PSMAddition: Lutetium Shows Promise in First-Line Treatment, but the Data Are Not Yet Mature
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ESMO 2025 Presidential Symposium (LBA6)results address another question in prostate cancer treatment. In PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC), the study showed that 177Lu-PSMA-617 radioligand therapy, used with standard androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARPI), significantly reduced the risk of cancer progression.
Prostate cancer treatment has transformed over the past 20 years. In the early 2000s, the only option in metastatic disease was generally androgen deprivation therapy (ADT). Over time, however, cancer developed resistance and began growing again.
In the 2010s, new drugs providing deeper androgen receptor pathway suppression (ARPIs) were introduced and substantially extended survival. Still, microscopic cancer cells could escape treatment in some patients, allowing disease to progress. This brought attention to a target abundant on cancer-cell surfaces: prostate-specific membrane antigen (PSMA) .
Using PSMA as an "address," radioligand therapy (177Lu-PSMA-617)selectively finds cancer cells and destroys them with radiation from within. First published in 2021, the VISION trial showed longer survival in advanced (castration-resistant) prostate cancer, leading to FDA approval. Announced in 2025, the PSMAddition study provided the first major evidence that this method could also be effective earlier, in the hormone-sensitive setting , in a large phase 3 trial.
In short, this study raises the possibility that "lutetium treatment" could be an early-line option in the future rather than only a last resort. The aim is to eliminate microscopic cancer remnants early, keeping the disease controlled for longer.
How Was the Study Conducted?
PSMAddition was a large study involving 1,144 prostate cancer patients. All patients were positive for PSMA , a target molecule on cancer-cell surfaces. Half received standard androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARPI) . The other half additionally received lutetium-177 (177Lu-PSMA-617) radioligand therapy.
The study asked whether adding lutetium prolonged the time before radiological progression, or radiographic progression-free survival—rPFS. Overall survival (OS), quality of life, and treatment-related adverse effects were also closely monitored.
📊 How Much Was Cancer Progression Reduced?
In the lutetium group, the risk of cancer progression fell by 28%. This was statistically significant (HR 0.72, p=0.002). Median time to progression could not yet be fully calculated because disease remained controlled in most patients.
🕒 Overall Survival (OS)
Survival data are not yet mature. The initial analysis showed no significant difference (HR 0.84; p=0.125). Several more years of follow-up are therefore needed for the full result.
💊 Side Effects and Quality of Life
Side effects were somewhat more frequent with lutetium (89% versus 70%). Serious adverse events were 22% versus 12%. The most common complaints were: dry mouth, fatigue, nausea, and low blood counts. Most were manageable.
The most notable finding was that quality of life did not deteriorate despite these side effects. Patients maintained quality of life similar to those receiving standard treatment in general health and daily activities. This suggests that lutetium is not only effective but also tolerable .
Results in Different Patient Groups
Interestingly, the benefit was not confined to a particular patient group. Patients with high or low tumor burden , those metastatic at initial diagnosis or with later relapse , showed similar effects. Treatment success was therefore broad and consistent.
| Parameter | Triple Treatment (Lutetium + ADT + ARPI) | Standard Treatment (ADT + ARPI) |
|---|---|---|
| Proportion of patients with cancer progression | 24.3% | 30.1% |
| rPFS difference (HR) | 0.72 (0.58–0.90), p=0.002 | |
What Did We Learn From the Other Study? (PR21)
Another study, PR21 , involved more advanced, hormone-resistant prostate cancer. Here, lutetium was compared with the chemotherapy drug docetaxel . The results showed that docetaxel remained more effective, suggesting that lutetium may work best earlier in the disease.
🔎 DROZDOGAN Academy Commentary
- Limited rPFS difference, no OS difference: Lutetium modestly prolonged the time before cancer progression, but no significant survival difference was seen. The results should therefore not be expected to change clinical practice immediately.
- Less favorable quality of life: Although side effects were manageable, patient-reported quality of life was somewhat lower in the lutetium arm. This suggests that the progression-time gain did not translate into a noticeable patient benefit.
- Not all PSMA-positive patients are the same: PSMA positivity alone is insufficient for appropriate patient selection. Factors such as PSMA uptake intensity (e.g., SUVmean) or biological subtypes are needed to identify subgroups that will benefit more .
- Too early for upfront lutetium: There are not yet enough data to make adding lutetium in hormone-sensitive disease standard treatment. Mature OS results and biomarker-based subgroup analyses should be awaited.
- Clinical message: For now, lutetium remains an approved, evidence-based option in resistant disease . Its use in the hormone-sensitive setting remains investigational and requires careful patient selection.
Sources
- Tagawa ST, et al. PSMAddition, ESMO 2025 LBA6. rPFS HR 0.72; p=0.002.
- Chi KN, et al. PR21, ESMO 2025 LBA89. OS: docetaxel superior (p=0.02).
- VISION (NEJM 2021;385:1091–1103) and TheraP (Lancet Oncol. 2022;23:1389–1397): background evidence for PSMA-RLT.
- Radiology. 2024;312:e233460 — PSMA PET SUVmean and its association with response.
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