Genomic Alterations and LuPSMA Outcomes in mCRPC: A Prognostic Insight

Genomic alterations like TP53, PTEN, and RB1 mutations are prevalent in metastatic castration-resistant prostate cancer (mCRPC), yet their impact on response to 177Lu-PSMA-617 (LuPSMA, Pluvicto) radioligand therapy remains underexplored. A recent retrospective study published in the Journal of Nuclear Medicine analyzed 72 mCRPC patients treated with at least one cycle of LuPSMA between October 2022 and October 2024, all of whom had undergone germline or somatic genomic testing.

The key finding: patients harboring TP53/PTEN/RB1 mutations exhibited significantly inferior overall survival (OS), even after adjustments for age and race, positioning these tumor suppressor gene (TSG) alterations as potential negative prognostic biomarkers in this setting.

Unlike OS, progression-free survival (PFS) was not compromised by TP53/PTEN/RB1, BRCA1/2, or CHEK2/PALB2/ATM mutations, and no individual aberration correlated with the degree of prostate-specific antigen (PSA) decline from baseline. This dissociation between survival endpoints underscores the nuanced role of genomics in radiopharmaceutical response—where short-term tumor control may persist despite accelerated lethality in mutated subsets. These results align with broader mCRPC data, such as ASCO 2024 abstracts showing TSG-mutated patients facing median OS as low as 35.8 months versus 67.2 months in wild-type counterparts during LuPSMA therapy.

For clinicians and researchers tracking precision oncology in prostate cancer, this work highlights the value of pre-LuPSMA genomic profiling to stratify risk. Patients with TP53/PTEN/RB1 co-losses, known drivers of aggressive, neuroendocrine-like phenotypes, may warrant intensified monitoring or combinatorial regimens, such as pairing LuPSMA with PARP inhibitors or novel ADCs.

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