A recent real-world study has revealed that Lutetium-177 prostate-specific membrane antigen (Lu-PSMA) radioligand therapy demonstrates superior cancer-control outcomes when used in early treatment lines for metastatic castration-resistant prostate cancer (mCRPC), potentially reshaping treatment algorithms for this challenging disease.
Superior Progression-Free Survival in Taxane-Naïve Patients
The study compared cancer-control outcomes in taxane-naïve mCRPC patients treated with Lu-PSMA after previous androgen receptor pathway inhibitor (ARPI) treatment versus those receiving either subsequent ARPI therapy or docetaxel chemotherapy.
Results showed that Lu-PSMA therapy provided a significant progression-free survival (PFS) advantage of approximately five months compared to ARPI treatment (13.3 vs. 8.2 months). This finding aligns with data from the phase III PSMAfore trial, which demonstrated a PFS of 12.0 vs. 5.6 months (HR: 0.42) favoring Lu-PSMA over ARPI in a similar patient population.
"These observations are especially noteworthy since Lu-PSMA in a real-world setting is equivalently used in similar patient cohorts as ARPI treatment, while mCRPC patients receiving docetaxel show substantially different baseline characteristics," the researchers noted.
Overall Survival Benefits
While the overall survival (OS) benefit for Lu-PSMA versus ARPI did not reach statistical significance in univariable analyses (HR: 0.64, p = 0.2), a clinically meaningful median OS difference of 68.9 months versus 39.1 months was observed favoring Lu-PSMA treatment. This advantage became statistically significant in multivariable Cox regression models adjusting for potential confounders.
When compared to docetaxel chemotherapy, Lu-PSMA demonstrated significantly superior outcomes in both PFS and OS analyses. This is particularly notable given that Lu-PSMA patients were generally at higher risk of death due to older median age and more advanced frailty status.
Efficacy in Elderly and Frail Patients
A complementary analysis of the Frankfurt Metastatic Cancer Database of the Prostate (FRAMCAP) provided valuable insights into Lu-PSMA efficacy in specific patient subgroups often underrepresented in clinical trials.
Among 312 mCRPC patients treated with Lu-PSMA, 24% were over 75 years old at the time of metastatic diagnosis. Importantly, no significant differences in PFS or OS were observed between patients aged ≤75 years versus >75 years, with median PFS of 12.7 vs. 11.7 months and median OS of 15.1 vs. 19.8 months, respectively.
Dr. Mike Wenzel, lead author of the FRAMCAP analysis, emphasized: "The current real-world cohort of Lu-PSMA mCRPC patients suggest feasible cancer-control outcomes such as PFS and OS for patients aged >75 years. Therefore, Lu-PSMA should be considered as a safe and important cornerstone in the treatment of elderly mCRPC patients."
Similarly, patients with Eastern Cooperative Oncology Group (ECOG) performance status ≥1 showed comparable PFS to those with ECOG 0 (12.0 vs. 13.0 months). While OS was initially worse for patients with higher ECOG scores (12.6 vs. 18.6 months), this difference disappeared after multivariable adjustment for baseline characteristics.
Cardiovascular Disease: A Significant Risk Factor
The FRAMCAP analysis revealed that patients with cardiovascular disease (CVD) had significantly worse outcomes when treated with Lu-PSMA. After multivariable adjustment, CVD remained an independent predictor for worse PFS (HR: 2.79, p < 0.01) and OS (HR: 5.14, p < 0.01).
"Especially patients with CVD should be treated with caution to prevent cardiotoxic events," the researchers cautioned, though they noted that prospective trials such as VISION and TheraP have not identified significant cardiotoxicity associated with Lu-PSMA that would necessitate routine pretreatment cardiac assessments.
Clinical Implications
These findings suggest Lu-PSMA therapy could be considered earlier in the treatment sequence for mCRPC patients, particularly after initial ARPI treatment failure. The data also support its use in elderly and frail patients who might not tolerate chemotherapy.
The researchers acknowledged several limitations, including the retrospective single-center design, potential selection bias due to PSMA-PET/CT screening (which excludes patients without PSMA expression), and differences in staging modalities between treatment groups.
Nevertheless, these real-world data provide valuable insights into the effectiveness of Lu-PSMA therapy across different patient populations and treatment settings, potentially expanding treatment options for patients with limited alternatives.
As Lu-PSMA continues to integrate into clinical practice, further research is needed to optimize patient selection, particularly regarding cardiovascular risk assessment, and to determine the ideal sequencing of this promising therapy within the evolving mCRPC treatment landscape.
