A first Phase III clinical trial called PSMAddition tested whether adding radioligand therapy ¹⁷⁷Lu-PSMA-617 (Pluvicto) to standard treatment earlier, at the hormone-sensitive stage could better treat metastatic prostate cancer. At this stage of the disease, the standard approach is a two-drug combination: standard hormone therapy (androgen deprivation therapy, ADT) plus a modern hormone-blocking drug (androgen receptor pathway inhibitor, ARPI). The main question the study was looking to answer (the primary endpoint) was whether adding this third treatment earlier in the disease could keep the cancer under control longer than the usual two-drug approach.

The study design

The trial included 1,144 patients from around the world. All had at least one metastatic PSMA-expressing lesion but were still responding to hormone therapy, i.e. not yet castration-resistant. Patients were randomly split into two equal groups:

• Experimental arm (572 men): received 6 cycles of ¹⁷⁷Lu-PSMA spaced 6 weeks apart, along with standard hormone therapy. 86% completed all 6 cycles, and over 93% received at least 4 cycles.
• Control arm (572 men): received standard hormone therapy alone (ADT + ARPI, with the “physician’s choice of abiraterone, enzalutamide, apalutamide, or darolutamide). Patients in this group could cross over to receive ¹⁷⁷Lu-PSMA-617 upon confirmed radiographic progression” (Brooks, 2025), which 16% eventually did. The number is relatively small and likely bears no danger of blurring the results.

What the trial measured

The primary endpoint was a so-called radiographic progression-free survival (rPFS) or how long patients went without their cancer showing progression on scans.

Other important measures included:

• Overall Survival (OS): whether patients lived longer overall,
• Complete and Overall Response Rates: how deeply their cancers responded,
• Time to progression to castration-resistant disease: how long it took before the cancer stopped responding to hormone therapy.

Key results

Delayed disease progression

Men in the experimental arm had a 28% lower risk of their cancer progressing or dying during the follow-up period compared with the control arm. This result is statistically significant.

Complete response rate

More patients achieved what is called a very deep response with ¹⁷⁷Lu-PSMA. About 57% of patients in the experimental group had no visible cancer on imaging — compared with about 42% in the standard-therapy group.

Overall response rate

Around 85% of patients given ¹⁷⁷Lu-PSMA showed tumor shrinkage or disappearance, versus about 81% with standard therapy alone.

Slower transition to harder-to-treat cancer

Once prostate cancer becomes hormone- or castration-resistant (i.e. no longer responds to hormone therapy), treatment options are fewer and outcomes are worse. Delaying this step is a major clinical advantage Adding ¹⁷⁷Lu-PSMA gave patients a 30% lower risk of reaching this resistant stage at any given time during the study. In plain terms, the cancer stayed controllable for longer.

A trend toward living longer

Early data suggest patients receiving ¹⁷⁷Lu-PSMA may live longer overall, but at the time of the report, the data were still immature, and more time is needed to see clear survival differences.

Adverse effects

Adding ¹⁷⁷Lu-PSMA caused more side effects, such as fatigue, dry mouth, nausea, and changes in blood counts, but most were manageable.

• Any grade: 98.4% vs 96.6%
• Grade ≥3: 51% vs 43%

The discussion around adverse effects needs to be more nuanced. There is a possibility that the experimental arm patients were overtreated with 6 cycles. We should not disregard the so-called ‘sink effect’, “whereby giving ¹⁷⁷Lu-PSMA to a patient with minimal or no residual PSMA-positive disease is potentially harmful, as normal tissues will be exposed to a higher dose of radiation” (Rashid K. Sayyid, 2025). Previous trials, like UpFrontPSMA showed complete response after just 2 cycles, leading to a possible conclusion that the radiation from all the cycles afterwards got absorbed by healthy tissue. An interim PET scan can offer an easy solution to this problem: no PSMA expression, no need for further cycles. At MINUTE Medical, this personalized, imaging-guided approach is already part of our routine practice, helping us determine the number of cycles, the radionuclides used, and the administered radiation dose.

Bottom line

Adding ¹⁷⁷Lu-PSMA to the standard two-drug treatment at the hormone-sensitive stage of metastatic prostate cancer:

• slowed disease progression significantly,
• increased the chances of deep or visible tumor responses,
• delayed progression to more aggressive, treatment-resistant stage,
• did cause more adverse effects, but careful calibrating and actually personalising the radioligand therapy through interim control PET scans could help reduce them

This trial strengthens the case for using targeted radioligand therapy earlier in the disease, potentially improving outcomes for men whose prostate cancer has spread but still responds to hormonal treatment.

 

Bibliography

Brooks, M. (28. Oktober 2025). Pluvicto in First-Line Hormone-Sensitive Prostate Cancer?  Medscape

ONCOLife. (5. November 2025). Radioligand Therapy Pluvicto Reduces Progression Risk by 28% in mHS Prostate Cancer. Health and Pharma

Rashid K. Sayyid, M. M.–T. (October 2025). ESMO 2025: Discussant – Phase III Trial of [177Lu]Lu-PSMA-617 Combined with ADT + ARPI in Patients with PSMA-Positive Metastatic Hormone-Sensitive Prostate Cancer (PSMAddition). Urotoday

Tagawa, D. S. (19. October 2025). PSMAddition data show Novartis Pluvicto™ delays progression to end-stage prostate cancer. Novartis