ATM-Altered Prostate Cancer May Be Especially Sensitive to Lu-177-PSMA

A new study suggests that ATM alterations could identify a subgroup of metastatic castration-resistant prostate cancer particularly likely to benefit from 177Lu-PSMA-617 (Pluvicto). The retrospective analysis included 205 men with mCRPC treated with Lu-177-PSMA-617 between 2022 and 2026, all of whom had next-generation DNA sequencing available.
ATM alterations were present in 12.7% of patients and were independently associated with better outcomes across all major endpoints.
Men with ATM-altered tumours had nearly three times the odds of achieving a PSA50 response compared with ATM-wild-type patients, with an odds ratio of 2.91. They also had substantially longer progression-free survival, HR 0.40, and overall survival, HR 0.39.
The study also found that not all homologous-recombination repair genes behaved the same way. BRCA2 alterations were not associated with better outcomes, while CDK12 alterations were linked to significantly worse progression-free and overall survival, with hazard ratios of 2.76 and 2.58, respectively. That supports analysing individual genes rather than grouping all HRR alterations together.

The ATM signal also held up when the investigators pooled their data with previously published studies. In that analysis, ATM alterations remained associated with improved overall survival, with a pooled hazard ratio of 0.36. By contrast, TP53 and AR alterations were associated with worse survival.
There is a plausible biological explanation. ATM is a central DNA-damage response protein, and loss of ATM function can impair repair of radiation-induced DNA damage. Since 177Lu delivers beta radiation directly to PSMA-expressing tumour cells, ATM-deficient cancers could theoretically be less capable of repairing that damage and therefore more vulnerable to radioligand therapy.
That interpretation is attractive, but it is not yet proven. This was a retrospective study, and ATM alteration may be acting partly as a prognostic marker rather than a truly predictive biomarker of Lu-177 sensitivity.
If confirmed prospectively, ATM could become one of the first genomic biomarkers helping identify patients particularly suited to PSMA radioligand therapy.
More broadly, the findings underline an important lesson: HRR genes should not automatically be treated as one biological group, because ATM, BRCA2 and CDK12 may influence response to Lu-177-PSMA in very different ways.

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