treatment, with scores returning to levels comparable to those seen with standard therapy alone. Importantly, global health status and pain outcomes remained stable throughout the study.

Taken together, these findings suggest that early intensification with PSMA-targeted radioligand therapy may introduce short-term treatment-related effects, but does not result in a sustained deterioration in quality of life.

For clinicians, this reinforces the importance of interpreting PRO data in context. Recognizing that initial declines may be temporary and reversible, rather than indicative of long-term impact.

Patient Selection: Not All PSMA-Positive Disease Is Equal

One of the most important insights from Dr. Freedland’s discussion relates to heterogeneity in PSMA expression.

Trial eligibility required PSMA-positive PET imaging. However, PSMA expression is not binary.

“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.”- explains Dr Freedland.

Emerging evidence suggests that:

• Higher PSMA expression correlates with better response to therapy

• Patients with low or heterogeneous uptake may derive less benefit

This raises critical questions:

• Should treatment be limited to patients with high PSMA expression?

• Can quantitative PET metrics improve patient selection?

• Should we incorporate additional biomarkers?

As imaging technologies evolve, more refined selection criteria will likely play a central role in optimizing outcomes.

Toward Personalization: Rethinking Fixed Treatment Schedules

In the PSMA Addition trial, patients received a fixed number of cycles (typically six). However, this approach may not reflect optimal real-world practice.

Dr. Freedland suggested a more adaptive strategy:

“Can we do two cycles… repeat imaging… see who’s benefiting… maybe even stop… Some may need more treatment.” 

This concept aligns with broader oncology trends toward response-adapted therapy, including:

• Early imaging to assess response

• De-escalation in responders

• Intensification or continuation in non-responders

While difficult to implement in phase III trials, this approach may become increasingly relevant in clinical practice as experience grows.

Clinical Implications: Where Does Pluvicto Fit in mHSPC?

The PSMA Addition trial provides proof-of-concept that PSMA-targeted radioligand therapy can improve outcomes in mHSPC. However, several questions remain before widespread adoption:

1. Magnitude of Benefit
The improvement in rPFS is statistically significant but modest compared with existing therapies.

2. Overall Survival
Mature OS data will be essential for determining clinical impact.

3. Toxicity and Quality of Life
QOL data would be an important determinant about which regimen to use for patient care.

4. Cost and Resource Utilization
Radioligand therapy requires specialized infrastructure and coordination.

5. Patient Selection
Identifying the patients most likely to benefit will be critical.

At present, Pluvicto in mHSPC should likely be viewed as an emerging option rather than a new standard of care.