Pluvicto+Xtandi increases survival and delays deterioration of quality of life better than Xtandi-alone in mCRPC

(Updated 2/18/2025)

Both Pluvicto (177LuPSMA-617) and Xtandi (enzalutamide) have been separately shown to delay progression and extend survival among metastatic and castration-resistant men with prostate cancer (mCRPC). Because they inhibit prostate cancer in different ways, it was hoped that combining them would have an additive benefit. In a clinical trial, enzalutamide temporarily increased expression of PSMA, so a synergistic effect is possible.

Emmett et al. reported the final results and the early results of the ENZA-p trial. 162 mCRPC patients with 2 or more risk factors were treated at 15 hospitals in Australia. Unlike the VISION trial, they did not have to previously receive docetaxel or 2nd line hormonal treatment for mCRPC. The risk factors were:

1. metastatic at original diagnosis in 55%
2. elevated LDH  (in 22%), ALP (in 45%), albumin in 9% (PSA> 5 ng/ml)
3. PSADT< 84 days in 58%
4. < 3 years since diagnosis in 58%
5. ≥5 bone in 56% or visceral metastases in 11%
6. pain requiring opiates in 13%
7. received abiraterone for mHSPC in 13% (docetaxel for mHSPC was allowed in 54%)

After 34 months of follow-up, the outcomes were:

• Overall mortality was 52% for the combo vs 67% for enza-only
• Overall survival was 34 months for the combo vs 26 months for enza-only
• Physical function quality-of-life (QOL) deterioration-free survival was enjoyed for 10.6 months if they got the combo vs 3.4 months if they got enza-only
• Overall health and QOL was enjoyed for 8.7 months if they got the combo vs 3.3 months if they got enza-only
• The combo got significantly higher scores from patients on overall health and QOL, fatigue and pain.
• The only QOL score where the combo was worse was xerostomia (dry mouth).

After 20 months of follow-up, the previously reported outcomes were:

• Median PSA Progression-Free Survival was 13.0 months for the combo vs 7.8 months for enza-only
• Median Radiographic Progression-Free Survival was 16 months for the combo vs 12 months for enza-only
• Percent with >50% PSA reduction was 93% for the combo vs 68% for enza-only
• Percent with >90% PSA reduction was 78% for the combo vs 37% for enza-only
• Improvement in pain scores were 61% for the combo vs 27% for enza-only
• Side effects for the combo vs enza-only were fatigue (75% vs 70%), nausea (47% vs 27%), and dry mouth (40% vs 10%).
• 81% received all 4 doses of Pluvicto.

Based on these results, Pluvicto combined with enza gives better outcomes than enza alone. It is unknown whether the combination gives better outcomes than Pluvicto alone. Overall survival for Pluvicto-alone was 15.3 months in the VISION trial, but patients in the VISION trial were more progressed (they all had previous chemo vs only half in this trial, and entirely when they were still hormone-sensitive).