TMPRSS2-ERG Shows Distinct Molecular Landscape in TALAPRO-2 Population With mCRPC

TMPRSS2-ERG in mCRPC |

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The presence of TMPRSS2-ERG fusions in circulating tumor DNA (ctDNA) was associated with differential gene alteration frequency, tumor mutational burden (TMB), and gene expression signatures, among other molecular characteristics in patients with metastatic castration-resistant prostate cancer (mCRPC), according to data from a post hoc analysis of the phase 3 TALAPRO-2 trial (NCT03395197) presented at the 2025 AACR Annual Meeting.1

The results demonstrated that ctDNA burden was higher in the presence of TMPRSS2-ERG, with mean tumor fraction values of 0.22 and 0.11 in those with (n = 97) and without (n = 584) the marker, respectively (P < .0001), consistent with poor prognosis. The respective median values were 0.14 and 0.00. TMB in the blood was low in patients irrespective of TMPRSS2-ERG, although a slightly higher median value was seen in patients with vs without TMPRSS2-ERG, at 3.79 mut/mB vs 2.53 mut/mB, respectively. The respective mean values were 4.16 and 4.44 (P = .0003).

“In TALAPRO-2, the presence of TMPRSS2-ERG in ctDNA is associated with a distinct tumor molecular landscape, including positive association with TP53 alterations, negative association with SPOP alterations, and Notch and Wnt-beta-catenin pathway activation,” Xinmeng Jasmine Mu, PhD, lead study author and director of computational biology at Pfizer, and coauthors, wrote in the poster. “The enhanced efficacy reported for talazoparib plus enzalutamide [Xtandi] vs placebo plus enzalutamide in patients bearing TMPRSS2-ERG in ctDNA is striking considering the high prevalence of TP53 alterations in this subgroup.”

TALAPRO-2 Trial Background and Exploratory Analysis Rationale

The double-blind, randomized, placebo-controlled, global TALAPRO-2 trial evaluated the combination of talazoparib plus enzalutamide vs placebo plus enzalutamide in sequentially enrolled cohorts of patients with mCRPC with (n = 399) or unselected for (n = 805) homologous recombination repair (HRR) gene alterations.

Previously, the combination of talazoparib and enzalutamide led to a statistically significant improvement in radiographic progression-free survival (rPFS; HR, 0.667; 95% CI, 0.551-0.807; P < .0001) and overall survival (OS; HR, 0.796; 95% CI, 0.661-0.958; P = .0155) vs placebo plus enzalutamide in patients with mCRPC.2 The combination was later approved by the FDA for the treatment of patients with HRR gene–mutated mCRPC based on earlier findings from TALAPRO-2 showing improved rPFS in this population (HR, 0.45; 95% CI, 0.33-0.61; P < .0001).3

Previous evaluation of non-HRR gene alterations have also shown an association between the presence of TMPRSS2-ERG in ctDNA and improved outcomes with talazoparib and enzalutamide vs placebo plus enzalutamide. TMPRSS2-ERG fusions are common in advanced prostate cancer, found in 13% of plasma ctDNA and 38% of tumor tissue samples, according to Foundation Medicine’s database. Similar frequency was found in the unselected TALAPRO-2 population, at 14% in ctDNA and 30% in tumor tissue.

With this information, investigators evaluated the relationship between ctDNA alterations and tumor gene expression with the presence of TMPRSS2-ERG in the unselected cohort of patients enrolled in TALAPRO-2.

Study Methods and Gene Alteration Frequency

The data that were retrospectively evaluated for this analysis included prospectively collected plasma ctDNA from the unselected TALAPRO-2 population. The analysis was based on the safety population (n = 681) for all genomic analyses, barring alteration prevalence which used the intent-to-treat population (ITT; n = 687). Gene alterations were identified through a clinical trial assay based on the FoundationOne Liquid CDx and were characterized as known or likely pathogenic variants. Archival/baseline tumor transcriptomic data were created using HTG’s Oncology Biomarker Panel, with 10 additional genes that are involved in PARP inhibitor sensitivity (n = 304).

The data cutoff for the analysis was August 16, 2022.

TMPRSS2-ERG fusions were found in 14% (n = 98) of the unselected TALAPRO-2 ITT population (n = 687).

“Multiple genes implicated in prostate cancer pathobiology…showed imbalances in alteration status in patients with TMPRSS2-ERG vs those without TMPRSS2-ERG in ctDNA,” the authors wrote. Patients with TMPRSS2-ERG also had alterations in TP53 (61%), AR (55%), PTEN (34%), ATM (8%), APC (11%), BRCA2 (12%), SPOP (0%), CDK12 (1%), and MLL2 (6%). Patients without TMPRSS2-ERG (n = 589) had a lower frequency of alterations in TP53 (34%; P < .0001), AR (30%; P < .0001), PTEN (13%; P < .0001), ATM (11%; P = .48), APC (8%; P = .24), BRCA2 (6%; P = .027), SPOP (7%; P = .002), CDK12 (7%; P = .032), and MLL2 (6%; P = .82).

Further Evidence of a Distinct Tumor Molecular Landscape

Additional results indicated that the tumor transcript that was the most elevated in patients with (n = 43) vs without (n = 242) TMPRSS2-ERG was ERG, with median values of 12.25 counts/million (CPM) and 8.85 CPM, respectively (P < .0001). The respective mean values were 11.86 CPM and 9.39 CPM. PARP1, BAIAP3, COL2A1, and CBLC were also seen on evaluation.

Finally, gene expression signature analysis revealed that Notch and Wnt-beta-catenin pathways were differentially activated in patients with tumors harboring TMPRSS2-ERG.

Mu noted that limitations of the study apart from it being retrospective and exploratory in nature include low ctDNA in some patients and not adjusting for several statistical comparisons.

Disclosures: No disclosures were listed for Mu.

Read more data presented from the 2025 AACR Annual Meeting around talazoparib and enzalutamide.

References

1. Mu XJ, Piulats JM, Laird AD, et al. Exploring the tumor molecular landscape associated withTMPRSS2-ERG: A post hoc analysis from the phase 3 TALAPRO-2 study of first-line (1L) talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA in metastatic castration-resistant prostate cancer (mCRPC). Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. CT102.
2. Agarwal N, Azad A, Carles J, et al. Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial. J Clin Oncol. 2025;43(suppl 5):LBA18. doi:10.1200/JCO.2025.43.5_suppl.LBA1
3. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. FDA. June 20, 2023. Accessed April 28, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate