Which Is Better in Prostate Cancer: Lutetium Therapy or Next-Generation Hormone Suppression?
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🔬 Is Pluvicto or Next-Generation Hormone Suppression More Effective in Metastatic Prostate Cancer?
The PSMAfore study has changed the approach to metastatic prostate cancer treatment!
Metastatic castration-resistant prostate cancer (mCRPC)is a stage in which standard hormonal treatments no longer suffice, seriously threatening quality of life and survival.
After progression on first-line androgen receptor pathway inhibitor (ARPI) treatment, such as abiraterone or enzalutamide, some patients switch to another ARPI. Although common, especially in older or chemotherapy-ineligible patients, this strategy is not the most effective option.
Although guidelines recommend taxane-based chemotherapy at this stage, toxicity risks or medical ineligibility mean it is not always feasible.
At this point, a new targeted treatment emerged as an alternative to the traditional ARPI-to-ARPI sequence:
Lutetium-177-PSMA-617 (Pluvicto) —a radioactive treatment targeting PSMA (prostate-specific membrane antigen).
This treatment had demonstrated efficacy after chemotherapy in the VISION trial . Now, the PSMAfore study shows that it can also be an effective, safe option before chemotherapy.
On March 28, 2025, the FDA expanded Pluvicto's indication based on these new data. Beyond a last resort, it can now be used earlier for patients wishing to delay chemotherapy .
📊 PSMAfore: Pluvicto Compared With ARPI
On July 16, 2025, Annals of Oncologypublished this phase 3 study in patients who had received one ARPI and were considered unsuitable for chemotherapy: taxane-naive, PSMA-positive mCRPC patients .
📌 Why Does It Matter?
- Although a second ARPI is common in practice, its efficacy is limited and it is not the first guideline-recommended option.
- Pluvicto was tested early in this population for the first time.
- The study offers patients wishing to delay chemotherapy an effective and better-tolerated option.
177Lu-PSMA-617 (Pluvicto), provided the following important benefits in PSMA-positive patients:
- Primary endpoint: radiographic progression-free survival (rPFS):
- Initial analysis: Median rPFS: 9.3 months vs. 5.55 months (HR: 0.41)
- Updated analysis: Median rPFS: 11.6 months vs. 5.59 months (HR: 0.49)
- Adverse effects: Grade 3-5 adverse events occurred with Pluvicto at lower rates .
- Quality-of-life measures: Many secondary endpoints, including time to deterioration, skeletal complications, and PSA response, also favored Pluvicto .
Overall survival (OS) showed no difference in the intention-to-treat analysis. The main reason was that 57% of ARPI patients later crossed over to Pluvicto.
Without adjustment for crossover, the true survival advantage may have been obscured.
In conclusion, PSMAfore showed that Pluvicto is a strong option at earlier stages as well as in later lines .
🧪 Study Design
- 468 PSMA-positive mCRPC patients were enrolled.
- Pluvicto Group (n=234): Received 6 cycles of lutetium-177-PSMA-617 at 7.4 GBq, every 6 weeks.
- ARPI Switch Group (n=234): Continued abiraterone or enzalutamide treatment.
- Crossover: ARPI patients could switch to Pluvicto after progression.
📈 Survival Results
| Treatment Group | Median Survival | HR and P Value |
|---|---|---|
| Pluvicto | 24.48 months | HR: 0.91, P = .20 |
| ARPI Switch | 23.13 months | — |
A 60.3% crossover rate may explain the lack of an apparent difference between groups.
However, adjusted analyses showed a significant survival benefit with Pluvicto (HR: 0.59) —suggesting earlier use may be more effective.
💊 Side-Effect Profile
Pluvicto was generally better tolerated. Grade 3 or higher adverse events were less frequent.
- Dry mouth: 60% (mostly mild)
- Anemia: 27% (mostly mild; only 6.2% severe)
📌 Conclusion and Clinical Commentary
In mCRPC progressing after first-line ARPI, Pluvicto emerged as a strong alternative.
- Survival benefit was confirmed in adjusted analyses.
- It is better tolerated.
- Earlier use may offer greater benefit.
These data suggest Pluvicto should be considered not only as a last resort but also among early-stage clinical decisions .
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