Identifying androgen receptor (AR) and genomic characteristics that define populations of patients with mHSPC who benefit from early PARP inhibition therapy with talazoparib.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5097-TPS5097
Author(s):  
Saro Kasparian ◽  
Leanne Burnham ◽  
Rick Kittles ◽  
Zj Sun ◽  
Fornati Bedell ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
African American ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Unmet Need ◽  
Cag Repeats ◽  
Parp Inhibition ◽  
Castration Resistance ◽  
Cellular Mechanisms

TPS5097 Background: A minority of men with mCRPC, those with DNA repair mutations, can benefit from PARP inhibitor therapy. In addition to DNA repair, PARP is used by cancer cells to interact with other cellular mechanisms including androgen receptors (AR). The next generation PARP inhibitor talazoparib can, in addition to inhibiting DNA repair, trap PARP, preventing it from carrying out its other functions. As progression in mHSPC is based on AR escape mechanisms, we predict that early exposure to PARP inhibition will delay progression. In addition, AR characteristics and function vary by ethnic populations. AR expression is inversely related with the number of polymorphic CAG repeats. As African American (AfrAm) men commonly have shorter CAG repeats in their AR, they may experience different response duration, but have been under-represented in clinical trials. Furthermore, CAG repeats may be associated with greater signaling through pathways such as wnt and Myc, which is associated with aggressive disease. Thus, studying intensified up-front therapy in a diverse prostate cancer population is a critical unmet need. Methods: 70 subjects will be treated with ADT + abiraterone + talazoparib. Outreach by our Division of Health Equities and accrual at community satellites located near diverse populations will be enlisted to accrue a target of 30% African American. Talazoparib will be dosed at 1mg daily (0.75 mg in renal insufficiency). LHRH and abiraterone formulations will be left to physician’s choice. PSA and safety labs will be checked every 4 weeks for the first 12 weeks. Imaging will be performed every 12 weeks for the first year then every 24 weeks if PSA is decreasing, or 12 weeks if rising. Data safety monitoring for toxicity after every 10 subjects have been accrued. Diversity of accrual will be evaluated after 30 subjects are enrolled; amendments will be made if the diversity goal is not achieved. Tissue genomics and ctDNA will be measured at baseline; ctDNA will be repeated after 4 weeks and at castration resistance. Endpoints: Primary: PSA nadir at 7 months has been found to be associated with overall survival and is achieved by 55% of men with mHSPC with ADT + abiraterone. With 70 subjects there is 97% power to confirm improved nadir rate of 75%, and 83% power to determine a nadir rate >70%. Secondary endpoints include objective response by RECIST 1.1 for subjects with measurable disease. radiographic progression free survival. Correlative objectives include comparing outcomes in subsets of men with high vs low number of AR CAG repeats, men with genomic alterations, and the change in ctDNA alteration fractions from baseline to 4 weeks and at progression. Progress: The trial is open to accrual as of Feb 2021. Sponsor: Pfizer/ Prostate Cancer Foundation RFP Clinical trial information: NCT04734730.

scholarly journals PARP Inhibitors in Prostate Cancer—The Preclinical Rationale and Current Clinical Development

Genes ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 565 ◽  
Author(s):  
Virtanen ◽  
Paunu ◽  
Ahlskog ◽  
Varnai ◽  
Sipeky ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Dna Repair ◽  
Therapeutic Potential ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Treatment Modalities ◽  
Cancer Type ◽  
Castration Resistance ◽  
Single Strand Break

Prostate cancer is globally the second most commonly diagnosed cancer type in men.Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms ofprostate cancer and castration resistance. Prostate cancer with DNA repair defects may bevulnerable to therapeutic targeting by Poly(ADP‐ribose) polymerase (PARP) inhibitors. PARPenzymes modify target proteins with ADP‐ribose in a process called PARylation and are inparticular involved in single strand break repair. The rationale behind the clinical trials that led tothe current use of PARP inhibitors to treat cancer was to target the dependence of BRCA‐mutantcancer cells on the PARP‐associated repair pathway due to deficiency in homologousrecombination. However, recent studies have proposed therapeutic potential for PARP inhibitorsin tumors with a variety of vulnerabilities generating dependence on PARP beyond the syntheticlethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initiallythought. Importantly, PARP‐associated DNA repair pathways are also closely connected toandrogen receptor (AR) signaling, which is a key regulator of tumor growth and a centraltherapeutic target in prostate cancer. In this review, we provide an extensive overview of publishedand ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss theunderlying biology. Several clinical trials are currently studying PARP inhibitor mono‐andcombination therapies in the treatment of prostate cancer. Integration of drugs targeting DNArepair pathways in prostate cancer treatment modalities allows developing of more personalizedcare taking also into account the genetic makeup of individual tumors.

scholarly journals Veliparib Is an Effective Radiosensitizing Agent in a Preclinical Model of Medulloblastoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Jessica Buck ◽  
Patrick J. C. Dyer ◽  
Hilary Hii ◽  
Brooke Carline ◽  
Mani Kuchibhotla ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Combination Therapy ◽  
Cellular Response ◽  
Molecular Subtype ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Parp Inhibition ◽  
Preclinical Model ◽  
Radiation Induced

Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new therapies critically important. As radiotherapy and chemotherapy act through the induction of DNA damage, the sensitization of cancer cells through the inhibition of DNA damage repair pathways is a potential therapeutic strategy. The poly-(ADP-ribose) polymerase (PARP) inhibitor veliparib was assessed for its ability to augment the cellular response to radiation-induced DNA damage in human medulloblastoma cells. DNA repair following irradiation was assessed using the alkaline comet assay, with veliparib inhibiting the rate of DNA repair. Veliparib treatment also increased the number of γH2AX foci in cells treated with radiation, and analysis of downstream pathways indicated persistent activation of the DNA damage response pathway. Clonogenicity assays demonstrated that veliparib effectively inhibited the colony-forming capacity of medulloblastoma cells, both as a single agent and in combination with irradiation. These data were then validated in vivo using an orthotopic implant model of medulloblastoma. Mice harboring intracranial D425 medulloblastoma xenografts were treated with vehicle, veliparib, 18 Gy multifractionated craniospinal irradiation (CSI), or veliparib combined with 18 Gy CSI. Animals treated with combination therapy exhibited reduced tumor growth rates concomitant with increased intra-tumoral apoptosis observed by immunohistochemistry. Kaplan–Meier analyses revealed a statistically significant increase in survival with combination therapy compared to CSI alone. In summary, PARP inhibition enhanced radiation-induced cytotoxicity of medulloblastoma cells; thus, veliparib or other brain-penetrant PARP inhibitors are potential radiosensitizing agents for the treatment of medulloblastoma.

scholarly journals Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1918 ◽  
Author(s):  
Sanne Venneker ◽  
Alwine B. Kruisselbrink ◽  
Inge H. Briaire-de Bruijn ◽  
Yvonne de Jong ◽  
Andre J. van Wijnen ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cell Lines ◽  
Dna Methyltransferase ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Parp Inhibition ◽  
Idh Mutation ◽  
Mutation Status ◽  
Chondrosarcoma Cell ◽  
Idh Mutations

Chondrosarcomas are chemo- and radiotherapy resistant and frequently harbor mutations in isocitrate dehydrogenase (IDH1 or IDH2), causing increased levels of D-2-hydroxyglutarate (D-2-HG). DNA repair defects and synthetic lethality with poly(ADP-ribose) polymerase (PARP) inhibition occur in IDH mutant glioma and leukemia models. Here we evaluated DNA repair and PARP inhibition, alone or combined with chemo- or radiotherapy, in chondrosarcoma cell lines with or without endogenous IDH mutations. Chondrosarcoma cell lines treated with the PARP inhibitor talazoparib were examined for dose–response relationships, as well as underlying cell death mechanisms and DNA repair functionality. Talazoparib was combined with chemo- or radiotherapy to evaluate potential synergy. Cell lines treated long term with an inhibitor normalizing D-2-HG levels were investigated for synthetic lethality with talazoparib. We report that talazoparib sensitivity was variable and irrespective of IDH mutation status. All cell lines expressed Ataxia Telangiectasia Mutated (ATM), but a subset was impaired in poly(ADP-ribosyl)ation (PARylation) capacity, homologous recombination, and O-6-methylguanine-DNA methyltransferase (MGMT) expression. Talazoparib synergized with temozolomide or radiation, independent of IDH1 mutant inhibition. This study suggests that talazoparib combined with temozolomide or radiation are promising therapeutic strategies for chondrosarcoma, irrespective of IDH mutation status. A subset of chondrosarcomas may be deficient in nonclassical DNA repair pathways, suggesting that PARP inhibitor sensitivity is multifactorial in chondrosarcoma.

scholarly journals Gynecologic Cancers: Emerging Novel Strategies for Targeting DNA Repair Deficiency

2016 ◽  
pp. e259-e268 ◽  
Author(s):  
Rebecca S. Kristeleit ◽  
Rowan E. Miller ◽  
Elise C. Kohn
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Inhibitor Therapy ◽  
Molecular Therapy ◽  
Parp Inhibition ◽  
Gynecologic Cancers ◽  
Brca Mutations ◽  
Individual Gene

The presence of a BRCA mutation, somatic or germline, is now established as a standard of care for selecting patients with ovarian cancer for treatment with a PARP inhibitor. During the clinical development of the PARP inhibitor class of agents, a subset of women without BRCA mutations were shown to respond to these drugs (termed “ BRCAness”). It was hypothesized that other genetic abnormalities causing a homologous recombinant deficiency (HRD) were sensitizing the BRCA wild-type cancers to PARP inhibition. The molecular basis for these other causes of HRD are being defined. They include individual gene defects (e.g., RAD51 mutation, CHEK2 mutation), homozygous somatic loss, and whole genome properties such as genomic scarring. Testing this knowledge is possible when selecting patients to receive molecular therapy targeting DNA repair, not only for patients with ovarian cancer but also endometrial and cervical cancers. The validity of HRD assays and multiple gene sequencing panels to select a broader population of patients for treatment with PARP inhibitor therapy is under evaluation. Other non-HRD targets for exploiting DNA repair defects in gynecologic cancers include mismatch repair (MMR), checkpoint signaling, and nonhomologous end-joining (NHEJ) DNA repair. This article describes recent evidence supporting strategies in addition to BRCA mutation for selecting patients for treatment with PARP inhibitor therapy. Additionally, the challenges and opportunities of exploiting DNA repair pathways other than homologous recombination for molecular therapy in gynecologic cancers is discussed.

Phase 2 biomarker-driven study of ipilimumab plus nivolumab (Ipi/Nivo) for ARV7-positive metastatic castrate-resistant prostate cancer (mCRPC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5035-5035 ◽  
Author(s):  
Karim Boudadi ◽  
Daniel L. Suzman ◽  
Brandon Luber ◽  
Hao Wang ◽  
John Silberstein ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Response Rate ◽  
Objective Response ◽  
Gene Mutations ◽  
Immune Checkpoint Blockade ◽  
Phase 2 ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Castrate Resistant

5035 Background: ARV7+ mCRPC is an aggressive phenotype with a median PFS of 3-4 mo and OS of 7-9 mo. We hypothesized that ARV7+ tumors would be enriched for DNA repair mutations, rendering them more responsive to combined immune checkpoint blockade. Methods: We enrolled 15 mCRPC pts with ARV7+ CTCs (using a CLIA-certified assay) into a single arm phase 2 study. Pts received Nivo 3 mg/kg plus Ipi 1 mg/kg every 3 wk x 4 doses, then maintenance Nivo 3 mg/kg every 2 wk. Targeted sequencing for DNA repair defects was performed on pretreatment tumor biopsies (n=11) or cell-free DNA (n=4). Primary endpoint: PSA50response rate. Secondary endpoints: objective response rate (ORR) in pts with measurable disease, durable PFS (lack of progression ≥24 wk), PSA‐PFS, radiographic (r)PFS, overall survival (OS), and frequency/intensity of AEs. Results: 15 ARV7+ men were enrolled, with median f/u 8.4 (range 1.9–10.5) mo. Median age was 65, 47% had ECOG ≥1, median PSA was 115 ng/mL, 67% had visceral/nodal mets, all had bone mets, and 60% had ≥4 prior regimens for mCRPC. Mean ARV7/AR ratio was 23% (range 3–75%). 6/15 men (40%) had pathogenic DNA repair gene mutations ( BRCA2, ATM, MSH6, FANCM, FANCA, POLH). Overall, the PSA50rate was 1/15 (7%), ORR was 2/8 (25%), durable PFS rate was 3/15 (20%), PSA-PFS was 3.0 (95%CI 2.1–4.9) mo, rPFS was 3.9 (95%CI 2.8–5.5) mo, and OS was 9.5 (95%CI 7.2–NA) mo. Outcomes appeared better in DNA repair deficient (DRD+) tumors vs. DNA repair proficient (DRD–) tumors (TABLE). 15 grade 3-4 treatment-related AEs occurred in 7/15 (46%) men (including 2 hepatitis, 2 colitis, 1 pneumonitis); there were no treatment-related deaths. Conclusions: In this first study targeting ARV7+ mCRPC, treatment with Ipi/Nivo had acceptable safety and encouraging efficacy, particularly in men with DRD+ tumors. DNA repair mutations may be enriched in ARV7+ prostate cancer. Clinical trial information: NCT02601014. [Table: see text]

Outcomes of talazoparib (TALA) versus physician's choice of chemotherapy (PCT) in patients (pts) with advanced breast cancer (ABC) and a germline BRCA (gBRCA) mutation by line of chemotherapy (CT) in the EMBRACA trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1071-1071
Author(s):  
Johannes Ettl ◽  
Sara A. Hurvitz ◽  
Hope S. Rugo ◽  
Kyung-Hun Lee ◽  
Lida A. Mina ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcomes ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Unmet Need ◽  
Progression Free Survival ◽  
Free Survival ◽  
Hormone Receptor Positive ◽  
The Us ◽  
Intent To Treat

1071 Background: The PARP inhibitor TALA was approved in the US for treatment of g BRCA-mutated ABC based in part on the EMBRACA study. Understanding the outcomes of EMBRACA pts relative to prior CT is a current unmet need. Methods: EMBRACA was a randomized Phase 3 trial comparing TALA 1 mg daily vs PCT (capecitabine, eribulin, gemcitabine, vinorelbine) in g BRCA-mutated ABC. Clinical outcomes were assessed by line of prior CT for ABC in intent-to-treat (ITT), triple-negative breast cancer (TNBC), and hormone receptor-positive (HR+) breast cancer cohorts. Results: 431 pts were randomized (ITT; TALA 287; PCT: 144). TALA was generally more effective than PCT across efficacy endpoints regardless of line of CT (Table). For the ITT population, TALA improved progression-free survival (PFS) and objective response rate (ORR) vs PCT for each line of CT assessed. Other prespecified subgroups (TNBC and HR+) will be presented. Conclusions: In pts with g BRCA-mutated ABC, TALA demonstrated improvements in clinical outcomes compared with PCT regardless of prior lines of CT. Clinical trial information: NCT01945775. [Table: see text]

TRITON3: An international, randomized, open-label, phase III study of the PARP inhibitor rucaparib vs. physician’s choice of therapy for patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination deficiency (HRD).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS389-TPS389 ◽  
Author(s):  
Charles J. Ryan ◽  
Wassim Abida ◽  
Alan Haruo Bryce ◽  
Arjun Vasant Balar ◽  
Igor Dumbadze ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Radiographic Progression ◽  
Objective Response ◽  
Phase Iii ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Patient Reported ◽  
Brca1 Brca2

TPS389 Background: Recent data have shown that up to 25% of patients with advanced prostate cancer, including mCRPC, have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or another homologous recombination DNA repair gene. Such mutations can be used as a molecular marker to select patients for targeted treatment with poly(ADP-ribose) polymerase inhibitors (PARPis), which are lethal to cells with HRD. Treatment with PARPis has shown preliminary evidence of antitumor activity in patients with mCRPC and a mutation in a homologous recombination DNA repair gene (Mateo et al. N Engl J Med. 2015;373:1697-708). These data provide a compelling rationale for evaluating rucaparib, a potent inhibitor of PARP1, PARP2, and PARP3, in patients with mCRPC associated with HRD. Methods: TRITON3 (NCT02975934) is a randomized, phase 3 study evaluating rucaparib 600 mg BID vs physician’s choice of abiraterone, enzalutamide, or docetaxel in patients with mCRPC and a deleterious germline or somatic BRCA1, BRCA2, or ATM mutation (identified by prior local testing or central testing during screening). Patients must have progressed on androgen receptor signaling–directed therapy in the mCRPC setting; prior PARPi treatment or chemotherapy for mCRPC are exclusion criteria. Patients will be randomly assigned in a 2:1 ratio to either rucaparib or physician’s choice, with the possibility for cross over from the comparator treatment to rucaparib upon radiographic progression confirmed by independent radiology review. The primary endpoint is radiographic progression-free survival (modified RECIST v1.1/PCWG3 criteria) assessed by independent radiology review. Secondary endpoints include objective response rate, duration of response, patient-reported outcomes, overall survival, and safety. Pretreatment blood samples collected from all patients will enable development of a noninvasive plasma-based companion diagnostic to select patients who may benefit from rucaparib treatment. Patients (≈400) will be enrolled at > 100 sites worldwide. Clinical trial information: NCT02975934.

A phase Ib/II study of niraparib combination therapies for the treatment of metastatic castration-resistant prostate cancer (NCT03431350).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5087-TPS5087 ◽  
Author(s):  
Sumit Kumar Subudhi ◽  
Ana Aparicio ◽  
Amado J. Zurita ◽  
Bernard Doger ◽  
William Kevin Kelly ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Parp Inhibitor ◽  
Rapid Identification ◽  
Abiraterone Acetate ◽  
Parp Inhibition ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Castration Resistant ◽  
Abstract Submission

TPS5087 Background: Assessing multiple therapies in a single clinical trial can facilitate the rapid identification of new agents for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). Niraparib (Nirap) is a highly selective PARP inhibitor, with potent activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair polymerases. PARP inhibition may be especially lethal in tumor cells with genetic DNA damage response deficits (DRD). Based on promising preclinical and clinical data, this study is designed as a master protocol with nirap as a backbone therapy. Combination 1 assesses the safety and efficacy of nirap plus JNJ-63723283 (JNJ-283), an anti-PD-1 monoclonal antibody. Combination 2 assesses nirap plus abiraterone acetate and prednisone (AA-P). Methods: This multicenter, global, open-label study is currently open at 18 sites in 5 countries of the planned XX sites, and is enrolling patients with mCRPC who have progressed on ≥1 androgen-receptor targeted therapy for mCRPC. Enrollment at time of abstract submission was 25 for combination 1. When combined with AA-P, the RP2D has been determined to be nirap 200 mg. The recommended phase-2 dose (RP2D) of nirap plus JNJ-283 was determined in Part 1 based on the incidence of specified adverse events and PK data to be 480 mg every 4 weeks. For Part 2 of the study, patients are assigned to receive oral niraparib daily plus JNJ-283 infusions once every four weeks until disease progression, unacceptable toxicity, death, study termination. Part 2 is described in the table. Clinical trial information: NCT03431350. [Table: see text]

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