TP53 Alterations Research Articles

Contribution of molecular characterization to the diagnosis of MPN in patients with low JAK2V617F variant allelic fraction in a real-world cohort.

Since 2008, the JAK2V617F mutation has been key for diagnosing myeloproliferative neoplasms (MPN) according to the World Health Organization criteria. However, the clinical and biological significance of low JAK2V617F variant allelic fraction (VAF) remains poorly understood. To address this, we performed a comprehensive molecular characterization of a monocentric real-world retrospective cohort of MPN patients with low JAK2V617F VAF, diagnosed between 2007 and 2019. Our analysis revealed that 46.3% of these cases had additional driver mutations into JAK2, CALR, and MPL genes associated with very low JAK2V617F VAF (median: 0.09%). Furthermore, next-generation sequencing of cases without these driver mutations showed that 67.7% harbored other mutations, including low VAF CALR mutations, as well as TP53 alterations or predisposition genes. These findings highlight the importance of comprehensive molecular analysis in conjunction with bone marrow biopsy (BMB). Notably, we found a negative BMB did not exclude an MPN diagnosis, and molecular results confirmed MPN in some patients even without BMB evidence. Integrating BMB findings, molecular data, and low JAK2V617F VAF with clinical assessments highlights the potential for misdiagnoses, especially in cases that might overlap with age-related clonal hematopoiesis. Our study emphasizes the need for extensive molecular investigation in cases of low JAK2V617F MPN to ensure accurate diagnosis and appropriate management.

TP53 deletion as an MRD-dependent risk factor in childhood B-ALL: A post hoc analysis from a prospective cohort.

The effect of TP53 alterations on childhood B-cell acute lymphoblastic leukemia (B-ALL) remains unclear. To investigate the prognostic value of TP53 deletion (TP53 del ) and TP53 mutation (TP53 mut ), this post hoc study used fluorescence in situ hybridization test to detect TP53 del in 907 newly diagnosed B-ALL patients from a prospective cohort of Chinese Children's Cancer Group ALL-2015 trial. Targeted gene sequencing was used to identify TP53 mut in 342 out of the 907 patients. TP53 del was detected in 4.4% of patients. The frequency of hypodiploidy was higher in TP53 del subgroup (7.5% vs. 0.5%, p = 0.002), but patients with TP53 del were less likely to have other recurrent genetic abnormalities, including BCR::ABL1, ETV6::RUNX1, TCF3::PBX1 and KMT2A rearrangements. Univariable and multivariable analyses indicated that TP53 del was an independent risk factor for overall survival (OS) and disease-free survival (DFS). Furthermore, stratification analysis revealed that TP53 del was associated with lower 5-year DFS in patients with positive minimal residual disease (MRD) after induction in the intermediate-risk group (0.0% vs. 58.0% [95% confidence interval [CI] 49.2%-68.3%], p < 0.001), suggesting an MRD-dependent pattern. However, somatic TP53 mut was not associated with poor survival (81.8% [95% CI 61.9%-100.0%] vs. 84.9% [95% CI 81.1%-89.0%], p = 0.971). In summary, TP53 del may serve as a predictor for poor prognosis in pediatric B-ALL. In particular, children in the intermediate-risk group with positive MRD and TP53 del may require more aggressive treatment.

SOX2 commands LIM homeobox transcription factors in choroid plexus development and tumorigenesis.

Choroid plexus (CP) tumors are rare brain neoplasms that mainly affect the pediatric population. Unlike benign CP papilloma (CPP), CP carcinoma (CPC) is an aggressive cancer with a dismal survival rate. Despite chromosome-wide rearrangements, drivers of most CP tumors remain elusive except recurrent alterations in TP53. Studies of signaling dysregulation may bring biological understanding of these malignancies. Previous studies implicated NOTCH signaling in CP tumors; we developed mouse models of CP tumors driven by NOTCH activation and Trp53 loss, respectively. This work examined the role of the transcription factor SOX2 in CP development and tumorigenesis. Multi-omics approaches were used to characterize cellular heterogeneity in NOTCH-driven CP tumors. SOX2 functions in the molecular signature of tumor cells were investigated. Single-cell transcriptomics and epigenetics methods identified diverse cell populations in tumors that resemble normal CP, such as epithelial and glial groups. Pseudo-time trajectory analysis indicated that NOTCH-driven CP tumor arises from bi-potential glial progenitors and retains a progenitor-like signature characterized by an enhanced SOX2 profile. SOX2 inactivation attenuated progenitor-like features and blunted tumor growth. Integrative omics studies revealed SOX2 binding to genes expressed in progenitors in the rhombic lip, including LIM homeobox transcription factors LMX1A and LMX1B. Consistently, SOX2 maintains progenitor identity through regulating their expression in CP tumors and during development, whereas LMX1A and LMX1B support SOX2 functions in tumor cell proliferation. Furthermore, spatial transcriptomics revealed aberrant SOX2 and LMX1A expression in human CP tumors. SOX2-LMX1 signaling maintains progenitor identity in CP development and tumor formation.

Molecular Alterations in TP53, WNT, PI3K, TGF-Beta, and RTK/RAS Pathways in Gastric Cancer Among Ethnically Heterogeneous Cohorts.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with significant racial and ethnic disparities in incidence, molecular characteristics, and patient outcomes. However, genomic studies focusing on Hispanic/Latino (H/L) populations remain scarce, limiting our understanding of ethnicity-specific molecular alterations. This study aims to characterize pathway-specific mutations in TP53, WNT, PI3K, TGF-Beta, and RTK/RAS signaling pathways in GC and compare mutation frequencies between H/L and Non-Hispanic White (NHW) patients. Additionally, we evaluate the impact of these alterations on overall survival using publicly available datasets. We conducted a bioinformatics analysis using publicly available GC datasets to assess mutation frequencies in TP53, WNT, PI3K, TGF-Beta, and RTK/RAS pathway genes. A total of 800 patients were included in the analysis, comprising 83 H/L patients and 717 NHW patients. Patients were stratified by ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were performed to compare mutation rates between groups and Kaplan-Meier survival analysis was used to assess overall survival differences based on pathway alterations among both H/L and NHW patients. Significant differences were observed in the TP53 pathway and related genes when comparing GC in H/L patients to NHW patients. TP53 mutations were less prevalent in H/L patients (9.6% vs. 19%, p = 0.03). Borderline significant differences were noted in the WNT pathway when comparing GC in H/L patients to NHW GC patients, with WNT alterations more frequent in H/L GC (8.4% vs. 4%, p = 0.08) and APC mutations being significantly higher (3.6% vs. 0.8%, p = 0.05). Although alterations in PI3K, TGF-Beta, and RTK/RAS pathways were not statistically significant, borderline significance was observed in genes related to these pathways, including EGFR (p = 0.07), FGFR1 (p = 0.05), FGFR2 (p = 0.05), and PTPN11 (p = 0.05) in the PI3K pathway and SMAD4 (p = 0.08) in the TGF-Beta pathway. Survival analysis revealed no significant differences among H/L patients. However, NHW patients with TP53 and PI3K pathway alterations exhibited significant differences in overall survival, while those without TGF-Beta pathway alterations also showed a significant survival impact. In contrast, WNT pathway alterations were not associated with significant survival differences. These findings suggest that TP53, PI3K, and TGF-Beta pathway disruptions may have distinct prognostic implications in NHW GC patients. This study provides one of the first ethnicity-focused analyses of TP53, WNT, PI3K, TGF-Beta, and RTK/RAS pathway alterations in GC, revealing significant racial/ethnic differences in pathway dysregulation. The findings suggest that TP53 and WNT alterations may play a critical role in GC among H/L patients, while PI3K and TGF-Beta alterations may have greater prognostic significance in NHW patients. These insights emphasize the need for precision medicine approaches that account for genetic heterogeneity and ethnicity-specific pathway alterations to improve cancer care and outcomes for underrepresented populations.

Anaplastic carcinoma of the ovary: A single-institution experience and molecular analysis.

Anaplastic carcinoma of the ovary: A single-institution experience and molecular analysis.

Investigating Intensity and Percentage of p53 Nuclear Expression in Prostate Cancer: Findings from a Cohort of U.S. Military Veterans.

Next-generation sequencing has revealed TP53 alterations in localized prostate cancer (PCa), suggesting growing clinical potential for p53 immunohistochemistry (IHC). Prior research supports the use of IHC for the detection of p53 overexpression to predict the presence of TP53 alterations known to be associated with adverse outcomes. However, to reach a consensus definition of p53 overexpression in PCa, further insights are needed. This study aimed to compare two fundamental approaches of evaluating p53 expression across a variety of specimens regarding PCa progression. This study included 84 patients (75% self-identified as African American) diagnosed with PCa between 1996 and 2021 at the DC VA Medical Center. Representative sections of core biopsies, radical prostatectomies, transurethral prostate resections, and metastatic deposits were examined. p53 nuclear expression was scored according to the highest intensity observed (0, 1+, 2+, 3+) and the percentage (0%, <1%, 1-5%, >5%) of tumor cells expressing any level of intensity in the aggregate tumor area. All slides were reviewed by two independent pathologists. Pertinent clinical data were collected. A total of 34 patients (40%) exhibited p53 nuclear expression, of which 18 (21%) showed the maximum (3+) intensity. The presence of maximum intensity, regardless of percentage, was found to be associated with Grade Group (p < 0.001), higher PSA at biopsy (p < 0.001), BCR (p < 0.001) and metastasis (p < 0.001). Importantly, maximum p53 intensity was identified only in patients who developed metastatic disease. Maximum (3+) p53 nuclear intensity of any percentage is highly associated with disease progression in PCa, suggesting that optimal determination of p53 overexpression should incorporate intensity.

Leukemic presentation in nodal mantle cell lymphoma is characterized by frequent SOX11 negativity, a poor risk genomic landscape including higher TP53 alterations, and worse overall survival.

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TP53-Mutated Myeloid Neoplasms: 2024 Update onDiagnosis, Risk-Stratification, and Management.

Alterations in the tumor suppressor gene TP53 are common in human cancers and are associated with an aggressive nature. Approximately 8%-12% of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) harbor TP53 mutations (TP53mut) and present immense challenges due to inherent chemoresistance and poor outcomes. As TP53mut are more common in older individuals and those with secondary/therapy-related myeloid neoplasms (MN), their incidence is expected to increase with an aging population and rising proportion of cancer survivors. Treatments used for other MN-intensive chemotherapy, hypomethylating agents, and the BCL-2 inhibitor venetoclax-do not improve the survival of TP53mut MN patients meaningfully. Additionally, further development of many promising agents has been discontinued, highlighting the challenges. Widespread acknowledgment of these problems led to the recognition of TP53mut MN as a distinct entity in the 5th edition of the World Health Organization and International Consensus Classifications. However, critical discrepancies between the two classifications may lead to under- or overestimation of the prognostic risk. Here, we review recent advances in the biology, diagnosis, and treatment of TP53mut MN. The development of TP53mut MN is positioned at the intersection of age, hereditary predisposition, and anti-cancer therapies. Precursor TP53mut clones can be detected years prior to the eventual leukemic transformation-raising the possibility of early intervention. We discuss the two classification systems and the bearing of the discrepancies between the two on timely and effective management. We provide novel evidence in the areas of discrepancies. Finally, we review the current therapeutic landscape and the obvious limitations of the currently used therapies.

18F-FDG PET/CT predicts the prognosis of patients with hepatocellular carcinoma undergoing liver transplantation

Introduction: In addition to radical resection, liver transplantation (LTx) is an effective treatment for hepatocellular carcinoma (HCC). However, tumor recurrence limits the efficacy of LTx in some patients. This study investigated the role of 18F-fludeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in predicting the prognosis of patients with HCC after LTx. Methods: A total of 278 consecutive patients with HCC who underwent pre-LTx PET/CT were divided into derivation (n = 178) and temporal validation (n = 100) cohorts and evaluated for PET/CT values, immunohistochemical (IHC) findings, and DNA sequencing of tumor tissues. Results: Patients with post-LTx recurrence exhibited significantly higher tumor maximum standardized uptake values (SUVmax) in pre-LTx PET/CT scans. Receiver operating characteristic (ROC) curve analyses identified the tumor SUVmax to liver SUVmax ratio (TSUVmax/LSUVmax) as the strongest predictor of post-LTx recurrence, with an optimal cutoff value of 1.43. Kaplan-Meier analyses demonstrated that a TSUVmax/LSUVmax &gt; 1.43 was associated with a shorter time to recurrence (TTR) and overall survival (OS) in both cohorts (p &lt; 0.001 for both). Multivariate Cox regression analyses confirmed that TSUVmax/LSUVmax &gt; 1.43 was an independent risk factor for tumor recurrence in both cohorts. IHC revealed that TSUVmax/LSUVmax &gt; 1.43 correlated with higher Ki-67 and CK19 expression. Next-generation sequencing (NGS) indicated that tumors with TSUVmax/LSUVmax &gt; 1.43 had more mutations and a higher tumor mutational burden (TMB). Furthermore, TSUVmax/LSUVmax &gt; 1.43 was significantly associated with mutations in TP53, EPPK1, MDM4, SLAMF7, SDHC, B4GALT3, RXRG and FCGR family genes, as well as TP53 and PI3K signaling pathway alterations. Conclusions: The preoperative TSUVmax/LSUVmax is a potential predictor of tumor recurrence in patients with HCC following LTx. Its use improves candidate selection and post-LTx management.

561 Low-Risk HPV Positive Giant Anal Condylomas Harbor Recurrent Alterations in TERT promoter, TP53, and CDKN2A

561 Low-Risk HPV Positive Giant Anal Condylomas Harbor Recurrent Alterations in TERT promoter, TP53, and CDKN2A

Genomic characterization of metastatic patterns in prostate cancer using circulating tumor DNA data from the SCRUM-Japan MONSTAR SCREEN project.

Genomic characterization of metastatic patterns in prostate cancer using circulating tumor DNA data from the SCRUM-Japan MONSTAR SCREEN project.

1199 P53 Staining Pattern in TP53-Mutated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) is Highly Predictive of the Underlying TP53 Alteration

1199 P53 Staining Pattern in TP53-Mutated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) is Highly Predictive of the Underlying TP53 Alteration

113P Relevance of RB1 and TP53 alteration detecting via liquid biopsy for neuroendocrine phenotype assessment and shifting

113P Relevance of RB1 and TP53 alteration detecting via liquid biopsy for neuroendocrine phenotype assessment and shifting

Impact of TP53 Alterations on Clinical Outcomes in Penile Squamous Cell Carcinoma

Impact of TP53 Alterations on Clinical Outcomes in Penile Squamous Cell Carcinoma

Transplantation outcomes of TP53-mutant AML and MDS: a single transplantation center experience of 63 patients.

Allogeneic hematopoietic stem cell transplantation is recommended for TP53-mutant acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) despite a high relapse rate and poor survival. To understand TP53 alterations on a molecular level and define stratified prognostic outcomes following transplantation, we performed targeted next-generation sequencing on 63 patients who underwent transplantation for TP53-mutant AML/MDS and profiled their molecular spectrum. Sixty-eight TP53 mutations were detected, with a median variant allele frequency of 46.8%. Copy number alterations at the TP53 locus were present in 19 patients (30%). Complex karyotype was detected in 48 patients (76%) and was significantly associated with larger TP53 clone size, bi-allelic status, and the absence of concurrent mutations, reflecting the high TP53 mutational burden. Specifically, 51 patients (81%) with the dominant TP53 clone greatly overlapped with those with the complex karyotype. Multivariable overall survival (OS) analysis identified AML (hazard ratio [HR], 2.51; P = 0.03) and TP53 clonal dominance (HR, 5.30; P = 0.002) as prognostic factors. One-year OS was worse in AML with the dominant TP53 clone than in others (13% vs 61%; P < 0.001). Our results underscore the utility of mutational profile-guided risk stratification in patients with TP53-mutant AML/MDS, and could aid in transplantation-related decision-making.

TP53 Deficiency in the Natural History of Prostate Cancer.

Prostate cancer remains a leading cause of cancer-related mortality in men, with advanced stages posing significant treatment challenges due to high morbidity and mortality. Among genetic alterations, TP53 mutations are among the most prevalent in cancers and are strongly associated with poor clinical outcomes and therapeutic resistance. This review investigates the role of TP53 mutations in prostate cancer progression, prognosis, and therapeutic development. A comprehensive analysis of preclinical and clinical studies was conducted to elucidate the molecular mechanisms, clinical implications, and potential therapeutic approaches associated with TP53 alterations in prostate cancer. TP53 mutations are highly prevalent in advanced stages, contributing to genomic instability, aggressive tumor phenotypes, and resistance to standard treatments. Emerging evidence supports the utility of liquid biopsy techniques, such as circulating tumor DNA analysis, for detecting TP53 mutations, providing prognostic value and facilitating early intervention strategies. Novel therapeutic approaches targeting TP53 have shown promise in preclinical settings, but their clinical efficacy requires further validation. Overall, TP53 mutations represent a critical biomarker for disease progression and therapeutic response in prostate cancer. Advances in detection methods and targeted therapies hold significant potential to improve outcomes for patients with TP53-mutated prostate cancer. Further research is essential to integrate TP53-based strategies into routine clinical practice.

Efficacy and safety of nivolumab plus ipilimumab in patients with metastatic variant histology (non-clear cell) renal cell carcinoma

BackgroundNivolumab plus ipilimumab (nivo/ipi) is a standard of care first-line (1 L) therapy for patients with metastatic clear-cell renal cell carcinoma (ccRCC), but its role in patients with metastatic, non-ccRCC...

Impact of variant allele frequency (VAF) of TP53 alterations and Signatera circulating tumor DNA (ctDNA) monitoring for patients (pts) with advanced urothelial carcinoma (aUC) treated with enfortumab vedotin (EV).

830 Background: EV is now a standard of care for pts with aUC, both as monotherapy and with pembrolizumab (EVP). Factors predictive of primary refractory disease (PRD) remain poorly understood. Prior investigation correlated low VAF pathogenic TP53 alterations on next-generation sequencing (NGS) with rapid progression on frontline (1L) platinum chemotherapy. Thus, we hypothesized that low TP53 alteration VAF would associate with inferior outcomes on EV. Methods: We generated an IRB-approved, HIPAA-compliant single institution retrospective database of pts with aUC who received EV monotherapy or in combination, starting 1/2019. Data cutoff was 9/2024. Baseline demographics, clinicopathologic features, and somatic NGS data were extracted from the electronic health record. PRD was defined as progressive disease (PD) on the first restaging scan after starting EV or earlier clinical progression resulting in death from disease. Signatera ctDNA was collected every 1-3 months. Statistical analysis included Fisher’s exact test. Results: We identified 82 pts with aUC who received EV, of whom 35 had available NGS data on tumor tissue. 22 pts (63%) had a TP53 alteration with reported VAF, with a median of 48.7% (range 12.1%-81.9%). Amongst the 35 pt cohort, at EV start, median age was 69 yrs, 65% male, 83% white, 40% never smokers, 23% with variant predominant histology, 17% upper tract disease, and metastatic sites included lymph node (77%), lung (26%), liver (20%), and bone (9%). 21 pts received EV as 1L therapy, and 14 pts received EV in the refractory setting (2L+). 21 pts received EVP, 1 pt received EVP with carboplatin, and 13 pts received EV monotherapy. Median follow-up time from EV start was 6.5 months, and 54% of pts were alive at data cutoff. For 1L EV, 29% (6/21) had PRD. Observed response rate (ORR) was 81% (13/16) at first restaging scan. For 2L+ EV, PRD rate was 43% (6/14), and ORR at first restaging scan was 55% (6/11). 8 of 22 pts (36%) with TP53 alteration had PRD. Pts with TP53 VAF below the median had 64% with PRD versus 9% with TP53 VAF above the median ( p =0.024). Among 22 pts with TP53 alterations, 4 pts had serial Signatera testing, of which 1 exhibited PRD. The pt with PRD had low TP53 VAF and persistently rising ctDNA values. 1 pt with low TP53 VAF had a decline in ctDNA that correlated with partial response on initial restaging scan before ctDNA rise corresponded with PD on the following scan, 1 pt with low TP53 VAF had persistent undetectable values, and 1 pt with high TP53 VAF had an initial detectable value become undetectable. Conclusions: Low TP53 alteration VAF was significantly associated with PRD to EV treatment, highlighting its potential as a predictive biomarker. ctDNA monitoring may be useful to monitor treatment response on EV. These findings are exploratory and must be validated in larger cohorts.

Carcinoma of prostate sequencing of tumor and clinical endpoints (CAPSTONE): Clinical implications of recurrent genomic alterations in lethal prostate cancer.

220 Background: Prostate cancer (PC) is genetically heterogeneous, and genomic alterations may impact prognosis and therapy response. We created CAPSTONE, a database of lethal PC that integrates comprehensive genomic sequencing with deep clinical phenotyping to explore the clinical implications of castrate resistant prostate cancer (CRPC) evolution. Methods: PC patients underwent tissue collection (4/05-7/21) for tumor RNA-sequencing and tumor/normal whole exome sequencing (HUM00046018, HUM00048105, HUM00067928, SU2C). Sequencing was processed using Turnkey Precision Oncology. We analyzed somatic and germline mutations, gene fusions, copy number alterations, and chromosomal instability (CIN) along with transcriptomic signatures and pathways. We collected clinical data (05/21-01/22) including overall survival from time of castrate resistant prostate cancer (OScrpc) and from time of biopsy (OSb). Patients were split into discovery and validation cohorts. We used cox proportional hazard models to evaluate OS. Results: Data was available for 454 men (n=192, n=262). Median follow up from CRPC was 32.1 (IQR: 14.7-50.1) and 33.3 (IQR: 20.9-55.6) months respectively. Median age at CRPC was 66 (IQR: 60-73) and 67 (IQR: 62-72) years. Of the 1,581 recurrently altered genes (&gt;2%), 72 had a significant (p&lt;0.01) univariate association with OS in the discovery cohort. From these, 3 (RB1, TP53, CDKN1B) were significantly associated with OS in the validation cohort (T1). Subgroup analysis revealed AR mutations but not amplifications were associated with improved OS (T1). AR amplifications were enriched in samples with TP53 alterations (p&lt;1.0e-3, p&lt;1.0e-3) and high CIN (p&lt;1.0e-3, p=8.7e-3). Finally, using discovery data, we generated a gene signature associated with OS independent of TP53, RB1, and CDKN1B and validated this signature in the validation cohort (T1). Conclusions: RB1, TP53, and CDKN1B were recurrently altered genes independently associated with worse OS in CRPC. Further, we identified a gene signature associated with poor OS in CRPC independent of these alterations. Association with OSb in CRPC. Discovery Validation (n=192) (n=262) Univariate HR (95% CI) [p] Multivariate HR (95% CI) [p] Univariate HR (95% CI) [p] Multivariate HR (95% CI) [p] OSb RB1 2.74 (1.69-4.43) [4.3e-5] 2.5 (1.47-4.24) [0.00067] 2.37 (1.53-3.68) [0.00012] 2.33 (1.49-3.63) [2e-04] TP53 2.23 (1.57-3.11) [5.9e-6] 2.55 (1.78-3.66) [3.8e-07] 1.52 (1.14-2.03) [0.0046] 1.48 (1.1-1.98) [0.0094] CDKN1B 3.39 (1.42-8.13) [0.0061] 3.46 (1.47-8.15) [0.0046] 2.47 (1.32-4.6) [0.0045] 2.86 (1.51-5.42) [0.0013] Gene signature 2.08 (1.72-2.5) [1.5e-14] 1.88 (1.56-2.28) [5e-11] 1.36 (1.17-1.57) [4.3e-05] 1.32 (1.13-1.53) [0.00035] AR amplification 1.03 (0.74-1.44) [0.86] - 1.15 (0.86-1.54) [0.34] - AR mutation 0.55 (0.3-1) [0.049] - 0.64 (0.4-1.02) [0.063] -

Phase 2 randomized study of high-risk metachronous oligometastatic prostate cancer with high-risk mutations treated with metastasis-directed therapy and niraparib/abiraterone acetate plus prednisone (KNIGHTS) trial.

TPS283 Background: Some patients with oligometastases may have the potential for long-term disease-free survival with just aggressive local therapy as shown by randomized trials for total consolidation of macroscopic metastases using metastasis-directed therapy (MDT). Long-term outcomes of pooled STOMP and ORIOLE trials in oligorecurrent metastatic castration-sensitive prostate cancer (omCSPC) demonstrated MDT improved progression free survival. However, men with high-risk mutations, including pathogenic alterations in ATM , BRCA1/2 , Rb1 , and TP53 , did poorly. Additional data suggests men with metastatic castration-resistant prostate cancer and similar mutations are sensitive to PARP inhibition (PARPi) with niraparib. We are launching a first-in-man biomarker-driven trial in omCSPC patients with high-risk mutations to evaluate the efficacy of MDT + androgen deprivation therapy (ADT) versus MDT + ADT + niraparib/abiraterone acetate plus prednisone (nira/AAP). Methods: This study is a multi-site, non-blinded, randomized phase II trial in patients with omCSPC. Men with histologically confirmed (at any site) omCSPC (≤3 metastases on standard imaging or ≤5 on Axumin/Choline/PSMA-PET/CT) and germ-line/somatic high-risk mutations ( TP53, BRCA1/2, PALB2, ATM, BRIP1, CHEK2, FANCA, RAD51B, RAD54L, MUTYH ) will be randomized (1:1) to MDT + 6- months ADT versus MDT + 6-months ADT + 6-months nira/AAP. A range of MDT radiation fractionation regimens are permitted. Subjects who meet eligibility criteria and qualify for enrollment will be stratified according to: (i) institution; (ii) conventional/enhanced imaging, (iii) PSADT &lt;6-months, (iv) initial surgery/radiation, and (v) BRCA1/2 status. This study has been IRB approved (NCT06212583). We assume an accrual time of 24 months, with 18 months of additional follow-up time, and will randomize a total of 88 patients (44 patients in each arm). The primary endpoint will be to assess frequency of PSA failure (&gt; 0.2 ng/mL post primary surgery or nadir + 2 post definitive radiation) with testosterone &gt;100 ng/dl at 18-months after randomization (powered for 20% improvement over control arm by Fisher’s exact test). Secondary endpoints will include toxicity, health-related quality of life (HRQoL), time to locoregional progression, time to distant progression, time to new metastasis, radiographic progression-free survival, and duration of response. Discovery correlatives associated with clinical outcome will be assessed by collection of including, but not limited to, cell free DNA, circulating-tumor cells, immunologic biomarkers, microbiota and radiomics. Clinical trial information: NCT06212583 .