Context-Dependent Prognostic Impact of PTEN Alterations (alt) in Metastatic Androgen Pathway Modulation Sensitive (mAPMS) Patients

Background
PTEN alts confer aggressive biology, yet targeting the PI3K–AKT pathway has yielded inconsistent results. Prior studies relied on PTEN IHC and did not account for PTEN alt subtype, PI3K pathway alt burden, or molecular lineage. We hypothesized the prognostic impact of PTEN alt depends on alt subtype, concurrent PI3K pathway alt and ERG lineage.

Methods
Using the Tempus Lens platform, de-identified real-world data from mAPMS patients undergoing Tempus xT NGS were analyzed. Eligible patients received 1L ADT-based systemic therapy. PTEN and ERG fusion status were assessed by NGS (DNA & RNA). rwOS and rwTTNT were assessed by Kaplan–Meier and defined as time from 1L treatment to death/last follow and progression/death/last follow up, respectively. Hazard ratios were estimated using Cox proportional models.

Results
Among 4,853 patients (~25% PTEN alt), median age was 68, with more African Americans in the PTEN-wt group (15%) vs. PTEN-alt (8.0%), while liver metastases were higher in PTEN-alt tumors compared to PTEN-wt (5.2% vs 3.1%). PTEN-alt tumors showed a distinct somatic alteration profile, with higher rates of TP53 (42% vs 30%) and RB1 (7.7% vs 4.4%) alt (both p<0.001). Overall, PTEN alt nor subtype nor PI3K alt burden impacted outcomes. ERG fusions were enriched in PTEN-alt tumors (47% vs 27%, p<0.001). In the PTENdel vs wt groups, PTEN signature scores were elevated, predominantly in ERG- tumors. In ERG+ tumors, outcomes did not differ by PTEN status. In contrast, inferior rwOS was observed among ERG- tumors; within this stratum, PTEN-del (HR 1.37, p = 0.003) and increased PI3K pathway alt burden (1 alt: HR 1.44; 2 alt: HR 1.23; global p < 0.001) were each associated with worse rwOS.

Conclusion
PTEN alt alone was not prognostic in prostate cancer overall. PTEN/PI3K pathway effects were context-dependent, emerging only in ERG- tumors. These results highlight how comprehensive NGS can identify a high-risk subgroup and refine patient selection for treatment intensification in clinical trials.