scholarly journals Loss of PTEN-assisted G2/M checkpoint impedes homologous recombination repair and enhances radio-curability and PARP inhibitor treatment response in prostate cancer

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
W. Y. Mansour ◽  
P. Tennstedt ◽  
J. Volquardsen ◽  
C. Oing ◽  
M. Kluth ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Treatment Response ◽  
Parp Inhibitor ◽  
Homologous Recombination Repair ◽  
Recombination Repair ◽  
Inhibitor Treatment

318 Olaparib plus pembrolizumab in patients with previously treated advanced solid tumors with homologous recombination repair mutation and/or homologous recombination repair deficiency: KEYLYNK-007

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A344-A344
Author(s):  
Timothy A Yap ◽  
Mallika Dhawan ◽  
Andrew E Hendifar ◽  
Michele Maio ◽  
Taofeek K Owonikoko ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Homologous Recombination Repair ◽  
Advanced Solid Tumors ◽  
Repair Deficiency ◽  
Recombination Repair ◽  
Modified Recist ◽  
Previously Treated

BackgroundTreatment with the anti–PD-1 antibody pembrolizumab has improved clinical outcomes in multiple previously treated advanced solid tumors. The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity as monotherapy in patients with previously treated advanced ovarian, breast, pancreatic, and prostate cancers with BRCA1/BRCA2 mutations (BRCAm). Activity was also seen in patients with previously treated advanced solid tumors with other homologous recombination repair mutation (HRRm) and in those with ovarian cancer with homologous recombination repair deficiency (HRD) phenotype. PARP inhibitors have been found to increase interferon signaling and tumor infiltrating lymphocytes, enhancing tumor susceptibility to immune checkpoint blockade. Antitumor activity of PD-(L)1 plus PARP inhibition was found to be higher than expected with either agent alone in patients with recurrent ovarian cancer regardless of BRCAm or HRD status and in patients with BRCAm breast cancer. KEYLYNK-007 (NCT04123366) evaluates the antitumor activity and safety of olaparib in combination with pembrolizumab in patients with previously treated advanced solid tumors with HRRm and/or HRD.MethodsThis phase 2, nonrandomized, multicenter, open-label study will enroll approximately 300 patients aged ≥18 years with histologically/cytologically confirmed, previously treated, advanced solid tumors with HRRm and/or HRD per Lynparza HRR-HRD assay (Foundation Medicine, Inc., Cambridge, MA, USA), with an ECOG PS of 0-1. Patients will be grouped by biomarker status: subgroup 1: BRCAm; subgroup 2: HRRm without BRCAm; and subgroup 3: HRD positive without HRRm (loss of heterozygosity score ≥16 per Lynparza HRR-HRD assay). Patients will receive olaparib 300 mg twice daily + pembrolizumab 200 mg intravenously Q3W (35 cycles) until PD, unacceptable AEs, intercurrent illness, investigator decision, withdrawal of consent, or pregnancy. Tumor imaging assessment by blinded independent central review (BICR) per RECIST v1.1 or Prostate Cancer Working Group (PCWG)–modified RECIST v1.1 for prostate cancer will occur Q9W for 12 months, then Q12W until PD, start of new anticancer treatment, withdrawal of consent, pregnancy, or death. AEs will be monitored throughout the study and for 30 days after final dose (90 days for serious AEs). The primary endpoint is ORR (RECIST v1.1 or PCWG–modified RECIST version 1.1 by BICR). Secondary endpoints include duration of response (DOR) and PFS (RECIST v1.1 or PCWG–modified RECIST v1.1 by BICR), OS, and safety. Point estimate and exact Clopper-Pearson CI for ORR, and Kaplan-Meier estimates for DOR, PFS, and OS will be calculated. A total of 89 sites are currently enrolling in 20 countries.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov identifier, NCT04123366Ethics ApprovalAn independent institutional review board or ethics committee approved the protocol at each study site, and the trial is being conducted in compliance with Good Clinical Practice guidelines and the Declaration of Helsinki.

scholarly journals Homologous Recombination Repair Gene Mutation Characterization by Liquid Biopsy: A Phase II Trial of Olaparib and Abiraterone in Metastatic Castrate-Resistant Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5830
Author(s):  
T. Hedley Carr ◽  
Carrie Adelman ◽  
Alan Barnicle ◽  
Iwanka Kozarewa ◽  
Sally Luke ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Phase Ii ◽  
Phase Iii ◽  
Response To Treatment ◽  
Homologous Recombination Repair ◽  
Molecular Testing ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Recombination Repair

Background: Phase III randomized trial data have confirmed the activity for olaparib in homologous recombination repair (HRR) mutated metastatic castration-resistant prostate cancer (mCRPC) post next-generation hormonal agent (NHA) progression. Preclinical data have suggested the potential for a combined effect between olaparib and NHAs irrespective of whether an HRR gene alteration was present. NCT01972217 was a randomised double-blind Phase II study which evaluated olaparib and abiraterone versus placebo and abiraterone in mCRPC patients who had received prior chemotherapy containing docetaxel. The study showed that radiologic progression was significantly delayed by the combination of olaparib and abiraterone regardless of homologous recombination repair mutation (HRRm) status. The study utilized tumour, blood (germline), and circulating tumour DNA (ctDNA) analysis to profile patient HRRm status, but tumour tissue provision was not mandated, leading to relatively low tissue acquisition and DNA sequencing success rates not representative of real-world testing. Patients and methods: Further analysis of germline and ctDNA samples has been performed for the trial to characterize HRRm status more fully and robustly analyse patient response to treatment. Results: Germline and plasma testing increased the HRRm characterized population from 27% to 68% of 142 randomized patients. Tumour-derived variants were detectable with high confidence in 78% of patients with a baseline plasma sample (71% of randomized patients). There was high concordance across methodologies (plasma vs. tumour; plasma vs. germline). The HR for the exploratory analysis of radiographic progression-free survival was 0.54 (95% CI: 0.32–0.93) in favour of olaparib and abiraterone in the updated HRR wild type (HRRwt) group (n = 73) and 0.62 (95% CI: 0.23–1.65) in the HRRm group (n = 23). Conclusion: Our results confirm the value of plasma testing for HRRm status when there is insufficient high-quality tissue for multi-gene molecular testing. We show that patients with mCRPC benefit from the combination of olaparib and abiraterone treatment regardless of HRRm status. The combination is currently being further investigated in the Phase III PROpel trial.

scholarly journals Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer

2019 ◽  
Author(s):  
Zsofia Sztupinszki ◽  
Miklos Diossy ◽  
Marcin Krzystanek ◽  
Judit Borcsok ◽  
Mark Pomerantz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Next Generation Sequencing Data ◽  
Parp Inhibition ◽  
Sequencing Data ◽  
Mutational Signatures ◽  
Homologous Recombination Deficiency ◽  
Platinum Based Chemotherapy ◽  
Inhibitor Treatment

AbstractBackgroundProstate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. It is not clear, however, whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, rendering them sensitive to HR-directed therapies.To identify a more comprehensive set of prostate cancer cases with homologous recombination deficiency (HRD) including those cases that do not harbor mutations in known HR genes.HRD levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. Whole genome (n=311) and whole exome sequencing data (n=498) of both primary and metastatic prostate adenocarcinomas (PRAD) were analyzed.ResultsKnown BRCA-deficient samples showed robust signs of HR-deficiency associated mutational signatures. HRD-patterns were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR related genes. Patients with HRD signatures had a significantly worse prognosis than patients without signs of HRD.ConclusionsThese findings may expand the number of cases likely to respond to PARP-inhibitor treatment. Based on the HRD associated mutational signatures, 5-8 % of prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).

scholarly journals Pan-cancer Analysis Identifies LMNB1 as a Target to Redress Th1/Th2 Imbalance and Enhance PARP Inhibitor Response in Human Cancers

2021 ◽  
Author(s):  
Haixiang Qin ◽  
Yingqiang Lu ◽  
Lin Du ◽  
Jingyan Shi ◽  
Haoli Yin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parp Inhibitor ◽  
Homologous Recombination Repair ◽  
Human Cancers ◽  
Th2 Cell ◽  
Recombination Repair ◽  
Cancer Types ◽  
Pan Cancer ◽  
Inhibitor Treatment

Abstract Background: Emerging evidence suggests that LMNB1 is involved in the development of multiple cancer types. However, there is no study reporting the potential role of LMNB1 in a systematic pan-cancer manner.Methods: The gene expression level and potential oncogenic roles of LMNB1 in The Cancer Genome Atlas (TCGA) database were analyzed with Tumor Immune Estimation Resource version 2 (TIMER2.0), Gene Expression Profiling Interactive Analysis version 2 (GEPIA2), UALCAN and Sangerbox tools. Pathway enrichment analysis was carried out to explore the possible mechanism of LMNB1 on tumorigenesis and tumor progression. The therapeutic effects of LMNB1 knockdown combined with PARP inhibition on human cancers were further investigated in vitro. Results: LMNB1 upregulation is generally observed in the tumor tissues of most TCGA cancer types, and is verified in kidney renal clear cell carcinoma using clinical specimens of our institute. High level of LMNB1 expression usually predicts poor overall survival and disease free survival for patients with tumors. Mechanically, LMNB1 level is positively correlated with CD4+ Th2 cell infiltration and DNA homologous recombination repair gene expression. In vitro experiments reveal that targeting LMNB1 has a synergistic effect on prostate cancer with PARP inhibitor treatment. Conclusions: LMNB1 is a biomarker of CD4+ Th2 cell infiltration and DNA homologous recombination repair in human cancers. Blockage of LMNB1 combined with PARP inhibitor treatment could be a promising therapeutic strategy for patients with cancers.

The prognostic significance of homologous recombination repair pathway alterations in metastatic hormone-sensitive prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 150-150
Author(s):  
Justin Shaya ◽  
Aaron Lee ◽  
Angelo Cabal ◽  
Justine Panian ◽  
James Michael Randall ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Cox Regression ◽  
De Novo ◽  
Prognostic Significance ◽  
Parp Inhibitors ◽  
Homologous Recombination Repair ◽  
Significant Difference ◽  
Recombination Repair ◽  
Hormone Sensitive

150 Background: Little is known about the clinical course of patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC) who harbor alterations in the homologous recombination repair (HRR) pathway. Here, we examine the outcomes of men with mHSPC with HRR alterations. Methods: Single center, retrospective analysis of men with mHSPC who underwent next generation sequencing from 2015-2020. The primary endpoint was to assess the time from diagnosis of mHSPC to onset of castrate resistance (mCRPC), as defined by PCWG3 criteria, in pts with HRR alterations vs wild type (WT). Both somatic and germline HRR alterations were permitted. Univariate and multivariate Cox regression were used to assess the effect of HRR alterations on time to mCRPC. Secondary endpoints included time to mCRPC stratified by HRR gene and time to treatment failure (TTF) in HRR altered vs WT pts, stratified by therapy. Results: We identified 151 men with mHSPC for the study. Median age was 66 years and 62% (n = 93) had de novo metastatic disease. 25% (n = 37) had HRR alterations detected and the most common alterations were in BRCA2 (n = 15), ATM (n = 10), CDK12 (n = 7). 78.4% (n = 29) of alterations were somatic and 13.5% (n = 5) of pts had co-alterations in 2 HRR genes. Time to mCRPC was significantly decreased in pts with HRR alterations vs WT (12.7 vs 16.1 mos, HR- 1.95, p- 0.02). In multivariate analysis, the effect of HRR alterations on time to mCRPC remained statistically significant when adjusting for age, mHSPC therapy, presence of visceral metastases, and PSA (adjusted HR- 1.69, p-0.02). Stratified by individual HRR gene, pts with BRCA2, CDK12, or co-occurring alterations had significantly decreased time to mCRPC compared to other HRR alterations (Table). In terms of mHSPC therapy, 45.7% were treated with ADT alone, 27.8% with an androgen receptor signaling inhibitor (ARSI), and 26.5% with docetaxel. TTF was inferior in HRR altered vs WT pts (10.8 vs 13.8 mos, p-0.004, HR- 1.84). Stratified by therapy, TTF was inferior in HRR altered vs WT pts treated with ADT alone (8.9 vs 13.3 mos, p- 0.019, HR-1.94) and there was no significant difference in TTF in HRR altered vs WT pts treated with either the addition of an ARSI or docetaxel. Conclusions: HRR alterations are associated with worsened outcomes in mHSPC patients. Given the established role of PARP inhibitors in mCRPC, these data highlight an opportunity to explore the use of PARP inhibitors in mHSPC to potentially improve outcomes. [Table: see text]

Research progress of PARP inhibitor monotherapy and combination therapy for endometrial cancer.

2021 ◽  
Vol 22 ◽  
Author(s):  
Ke Shen ◽  
Li Yang ◽  
Fei-Yan Li ◽  
Feng Zhang ◽  
Lei-Lei Ding ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Homologous Recombination ◽  
Tumor Cells ◽  
Checkpoint Inhibitors ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Research Progress ◽  
Homologous Recombination Repair ◽  
Recombination Repair

: Endometrial cancer is one of the three most common malignant tumors in the female reproductive system. Advanced and recurrent endometrial cancers have poor prognoses and lack effective treatments. Poly(ADP-ribose) polymerase (PARP) inhibitors have been applied to many different types of tumors, and they can selectively kill tumor cells that are defective in homologous recombination repair. Endometrial cancer is characterized by mutations in homologous recombination repair genes; accordingly, PARP inhibitors have achieved positive results in off-label treatments of endometrial cancer cases. Clinical trials of PARP inhibitors as monotherapies and within combination therapies for endometrial cancer are ongoing. For this review, we searched PubMed with "endometrial cancer" and "PARP inhibitor" as keywords, and we used "olaparib", "rucaparib", "niraparib" and "talazoparib" as search terms in clinicaltrials.gov for ongoing trials. The literature search ended in October 2020, and only English-language publications were selected. Multiple studies confirm that PARP inhibitors play an important role in killing tumor cells with defects in homologous recombination repair. Its combination with immune checkpoint inhibitors, PI3K/AKT/mTOR pathway inhibitors, cell cycle checkpoint inhibitors, and other drugs can improve the treatment of endometrial cancer.

Olaparib for the treatment of metastatic prostate cancer

2021 ◽  
Author(s):  
Corinne Maurice Dror ◽  
Alexander W Wyatt ◽  
Kim N Chi
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Metastatic Prostate Cancer ◽  
Additional Treatment ◽  
Parp Inhibition ◽  
Homologous Recombination Repair ◽  
Recombination Repair ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Molecular Landscape

Recent innovations in the treatment of metastatic prostate cancer have improved patient outcomes. Nonetheless, this disease remains fatal and additional treatment approaches are needed. Greater understanding of the molecular landscape of metastatic prostate cancer has revealed recurrent alterations in key pathways amenable to therapeutic targeting. One such pathway is DNA repair, particularly alterations in genes directly or indirectly associated with homologous recombination repair found in up to one-quarter of patients with metastatic castrate-resistant prostate cancer (mCRPC). Olaparib, an inhibitor of poly-ADP-ribose polymerase, has recently gained approval for the treatment of mCRPC harboring alterations in homologous recombination repair genes. This review will provide a summary of evidence regarding PARP inhibition in the treatment of mCRPC, with a specific focus on olaparib.

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