Homologous Recombination Repair Deficiency Research Articles

Abstract PO2-03-09: Cost-effectiveness analysis of RAD51 functional biomarker for platinum sensitivity in the GeparSixto trial

Abstract Background: Homologous recombination repair deficiency (HRD) has long been recognized as a predictive biomarker for platinum sensitivity and is present in up to 60% of early triple negative breast cancers (TNBC). Different commercial and lab-developed assays to measure HRD are available, but they do not necessarily reflect homologous recombination functionality. Functional HRD, defined by a low score in RAD51 foci, is emerging as an accurate and dynamic biomarker to predict DNA damaging agents’ response. We performed a cost-effectiveness evaluation of the RAD51 test compared to tumor BRCA1/2 mutation (tBRCA1/2) or genomic HRD by Myriad Mychoice® to identify patients sensitive to platinum-based chemotherapy within the GeparSixto trial. Methods: The effectiveness measure was the primary outcome of the GeparSixto study: rate of pathological complete response (pCR), defined as ypT0 ypN0. The pharmacological costs were calculated following treatment protocol of GeparSixto where TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Bevacizumab was excluded from the cost analysis as it is not administered by standard practice. The cost of a session/stay at the day hospital was added, as well as the cost of the test used, comparing 4 scenarios: All comers (assuming all patients receiving PMCb); RAD51 test (assuming RAD51 ≤10% received PMCb and RAD51 >10% received PM); tBRCA1/2 test (assuming tBRCA1/2 mutated received PMCb and tBRCA1/2 non-mutated received PM) and genomic HRD by Myriad Mychoice® (HRD score ≥42 received PMCb, and HRD score <42 received PM). The available commercial costs were considered for tBRCA1/2 and Myriad Mychoice®, and the VHIO performance cost was considered for the RAD51 test. Parameter uncertainties were assessed by means of one-way and probabilistic sensitivity analyses. Results: All comers total cost was 20,530€ per patient, with associated pCR rate of 54.5%. Functional RAD51 test was associated with a pCR probability of 55.1% with a Δ cost of 198€, as opposed to tBRCA1/2 which presented a pCR rate of 40.1% with a Δ cost of 814€, and genomic HRD with 47% pCR rate and the higher Δ cost of 1,023€ per patient, when compared to all comers. The incremental cost-effectiveness ratio (Δ cost/Δ pCR) was 33,000 for RAD51 test and dominated in both tBRCA1/2 and genomic HRD tests. These results were robust on one way and probabilistic sensitivity analyses. Conclusion: The most efficient scenarios are the functional RAD51 test and all comers. Both tBRCA1/2 and genomic HRD by Myriad Mychoice® scenarios provide worse health outcomes at a higher cost, based on the data of the GeparSixto trial. This study highlights the potential overall benefit of functional HRD biomarkers to predict PARPi sensitivity. Citation Format: Isabel Pimentel, Carles Forné, Alba Llop-Guevara, Misericòrdia Carles-Lavila, Violeta Serra, Montserrat Rué, Judith Balmaña. Cost-effectiveness analysis of RAD51 functional biomarker for platinum sensitivity in the GeparSixto trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-03-09.

Abstract PO2-08-11: The MAGIC study: Universal whole genome tumour and germline sequencing of newly diagnosed breast cancer identifies a high proportion of ER+ BRCA-like tumours

Abstract Background: Identification of germline mutations in hereditary breast cancer (HBC) genes can have profound benefits in the treatment of breast cancer (BC) and manging risk for patient and the family. In addition, sequencing of the tumours can reveal clinically relevant somatic features, such as homologous recombination deficiency (HRD) and mutational signatures, that can guide treatment which are not discernible by germline sequencing alone. We hypothesised that current standard of care where women diagnosed with BC are not routinely offered tumour sequencing is suboptimal as fails to exploit all therapeutic vulnerabilities which can be exploited in the treatment of BC. The MAGIC study is the first prospective trial in Australia of unselected invasive BCs in general oncology practice combining both germline and tumour sequencing. Methods: The MAGIC study included a total of 651 consecutive consented patients presenting with non-metastatic BC between June 2020 to March 2023. It included invasive BC, high-grade DCIS and pleomorphic LCIS. The sequencing was conducted in two phases; for phase one, 157 cases underwent whole genome sequencing (WGS) on both germline and matched BC DNA while for phase two, 494 cases underwent only germline whole exome sequencing. Germline variants were interrogated for pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, BARD1, BRIP1, RAD51B, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2, CDH1, PTEN, STK11, TP53 and NTHL1. Tumour homologous recombination (HR) repair deficiency was calculated using HRDetect (Nat Med 2017;23:517). For BCs showing a high HRDetect score ( >0.75) all HBC gene promoter CpG islands were assessed for hypermethylation using the Twist NGS Methylation system. Mutational signatures were calculated from somatic mutations identified from whole genome sequenced BCs using the DeconstructSig package in R (Genome Biol. 2016;17:31) and referenced against the COSMIC v2 signature catalogue. Results: Actionable germline variants in any HBC gene were identified in 7.7% of cases (7.8% of invasive and 6.1% of in situ BC) with 5.2% having an actionable mutation in an HR pathway gene (BRCA1, BRCA2, PALB2 and RAD51C). Most cases with pathogenic variants showed bi-allelic inactivation in the tumour. All BRCA1, BRCA2 and PALB2 tumours showed high HRDetect and/or HRD scores consistent with loss of HR repair function, indicating them to be the underlying hereditary driver of the BC. One BC with a pathogenic PMS2 variant showed retention of the wild-type allele with no evidence of a mismatch repair mutational signature suggesting PMS2 was not the driver of this BC. Of the 157 BC in phase one that underwent WGS and did not have a germline pathogenic HBC gene variant, 16% (18/117 invasive and 3/13 DCIS) had an HRDetect score of >0.7 indicative of a homologous recombination repair defect and therefore biologically a “BRCA-like” tumour. Of these 21 BRCA-like cases, only 3 invasive BCs had clear somatic bi-allelic inactivation of an HBC gene that could explain the high HRDetect score (2 BRCA1 and 1 BRCA2). One of the 21 BRCA-like cases had a germline variant of unknown significance (VUS) in an HBC gene (a BRCA2 missense variant in an ER+ tumour. The tumour showed loss of the wild-type allele). Of the BRCA-like cases, 71% were ER positive which included 3 invasive lobular cancers. Conclusion: Tumour sequencing identified three times as many cases that might be eligible for HR repair defect targeted therapy than germline testing alone (16% versus 5.2%). Unlike a previous study (Ann Oncol., 2019 30:1071-1079), the majority of the BRCA-like BCs were ER+ with no evidence of a VUS in a known HBC gene suggesting these are driven by novel germline or somatic mutations in genes involved in DNA HR repair. Citation Format: Ian Campbell, Lisa Devereux, Kirsten Hogg, Luxi Lal, Michelle Sinclair, Lesley Stafford, Magnus Zethoven, Anita Skandarajah, Paul James, Geoffrey Lindeman, Bruce Mann, Dilanka De Silva. The MAGIC study: Universal whole genome tumour and germline sequencing of newly diagnosed breast cancer identifies a high proportion of ER+ BRCA-like tumours [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-08-11.

Homologous Recombination Repair Deficiency in Metastatic Prostate Cancer: New Therapeutic Opportunities.

More than 20% of metastatic prostate cancer carries genomic defects involving DNA damage repair pathways, mainly in homologous recombination repair-related genes. The recent approval of olaparib has paved the way to precision medicine for the treatment of metastatic prostate cancer with PARP inhibitors in this subset of patients, especially in the case of BRCA1 or BRCA2 pathogenic/likely pathogenic variants. In face of this new therapeutic opportunity, many issues remain unsolved. This narrative review aims to describe the relationship between homologous recombination repair deficiency and prostate cancer, the techniques used to determine homologous recombination repair status in prostate cancer, the crosstalk between homologous recombination repair and the androgen receptor pathway, the current evidence on PARP inhibitors activity in metastatic prostate cancer also in homologous recombination repair-proficient tumors, as well as emerging mechanisms of resistance to PARP inhibitors. The possibility of combination therapies including a PARP inhibitor is an attractive option, and more robust data are awaited from ongoing phase II and phase III trials outlined in this manuscript.

Abstract P30: MUTATIONAL SIGNATURE ASSIGNMENT HETEROGENEITY IS WIDESPREAD AND CAN BE ADDRESSED BY ENSEMBLE APPROACHES

Abstract Single base substitution (SBS) mutational signatures have become standard practice in cancer genomics. In lieu of de novo signature extraction, reference signature assignment allows users to estimate the activities of pre-established SBS signatures within individual malignancies. Several tools have been developed for this purpose, each with differing methodologies. However, due to a lack of standardization, there may be inter-tool variability in signature assignment. We deeply characterized three assignment strategies and five SBS signature assignment tools. We observed that assignment strategy choice can significantly influence results and interpretations. Despite varying recommendations by tools, Refit performed best by reducing overfitting and maximizing reconstruction of the original mutational spectra. Even after uniform application of Refit, tools varied remarkably in signature assignments both qualitatively (Jaccard Index = 0.38 – 0.83) and quantitatively (Kendall tau-b = 0.18 – 0.76). This phenomenon was exacerbated for “flat” signatures such as the homologous-recombination repair deficiency (HRD) signature SBS3. An ensemble approach (EnsembleFit), which leverages output from all five tools, increased SBS3 assignment accuracy in BRCA1/2-deficient breast carcinomas. After generating synthetic mutational profiles for thousands of pan-cancer tumors, EnsembleFit reduced signature activity assignment error 15.9 – 24.7% on average using COSMIC and non-standard reference signature sets. We have also released the EnsembleFit web portal (https://www.ensemblefit.pittlabgenomics.com) for users to generate or download ensemble-based SBS signature assignments using any strategy and combination of tools. Overall, we show that signature assignment heterogeneity across tools and strategies is non-negligible and propose a viable, ensemble solution. Citation Format: Wu Jialun Andy, Akila Perera, Linganesan Kularatnarajah, Anna Korsakova, Jason James Pitt. MUTATIONAL SIGNATURE ASSIGNMENT HETEROGENEITY IS WIDESPREAD AND CAN BE ADDRESSED BY ENSEMBLE APPROACHES [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P30.

Abstract LB406: Synergistic antitumor effect of FRα TOP1i antibody drug conjugate, AZD5335, in combination with the PARP1 inhibitor, saruparib (AZD5305), in preclinical models of ovarian cancer

Abstract Folate receptor alpha (FRα) is a cell surface GPI-anchored protein overexpressed in several solid tumors with highest prevalence in ovarian cancer and lung adenocarcinoma but restricted expression in normal tissues. AZD5335, an FRα-targeting antibody conjugated to AZ’s proprietary topoisomerase 1 inhibitor (TOP1i) payload, AZ14170132, is currently being investigated in the FONTANA Phase 1/2 clinical trial (NCT05797168). Since homologous recombination repair deficiency (HRD) and mutations in genes involved with homologous recombination repair (HRRm+) are associated with sensitivity to DNA damaging agents, we evaluated the efficacy of AZD5335 in ovarian cancer patient-derived xenograft (PDX) models assessed for HRRm, as described1. Sixteen ovarian cancer PDX models were each treated with a single dose of AZD5335 (5 mg/kg IV). Of the HRRm- cohort, 8/11 (73%) cohort responded to treatment with a tumor regression >30% from baseline. In the HRRm+ cohort 4/5 (80%) responded to AZD5335. PARP1 can act as a positive regulator of genomic stability by counteracting TOP1-induced DNA damage (Malanga and Althaus, 2004) that led to the hypothesis that the efficacy of TOP1i drugs can be enhanced by combination with PARP inhibitors. To evaluate for potential synergy of AZD5335 with the PARP1 inhibitor, saruparib (AZD5305): Three FRα-expressing cancer cell lines, KB, IGROV-1 and OVCAR-3, were treated with AZD5335 +/- saruparib, revealing evidence of synergistic cytotoxicity. These results encouraged us to investigate this combination in pre-clinical HRRm+ in vivo xenograft models (OVCAR-3 and OV2022F). In OVCAR-3 xenograft models, single agent activity with saruparib (1 mg/kg PO QD x28) was 37% tumor growth inhibition (TGI) and with AZD5335 (0.625 mg/kg IV x1) was 50% TGI while combined administration at the same doses improved TGI to 86%. Similar combinatorial activity was seen in OV2022F with TGI 61%, 54%, and 97% for saruparib, AZD5335, and saruparib +AZD5335, respectively. In conclusion, AZD5335 exhibits a similar degree of single agent antitumor activity in both HRRm+ and HRRm- preclinical models, and the efficacy can be potentiated by combining with the PARP inhibitor, saruparib. 1. Clarke et al. 2022, NEJM Evid 2022;1(9) DOI: 10.1056/EVIDoa22000432. Malanga and Althaus 2004, JBC 2004; 279(7) DOI: 10.1074/jbc.C3004372003. Citation Format: Marco Gymnopoulos, Ravinder Tammali, Ana De Almeida, Jixin Wang, Claire Myers, Mark Albertella, Paula G. Fraenkel, Puja Sapra. Synergistic antitumor effect of FRα TOP1i antibody drug conjugate, AZD5335, in combination with the PARP1 inhibitor, saruparib (AZD5305), in preclinical models of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB406.

Abstract CT261: Phase II trial of nivolumab in combination with talazoparib in patients with unresectable or metastatic melanoma and mutations in BRCA or BRCA-ness

Abstract Novel therapies are needed for anti-PD-1 refractory metastatic melanoma. Few therapies rationally target biologically selected subpopulations of melanoma. In the Cleveland Clinic Familial Melanoma Registry, a high rate of germline mutations in proteins that regulate DNA repair were seen. PARP inhibitors can lead to synthetic lethality and clinical benefit in patients with BRCA mutations or mutations associated with DNA damage repair (“BRCAness phenotype”). Additionally, preclinical models have shown that PARP inhibitors lead to STING activation, raising the hypothesis that combination therapy with anti-PD-1 could augment immune responses. We conducted a phase II trial evaluating the combination of the PARP inhibitor talazoparib with nivolumab in patients with metastatic melanoma harboring germline or somatic DNA repair mutations. We enrolled a cohort of patients with multiple melanoma subtypes including cutaneous melanoma (3), melanoma arising from a blue nevus (2) and uveal melanoma (2). Mutant DNA repair genes included BAP1 (4), BRCA2 (1), ATM (1), ATR (1) and ARID2 (1), 3 of which were germline. The patient population had highly refractory disease with 6 of 7 patients having progression after ipilimumab + nivolumab (5 of these were primary progression). The 7th patient had a recurrence after adjuvant nivolumab. Of the 7 patients enrolled, all progressed within 6 months (using RECIST and iRECIST criteria).The toxicity profile was consistent with known profile of PARP inhibitors (anemia). Although patient enrollment was limited, this study suggests that in heavily pretreated patients selected for DNA repair mutations the combination of PARP inhibitors and anti-PD-1 has no effect on RECIST-based tumor response. Additional studies are needed. Possible alternative selection strategies include evaluating for genomic evidence of homologous recombination repair deficiency (HRD) or targeting specific mutations (BRCA). TABLE 1: NAND Patient Characteristics and Treatment Outcome Age Subtype of Melanoma Gene Alteration Somatic or Germline TMB BRAF Status Prior Therapy Status of Prior IO response Clinical Trial Response 76 Cutaneous ATM Germline N/A WT Nivolumab Progression after Adjuvant Progression 32 Cutaneous ATR Somatic 4.2 V600E Ipilimumab + Nivolumab Primary Progression Progression 75 Uveal BRCA2 and BAP1 Germline 1.3 WT Ipilimumab + Nivolumab Primary Progression Progression 45 Cutaneous/Blue Nevus BAP1 Somatic 0.0 WT Ipilimumab + Nivolumab Primary Progression Progression 51 Cutaneous/Blue Nevus BAP1 Germline 1.6 WT Ipilimumab + Nivolumab Primary Progression Progression 69 Uveal BAP1 Somatic 1.6 WT Pembrolizumab Primary Progression Progression 61 Cutaneous ARID2 Somatic 17.9 WT Ipilimumab + Nivolumab Secondary Resistance Progression Citation Format: James Isaacs, Tamara A. Sussman, Lucy B. Kennedy, Joshua Arbesman, Brian Gastman, Millennia Zhou, Emily Zabor, Claudia Diaz-Montero, Jennifer Ko, Pauline Funchain. Phase II trial of nivolumab in combination with talazoparib in patients with unresectable or metastatic melanoma and mutations in BRCA or BRCA-ness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT261.

Abstract 2504: Determining tumour homologous recombination repair status in PDX and clinical samples using automated RAD51 scoring

Abstract PARP inhibitors (PARPi) as monotherapy are approved in a wide variety of cancers that show genetic alterations that result in homologous recombination repair (HRR) deficiency. Current genomic scar tests for HRR deficiency (HRD) are predictive of response to PARPi on a population scale but they may fail to provide a real-time functional status of HRR in an individual. RAD51 is a critical DNA repair factor that functions in HRR to safeguard the integrity of the genome and could be a useful patient selection biomarker for PARPi response.During HRR, RAD51 forms filamentous structures to facilitate repair, which can be visualised by direct immunofluorescence (IF) as nuclear foci. Quantification of these RAD51 foci has been shown to be a functional readout of HRR status, however current manual counting of foci is challenging and can result in high inter-observer variability. In order to standardise RAD51 quantification, we aimed to develop an image analysis solution.Tumour samples from patient derived xenograft (PDX) studies and human tissues from commercial sources and clinical trials were co-stained with IF for RAD51 and geminin, as a marker of cells in S/G2 phase of the cell cycle. Manual scoring was performed as reported previously. Visiopharm was used to create and image analysis pipeline in allowing delineate tumour epithelial areas, detection of the geminin positive nuclei and RAD51 foci within these and the quantification of the foci.We have successfully developed an image analysis solution to select geminin positive proliferating tumour cells from PDX and clinical material, then quantify the RAD51 foci within these cells. There is a good correlation with manual scores with a similar accuracy to the manual inter-observer variability (PDX: R2 = 0.76, F1 = 0.95 [n=34]; breast cancer samples: R2 = 0.72, F1 = 0.92 [n=33]). Developing and image analysis solution has challenges due to several factors such as pan-nuclear staining of non-focus forming RAD51 being variable across samples, manual scoring using a wider Z-plane, susceptibility of RAD51 to pre-analytical factors and the fact that a duplex IF stain with geminin is required to mark actively replicating cells.The frequent inactivation of HRR is known to sensitise cancer cells to PARP inhibitors, we demonstrate a quantitative functional readout of HRR competency using RAD51 foci staining and an image analysis algorithm. This solution may enable the use of RAD51 foci as a patient selection biomarker for PARP inhibitors by providing an objective, robust and reproducible algorithm for scoring. Citation Format: Jack Robertson, Jack Ashton, Gemma N. Jones, Gordon Mills, Tugba Y. Ozmen, Matthew J. Rames, Soonyoung Park, Paul Waring, Natalia Lukashchuk, Elizabeth Harrington. Determining tumour homologous recombination repair status in PDX and clinical samples using automated RAD51 scoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2504.

Abstract 4336: Homologous recombination repair deficiency, and not recurrence, determines mutational burden and clonal dynamics in high grade serous ovarian cancer

Abstract High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy, killing more than 9,000 women each year in the United States. Nearly 80% of patients with HGSOC will experience recurrence within 5 years, but little is known about the mechanisms that drive this process. Up to 60% of the genome in an HGSOC tumor is impacted by structural variant mutations and pronounced intratumoral heterogeneity. Intratumor heterogeneity is believed to be a key feature of recurrence and therapy resistance with some evidence indicating diverse and complex mechanisms of the seeding of metastatic sites and recurrent tumors. We included 35 HGSOC patients for whom paired chemo-naive and chemoresistant tumors as well as germline DNA was available. Whole genome sequencing was used to identify somatic single nucleotide variants (SNV) insertion/deletion variants (indels), and structural variants (SVs) in each tumor. The number of somatic SVs and indels was higher in tumors with homologous recombination repair deficiency (HRD; P=0.000252 SVs, P=0.00385 Indel) but was not affected by recurrent status (P=0.826 SV, P=0.145 SNV/indel). Clonal composition and dynamics were measured using SNVs/indels as tumors progressed from chemo-naïve primary samples to recurrent chemo-resistant tumors. Surprisingly, few changes were observed in clonal abundance and complexity through progression. When this analysis was repeated with SVs homologous recombination repair proficient tumors tend to be polyclonal while HRD tumors tend to be monoclonal. Five denovo structural variant signatures were identified in our cohort and led to three distinct structural variant classes tumors defined by deletion, tumors defined by duplication, and tumors defined by copy number neutral changes (inversions, translocations and balanced complex events). Patients with tumors defined by deletions and copy number neutral changes carry pathogenic SVs correlating with reduced survival (P=0.00023), while DNA gains are less subject to pathogenic alterations. Each class displayed distinct regions of the chromosome that was frequently affected by large scale SV events (>5Mb), which was also observed in the HRP/HRD status. Although no regions were notably altered across recurrence, GO analysis revealed that recurrent tumors have a significantly reduced immune response, which was not seen in the primary tumors. Within a subset of tumors, we are plan to utilize Oxford Nanopore Technologies ultra long read sequencing which will allow for confirmation of SVs observed in the WGS as well as identification of more complex events that cannot be deciphered using WGS techniques. Citation Format: Michael A. Diaz, Nicole Gull, Pei-Chen Peng, Kate Lawrenson, Bobbie J. Rimel, Jenny Lester, Beth Karlan, Simon A. Gayther, Michelle R. Jones. Homologous recombination repair deficiency, and not recurrence, determines mutational burden and clonal dynamics in high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4336.

Abstract 4534: HSK40495, a highly selective PARP1 inhibitor with improved hematopoietic safety for the treatment of HRD cancers

Abstract It is well known that several PARP inhibitors have been approved for tumors with homologous recombination repair deficiencies (HRD), such as BRCA mutations. However, the common side effect of these inhibitors is hematologic toxicity, which limits their therapeutic index and combination potential with first-line chemotherapies. One possible reason is that currently approved PARP inhibitors do not specifically target PARP1, and might also affect other PARP family members. Recent studies have shown that the synthetic lethality caused by PARP trapping with HRD is mainly dependent on PARP1 inhibition, but not other PARP family members. Accordingly, we developed a selective PARP1 inhibitor that effectively inhibits tumor growth with less hematologic toxicity. HSK40495 is a potent PARP1 inhibitor with highly selectivity of PARP2. HSK40495 inhibited PARP1 enzymatic activity with a single digit nanomolar potency and with greater than 5000-fold selectivity against PARP2 in the protein binding assay. In addition, HSK40495 exhibited potent anti-proliferation activity in both DLD1(BRCA KO) cell and MDA-MB-436 cell, while had minimal effects against BRCA-WT DLD1 cell up to 30 µM in an anti-proliferation assay. In a subcutaneous MDA-MB-436 xenograft tumor model, HSK40495 administered orally once daily achieved excellent tumor growth inhibition of 100% at 3mg/kg. HSK40495 demonstrated significant PARylation inhibition in tumor tissues. Importantly, in CD34+ human bone marrow progenitor cell, HSK40495 showed improved cytotoxicity when compare to first-generation PARP inhibitor, Talazoparib. Meanwhile, in a lineage-specific hematotoxicity assay, HSK40495 exhibited improved cytotoxic safety in the process of differentiation of myeloid, erythroid and megakaryocyte compared with Talazoparib treatment. In summary, HSK40495, a highly selective PARP1inhibitor over other PARP family members, exhibits excellent pharmacological and safety properties, and also has the favorable pharmacokinetics profile in preclinical studies. All these findings suggest that HSK40495 has the great potential to be a promising PARP1 inhibitor for further development in the patients with HRD tumors. Citation Format: Fan Li, Xiaoli Gou, Lei Chen, Qingyuan Meng, Yao Li, Hongjiao Dong, Pingming Tang, Ju Wang, Pangke Yan. HSK40495, a highly selective PARP1 inhibitor with improved hematopoietic safety for the treatment of HRD cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4534.

Abstract 4533: Identification of DAT-2000A, a novel potent PARG inhibitor that selectively inhibits PARPi-resistant and homologous-recombination-deficient tumors

Abstract A significant portion of patients with homologous recombination repair deficiencies(HRD) do not respond to PARP inhibitors, and even among those who initially respond, resistance often develops after PARP inhibitor treatment. This underscores the unmet clinical need to address the challenges in the treatment of HRD patients. Poly (ADP-ribose) glycohydrolase (PARG) plays a key role in hydrolyzing PAR chains from PARylated protein substrates, such as PARP1, serving as a critical checkpoint in DNA damage repair and the control of DNA replication stress. Therefore, PARG has emerged as a promising target for cancer therapy. Cancer cells experiencing replication stress, such as HRD breast cancer cells and those resistant to PARPi, exhibit sensitivity to PARG inhibition. DAT-2000A is a potent, selective, orally bioavailable small-molecule inhibitor of PARG, which directly binds to the catalytic domain of PARG, inducing the accumulation of poly-PAR chains at DNA lesions, and exhibits notable anti-proliferative activity across a wide range of HRD tumors both in vitro and in vivo. Biochemical assays confirm DAT-2000A's high potency and selectivity as an inhibitor of PAR-chain hydrolysis. In cellular assays, DAT-2000A demonstrates selective sensitivity in HRD cells, distinguishing itself from PARPi across various indications. Preclinical studies involving CDX and PDX xenograft models reveal that DAT-2000A exerts robust anti-tumor effects in both PARPi-sensitive and -resistant settings. Furthermore, it induces a dose and time-dependent accumulation of PAR chains, which may serve as a reliable pharmacodynamic biomarker indicative of PARG target engagement. In conclusion, DAT-2000A represents an innovative targeted therapy that warrants further investigation in clinical trials for the treatment of HRD cancers and beyond. Citation Format: Dan Yan, Yan Zhang, Zhangqi Yu, Yao Zhang, Jingxi Zhang, Bin Wang, Huixian Chen, Jingxue Shi, Zhiwei Bao, Xiaoling Lin, Jincong Zhuo, Kevin Zhou. Identification of DAT-2000A, a novel potent PARG inhibitor that selectively inhibits PARPi-resistant and homologous-recombination-deficient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4533.

Abstract 7132: Preclinical characterization of LAE119, a novel PARP1 selective inhibitor and trapper

Abstract Current PARP inhibitors primarily target PARP1/2 and demonstrate high efficacy against tumors with deficiencies in homologous recombination repair, such as those with BRCA mutations. However, these inhibitors are also associated with significant hematological toxicities. Studies have indicated that the synthetic lethality observed with BRCA mutations is mainly driven by PARP1, while PARP2 is not essential in this context. PARP2 has been shown to be crucial for the survival of hematopoietic stem/progenitor cells in animal models. Therefore, selective inhibition of PARP1 could potentially reduce toxicity and improve therapeutic outcomes. Here we introduce LAE119, a potent and selective PARP1 inhibitor and PARP1-DNA trapper. It demonstrates more than a 1000-fold selectivity for PARP1 DNA trapping compared to PARP2. In comparison to most PARP inhibitors including AZD5305, LAE119 exhibits extremely long residence time on PARP1 in both biochemical and cellular assays. It demonstrates robust anti-proliferation activity against BRCA2−/− DLD-1 cells and MDA-MB-436 cells, with IC50 value of 0.6 nM in both cell lines. In CAL51 cells, which has a BRCA2 mutation but with low PARP1 expression level and are much less sensitive to AZD5305, LAE119 demonstrates much better activity than AZD5305, particularly when PARP1 level is increased with transgene expression. LAE119 demonstrated substantial tumor inhibition in MDA-MB-436 and Capan-1 xenograft models. LAE119 also displays favorable ADME properties and PK profiles. It has high tumor/plasma ratio which is beneficial for sustainable anti-tumor effect and reduction of off-target effects. In rat hematologic toxicity study, LAE119 at 10 mpk QD dose was well tolerated and had minimal effects on hematologic parameters. Both in vitro and in vivo data strongly support the further clinical investigation of LAE119. Citation Format: Ming Li, Yan Chen, Junyan Chen, Ling Jiang, Xiaofen Lin, Justin Gu. Preclinical characterization of LAE119, a novel PARP1 selective inhibitor and trapper [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7132.

Abstract 4349: Characterization of a centrosome loss-induced tumorigenic signature in prostate epithelial cells

Abstract Prostate cancer (PCa) stands as the second leading cause of cancer death in American men, with overtreatment being common given the difficulty in distinguishing between indolent and aggressive cases. Unlike many cancers, PCa lacks hallmark mutations in key oncogenes and tumor-suppressor genes. Instead, PCa exhibit extensive genomic rearrangements and chromosomal instability (CIN). CIN occurs during PCa progression, producing ETS gene family fusions, PTEN loss and androgen receptor amplification. Importantly, the mechanism underlying CIN in PCa remains unclear. Previously, we found that cell within early-grade human primary prostate adenocarcinomas (PRAD) frequently lack centrosomes, and this frequency correlates with tumor grade. We demonstrated that transient removal of centrosomes within non-tumorigenic human prostate epithelial cells (hPrEC) induces CIN and was, strikingly, sufficient to transform subpopulations of cells capable of producing xenograft tumors in mice. To unravel the molecular mechanisms underlying this path to tumorigenesis, we isolated DNA and RNA from parental hPrECs, clonal lines subjected to transient centrosome loss, and xenograft tumor cells and performed whole genome sequencing (WGS) and bulk RNA-seq. This allowed us to characterize the genomic profiles induced by centrosome loss and to identify an associated mutational signature. We used MUTECT2 to identify single nucleotide variants. Kataegis loci were observed on multiple chromosomes in all transient centrosome removal samples. Copy number variations were also detected in these samples using FACETS and SEQUENZA. Next, we extracted the copy number (CN) signature with SigProfiler and Sigminer, comparing it to COSMIC CN signatures and WGS data from PRAD patients. Our results revealed that the transient centrosome loss signature bears similarity to CN signatures associated with chromothripsis, loss of heterozygosity, and homologous recombination repair deficiency. Patients with PRAD displaying the centrosome loss CN signature had a poorer prognosis. Additionally, our CN analysis discovered that centrosome loss induced mosaic loss of chromosome Y in our samples. To detect structural variations, we employed DELLY, MANTA, SVABA, revealing a high occurrence of both non-clustered and clustered translocations in transient centrosome loss samples. These translocations were validated in our RNA-seq data using STAR-Fusion. Ongoing analyses include inferring CNV from PCa scRNA-seq data, and determining cell populations with the centrosome loss CN-signature and their associated transcriptome features. This work unveils a comprehensive genomic profile stemming from centrosome loss and demonstrates its role in driving oncogenesis in PCa. These findings have the potential to establish centrosome loss as a hallmark in PCa stratification, and lead to a significant advancement in prostate tumor treatment. Citation Format: Jiawen Yang, Diogo de Oliveira Pessoa, John M. Ryniawec, Emily Loertscher, Anne E. Cress, Megha Padi, Gregory C. Rogers. Characterization of a centrosome loss-induced tumorigenic signature in prostate epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4349.

Abstract 6472: Response to PARP inhibitors in patients with breast cancer metastatic to the central nervous system

Abstract Background: Central nervous system (CNS) metastasis from breast cancer can be challenging to treat due to the limited blood brain barrier penetration of many systemic therapies. PARP inhibitors (PARPi) block single-strand DNA break repairs and have activity in cancers with homologous recombination repair deficiency; they are FDA approved for patients with metastatic HER2 negative breast cancer with germline BRCA1/2 mutations. While preclinical studies suggest that PARPi have CNS penetration, clinical data is limited. The goal of our study is to describe the clinical benefit of PARPi in patients with breast cancer CNS metastasis. Methods: This retrospective case series was conducted at three academic cancer centers (Johns Hopkins, Dana-Farber, and Duke) and included patients with the following criteria: (1) age≥18 years with a breast cancer diagnosis (any subtype); (2) diagnosis of parenchymal brain metastasis or leptomeningeal disease (LMD); and (3) received PARPi (olaparib, talazoparib) for CNS metastasis. Clinical and pathologic information were analyzed with descriptive statistics (median, range) and Kruskal-Wallis rank sum tests. Survival analysis was performed using Kaplan-Meier curves with log-rank p-values. Results: Although this analysis includes one center’s experience, we will present a combined dataset (N = 45) at the main conference. 11 patients were identified at Johns Hopkins. 4 (36.4%) were Black and 6 (54.5%) were White; 6 (54.5%) had ER+HER2- disease and 5 (45.5%) had TNBC at time of brain metastasis; 5 (45.5%) had BRCA1 mutations, 5 (45.5%) had a BRCA2 mutations, and 1 patient (9%) had a BARD1 mutation; 7 (63.6%) had brain metastasis and 4 (36.4%) had LMD. Median lines of therapy prior to PARPi was 6 [1 - 11]; 8 patients (72.7%) had previous CNS radiation (5 SRS and 3 WBRT) and 3 (27.3%) had previous CNS surgery. On average, patients remained on PARPi for 5 months [0.5 - 66], and overall survival (OS) time from PARPi to death was 16 months [2 - 66]. Time on PARPi was 5 months [2 - 66] for patients with brain metastasis and 3 months [0.5 - 10] for those with LMD (p=0.22). Duration of PARPi and OS did not differ significantly between ER+HER2- and TNBC (p=0.74 and 0.69, respectively), BRCA 1 and 2 (p=0.78 and 0.72, respectively), or brain and LMD metastasis (p=0.22 and 0.91, respectively). Black patients had significantly shorter PARPi duration and survival than White patients (PARPi 2 vs. 8 months, p=0.028 and OS 4 vs 18 months, p=0.028). Prior CNS radiation was significantly associated with longer PARPi duration and survival (PARPi 5 vs 1 month, p=0.02 and OS 17 vs. 3 months, p=0.032). Prior CNS surgery was significantly associated with longer PARPi duration, but not overall survival (PARPi 18 vs 3 months, p=0.05 and OS 28 vs. 7 months, p=0.14). Conclusions: PARPi are associated with significant clinical benefit in patients with breast cancer CNS metastasis. Larger data series will help confirm these observations. Citation Format: Seoho Lee, Rani Bansal, Melissa E. Hughes, Amanda E. Van Swearingen, Heather N. Moore, David O. Kamson, Solmaz Sahebjam, Greg Kirkner, Anna Gorfinkel, Sarah Sammons, Nancy U. Lin, Carey Anders, Cesar A. Santa-Maria. Response to PARP inhibitors in patients with breast cancer metastatic to the central nervous system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6472.

Abstract 538: Establishment of PARP inhibitor-induced resistant patient-derived ovarian cancer xenograft models

Abstract Introduction: Poly (ADP-ribose) polymerases (PARPs) can recruit DNA repair effectors and cope with DNA single-strand breaks. For DNA double-strand breaks (DSB), there are two main repair mechanisms: non-homologous end joining repair (NHEJ) which is prone to error due to infidelity events, and BRCA1/2 mediated homologous recombination repair (HR) restoring the original sequence. Therefore, inhibition of PARPs may cause both single stranded break repair deficiency and HR deficiency in BRCA1/2 deficient patients, leading to cell death. The concept of “synthetic lethality” has led to the development of PARP inhibitors, including Olaparib, Niraparib and Rucaparib in clinical practice. Despite encouraging efficacy of these PARP inhibitors, acquired resistance, such as HR repair restoration, drug efflux pump upregulation and replication fork protection, has limited their clinical benefits. Therefore, to investigate novel therapeutic strategies which can overcome the acquired resistance, we established patient-derived xenograft (PDX) ovarian cancer models with PARP inhibitor-induced resistance. Methods: OV9402, an ovarian cancer PDX model with BRCA 1 c.3155del, was implanted subcutaneously and treated with Niraparib at 35 mg/kg, daily, for 129 days. Relapse tumors (tumor #1 and tumor #2) were isolated and inoculated into naïve mice. Then the 2nd round of treatment (Niraparib, 35 mg/kg, daily) was given when the mean tumor volume reached 140 mm3. The tumors showing no significant response to Niraparib were collected on either day 32 (#1 derived tumor model) and day 22 (#2 derived tumor model) after randomization and their gene changes were analyzed by RNA sequencing (RNA-seq). Results: Niraparib significantly inhibited OV9402 tumor growth, with complete regression observed in nine out of ten mice on day 54 after the 1st round of treatment. However, tumor regrowth was observed in two out of the nine mice from day 68 onwards. The relapsed tumors (tumor #1 and tumor #2) from these two mice were collected and re-inoculated into 5 naïve mice to establish tumor models for the 2nd round of Niraparib treatment, separately. For #1 derived tumor model, all the tumors presented complete resistance to the Niraparib treatment. RNA-seq data showed that the gene expression of ABCB1, which encodes for efflux pumps, was upregulated. In parallel, complete resistance to Niraparib was observed in all the tumors derived from 2# tumor bearing mice. The RNA-seq data demonstrated that an acquired secondary genetic deletion on BRCA1 genes, which restored the functional protein expression loss in the parental line and restored HR repair, was found in the tumors. Conclusion: Ovarian cancer PDX models that have effectively developed resistance to PARP inhibitors have the potential to serve as valuable preclinical tools to evaluate potential next-generation PARP inhibitors and innovative combination strategies. Citation Format: Li Hua, Shuang Li, Chenpan Nie, Xiaobo Chen, Guo Sheng, Ludovic Bourre, Jingjing Wang. Establishment of PARP inhibitor-induced resistant patient-derived ovarian cancer xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 538.

Abstract 4532: Discovery of DAT-1000A, a potent Polθ inhibitor that significantly enhances anti-tumor efficacy in combination with PARP inhibitor in homologous-recombination-deficient tumors

Abstract Cancers exhibiting homologous recombination (HR) repair deficiencies due to mutations in genes like BRCA1 or BRCA2 rely on alternative DNA damage response (DDR) pathways to uphold genomic integrity. This vulnerability allows for the targeted disruption of these pathways through synthetic lethality approaches. DNA polymerase theta (Polθ, encoded by POLQ) assumes a crucial role in mending DNA double-strand breaks (DSB) via microhomology-mediated end-joining (MMEJ), one of the principal pathways for repairing DNA DSB. Notably, Polθ expression is minimal in normal tissues but becomes upregulated in HR-deficient cancer cells, positioning Polθ as a prime target for synthetic lethality in HRD cancers. Reversion mutations in HR-related genes frequently employ micro-homology deletion mechanisms. Consequently, the inhibition of Polθ holds the potential to thwart the emergence of PARPi resistance, primarily driven by BRCA reversion mutations. In this context, we introduce DAT-1000A, a novel small-molecule Polθ inhibitor exhibiting potent activity with a single-digital nanomolar IC50 value. Its efficacy in MMEJ functional assays validates its on-target cellular activity. Assessments of cell viability in HR-deficient BRCA2-KO DLD-1 cells, compared to their parental counterparts, reveal a striking synthetic lethality window exceeding 500-fold. Additionally, DAT-1000A displays synergistic anti-proliferative effects when combined with PARP inhibitors in BRCA1/2-mutated cells. In BRCA1/2-mutated xenograft models, DAT-1000A demonstrates robust and sustained tumor regression, as evidenced by the level of γH2AX, a common marker for double-strand breaks, which closely correlates with anti-tumor efficacy. Importantly, high-dose DAT-1000A treatment in mice elicits no significant abnormalities, underscoring its excellent tolerability. Collectively, DAT-1000A emerges as a novel Polθ inhibitor, offering both potent activity and a favorable safety profile, and holds promise for advancing therapeutic options in the realm of HRD cancer treatment. Citation Format: Dan Yan, Yao Zhang, Yan Zhang, Jingxi Zhang, Bin Wang, Huixian Chen, Jingxue Shi, Xiaoling Lin, Jincong Zhuo, Kevin Zhou. Discovery of DAT-1000A, a potent Polθ inhibitor that significantly enhances anti-tumor efficacy in combination with PARP inhibitor in homologous-recombination-deficient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4532.

Abstract 3887: The origins and clinical impact of extrachromosomal DNA across 39 cancers

Abstract Extrachromosomal DNA (ecDNA) is emerging as a major contributor to cancer drug resistance and poor outcome in many cancer types. To understand the underlying genetic and mutational processes associated with ecDNA formation and presence, we conducted an analysis of whole-genome sequencing data from 14,778 cancer patients representing 39 tumor types from the Genomics England cohort. Our findings revealed focal amplifications driven by ecDNA in 17.1% of tumor samples, exhibiting varying frequencies across tissues. Notably, liposarcomas (55.4%) and HER2+ breast cancers (46.4%) displayed higher rates compared to lower rates found in pancreatic adenocarcinomas (2%). In addition to oncogenic amplifications such as HER2 derived from ecDNA during cancer evolution, ecDNAs that did not contain oncogenes were enriched for immunomodulatory genes (e.g., CXCL6, LRRC32, and HLA-G). Immunomodulatory ecDNAs exhibited reduced T cell infiltration. In the context of intrinsic and environmental mutational processes, deamination clock-like, tobacco smoking, and APOBEC cytidine deaminase signatures positively correlated with ecDNA presence. Conversely, mismatch repair deficiency (MMRd) and POLD1/POLE deficiency signatures exhibited a negative correlation. Mutational processes associated with tobacco exposure, UV light, and spontaneous deamination primarily occurred before ecDNA formation, while signatures of homologous recombination repair deficiency tended to manifest post-ecDNA formation.Notably, ecDNA was enriched at metastatic sites and significantly associated with shorter overall survival in multivariable analysis (HR 1.31, 95% CI 1.17-1.47), underscoring its clinical relevance. This study enhances our understanding of the mutational processes and tissue contexts that shape the ecDNA landscape in human cancer and highlights its implications for clinical outcomes. Citation Format: Chris Bailey, Oriol Pich, Kerstin Thol, Jens Luebeck, Georgia Stavrou, Thomas B. Watkins, Natasha E. Weiser, Wei-Ting Lu, Jeanette Kittel, Robert Bentham, Natasha Sharma, Roberto Salgado, Dave Moore, Maria Litovchenko, King L. Hung, Alex J. Cornish, Bhargavi Dameracharla, Serena Nik-Zainal, Vineet Bafna, Howard Chang, Nicholas McGranahan, Nnennaya Kanu, Genomics England Consortium, Paul S. Mischel, Mariam Jamal-Hanjani, Charles Swanton. The origins and clinical impact of extrachromosomal DNA across 39 cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3887.

Intraductal Carcinoma of the Prostate versus Simulants: A Differential Diagnosis Growing in Clinical Impact.

Despite its first recognition even longer ago, in the past nearly 20 years, intraductal carcinoma of the prostate has become a standard histopathologic reporting parameter conveying a strong negative prognostic factor for prostatic adenocarcinoma. When seen at biopsy, intraductal carcinoma of the prostate is associated with risk for aggressive prostatectomy outcomes, including frequently high-grade, high-stage, high-volume disease, with increased risk for recurrence and progression. Multiple organizations, including the uropathology subspecialty societies to the World Health Organization, recognize and recommend reporting the presence of intraductal carcinoma, whether sampled in "pure" form or present with concomitant invasive adenocarcinoma. Moreover, emerging scholarship relates intraductal carcinoma to higher prevalence of homologous recombination repair deficiency mutations in prostatic adenocarcinoma, whether somatic or germline, which serve as indications for approved targeted therapies. Taken together, this is a diagnosis for the histopathologist not to miss. In view of these elevated stakes and the opportunity to further precision medicine, this review details neoplastic and non-neoplastic simulants in the differential diagnosis of intraductal carcinoma of the prostate.

Leveraging Off-Target Reads in Panel Sequencing for Homologous Recombination Repair Deficiency Screening in Tumor

Targeted tumor only sequencing has become a standard practice in cancer diagnostics. This study aims to develop an approach for robust copy number variant (CNV) calling in tumor samples using only off-target region (OTR) reads. We also established a clinical use case for homologous recombination deficiency (HRD) score estimation (HRDest) using the sum of telomeric allelic imbalance (TAI) and large-scale state transitions (LST) scores without the need for loss of heterozygosity (LOH) information. We demonstrated a strong correlation between HRD score and the sum of TAI + LST in the TCGA cohort (rho = 0.99, p < 2.2x 10-16) and in a clinical in-house cohort of 34 tumors (rho = 0.9, p = 5.1 x 10-13) comparing WES and targeted sequencing data. We compared HRDest scores from 1086 clinical cases to the TCGA data set and showed that there were no significant differences in HRD score distribution within the analyzed tumor types. As a control, commercially available HRD standards were also sequenced and the HRDest scores obtained from the OTR reads were well within the HRD reference range provided by the manufacturer. In conclusion, we showed that OTR reads of tumor-only panel sequencing can be used to determine genome-wide CNV profiles and to approximate HRD scores.

A Somatic BRCA2-Mutated Pancreatic Adenocarcinoma With Sustained Exceptional Response to Modified FOLFIRINOX.

Homologous recombination repair (HRR) pathway deficiency opens multiple therapeutic avenues within pancreatic cancer. Patients with HRR deficiency-associated gene mutations such as BRCA1, BRCA2, and PALB2 are more susceptible to platinum-based chemotherapies and in those with somatic BRCA mutations, PARP inhibitor therapy prolongs progression-free survival. The case discussed herein illustrates the therapeutic opportunities offered through the identification of HRR deficiency in pancreatic cancer, as well as the challenges associated with treatment and prevention of central nervous system metastases in long-term survivors of pancreatic cancer.

Impact of homologous recombination repair (HRR) or nucleotide excision repair (NER) deficiency on sensitivity to antibody drug conjugate (ADC) payloads in urothelial cancer.

Impact of homologous recombination repair (HRR) or nucleotide excision repair (NER) deficiency on sensitivity to antibody drug conjugate (ADC) payloads in urothelial cancer.