Combination Of Niraparib Research Articles

Open-label, phase 2 study of adebrelimab combined with fuzuloparib in the treatment of patients with HRD-positive, recurrent platinum-resistant ovarian cancer.

TPS5634 Background: Adebrelimab, a humanized anti-PD-L1 monoclonal antibody, selectively targets PD-L1 molecules to inhibit the PD-1/PD-L1 pathway, reversing tumor-induced immune tolerance and revitalizing the immune system's capacity to combat tumors. Fuzuloparib, a novel PARP inhibitor, impedes the activity of poly (ADP-ribose) polymerase, halting the DNA repair mechanism for single-stranded breaks, resulting in DNA damage accumulation and consequent cancer cell apoptosis. Emerging evidence strongly supports that PARP inhibitors significantly extend progression-free survival in homologous recombination-deficient (HRD)-positive ovarian cancer. The TOPACIO study demonstrated that the combination of niraparib and pembrolizumab for platinum-resistant ovarian cancer achieved an objective response rate (ORR) of 18%, with durable responses in patients. This underscores the potential of integrating PARP inhibitors with immune checkpoint inhibitors in clinical protocols. For platinum-resistant recurrent ovarian cancer, known for its challenging prognosis, we propose conducting exploratory clinical trials on the combination of adebrelimab and fuzuloparib, aiming to establish robust evidence for future clinical applications. Methods: This open-label, single-arm, Phase 2 study aims to evaluate the anti-tumor activity and safety of adebrelimab in combination with fuzuloparib in approximately 37 patients with HRD-positive, recurrent platinum-resistant epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer (hereinafter referred to as ovarian cancer). The primary endpoint is to determine the objective response rate of the combined treatment regimen, as defined by the Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints encompass disease control rate, progression-free survival overall survival, along with the assessment of safety and tolerability. Patients must be aged 18-70 years with an Eastern Cooperative Oncology Group performance status of 0–1 and have recurrent histologically confirmed ovarian cancer with HRD-positive tumor. Patients must have progressed within less than 6 months after the last treatment with platinum-containing chemotherapy. HRD status confirmed by testing BRCA gene, loss of heterozygosity, telomeric allelic imbalance and large-scale transition. Adebrelimab (20 mg/kg) is administered intravenously every 3 weeks and fuzuloparib (100mg) is administered orally twice daily as until the patient experiences disease progression, intolerable toxicity, or other study treatment discontinuation criteria are met. This clinical trial is in progress and 7 patients have been enrolled. Clinical trial information: NCT05753826 .

Demonstrating Bioequivalence for Two Dose Strengths of Niraparib andAbiraterone AcetateDual-Action Tablets Versus Single Agents: Utility of Clinical Study Data Supplemented with Modeling and Simulation.

The combination of niraparib and abiraterone acetate (AA) plus prednisone is under investigation for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC). Regular-strength (RS) and lower-strength (LS) dual-action tablets (DATs), comprising niraparib 100 mg/AA 500 mg and niraparib 50 mg/AA 500 mg, respectively, were developed to reduce pill burden and improve patient experience. A bioequivalence (BE)/bioavailability (BA) study was conducted under modified fasting conditions in patients with mCRPC to support approval of the DATs. This open-label randomized BA/BE study (NCT04577833) was conducted at 14 sites in the USA and Europe. The study had a sequential design, including a 21-day screening phase, a pharmacokinetic (PK) assessment phase comprising three periods [namely (1) single-dose with up to 1-week run-in, (2) daily doseon days 1-11, and (3) daily dose ondays 12-22], an extension where both niraparib and AA as single-agent combination (SAC; reference) or AA alone was continued from day 23 until discontinuation, and a 30-day follow-up phase. Patients were randomly assigned in a parallel-group design (four-sequence randomization) to receive a single oral dose of niraparib 100 mg/AA 1000 mg as a LS-DAT or SAC in period 1, and patients continued as randomized into a two-way crossover design during periods 2 and 3 where they received niraparib 200 mg/AA 1000 mg once daily as a RS-DAT or SAC. The design was powered on the basis of crossover assessment of RS-DAT versus SAC. During repeated dosing (periods 2 and 3, and extension phase), all patients also received prednisone/prednisolone 5 mg twice daily. Plasma samples were collected for measurement of niraparib and abiraterone plasma concentrations. Statistical assessment of the RS-DAT and LS-DAT versus SAC was performed on log-transformed pharmacokinetic parameters data from periods 2 and 3 (crossover) and from period 1 (parallel), respectively. Additional paired analyses and model-based bioequivalence assessments were conducted to evaluate the similarity between the LS-DAT and SAC. For the RS-DAT versus SAC, the 90% confidence intervals (CI) of geometric mean ratios (GMR) for maximum concentration at a steady state (Cmax,ss) and area under the plasma concentration-time curve from 0-24 h at a steady state (AUC 0-24h,ss) were respectively 99.18-106.12% and 97.91-104.31% for niraparib and 87.59-106.69 and 86.91-100.23% for abiraterone. For the LS-DAT vs SAC, the 90% CI of GMR for AUC0-72h of niraparib was 80.31-101.12% in primary analysis, the 90% CI of GMR for Cmax,ss and AUC 0-24h,ss of abiraterone was 85.41-118.34% and 86.51-121.64% respectively, and 96.4% of simulated LS-DAT versus SAC BE trials met the BE criteria for both niraparib and abiraterone. The RS-DAT met BE criteria (range 80%-125%) versus SAC based on 90% CI of GMR for Cmax,ss and AUC 0-24h,ss. The LS-DAT was considered BE to SAC on the basis of the niraparib component meeting the BE criteria in the primary analysis for AUC 0-72h; abiraterone meeting the BE criteria in additional paired analyses based on Cmax,ss and AUC 0-24h,ss; and the percentage of simulated LS-DAT versus SAC BE trials meeting the BE criteria for both. NCT04577833.

Arterial hypertension associated with PARPi: A meta-analysis of 41 placebo randomized controlled trials combined with a World Health Organization's pharmacovigilance study.

Arterial hypertension has been recently reported from randomized controlled trials (RCTs) assessing poly (ADP-ribose) polymerase inhibitor (PARPi). In a context of increasing use of PARPi, it is crucial to properly assess risk and incidence of this adverse event for clinical practice. We performed a systematic review and meta-analysis in MEDLINE, Cochrane CENTRAL and ClinicalTrials.gov up to January 4, 2023 with an ongoing surveillance up to June 7, 2023. RCTs comparing PARPi to placebo in adult patients with solid tumors were included if hypertension was reported. The primary outcome was the summary risk ratio (RR, with 95% CIs) of any hypertension of PARPi class in placebo RCTs. Secondary outcomes were the summary risk and incidence of hypertension of each individual PARPi. To provide clinical features of PARPi-associated hypertension, we independently queried the WHO's pharmacovigilance database, up to September 1, 2022. In total, 41 placebo RCTs (n = 15 264 adult patients) were included. PARPi class was not associated with an increased risk of hypertension compared with placebo. In individual analyses, the risk of hypertension was lower with olaparib than placebo (RR 0.77 [95% CI: 0.68-0.86], P < 0.01; I2= 19%, χ2 P = 0.26). Niraparib monotherapy increased the risk of any (RR 2.84 [95% CI: 1.76-4.57], P < 0.01; I2= 66%, χ2 P = 0.01) hypertension with a summary incidence of 19.87% (95% CI: 15.23-25.50). In real-life setting, niraparib-associated hypertension occurs within 20 days and was serious in 66%. Co-prescription of at least one antihypertensive or therapy-induced hypertension was reported in 20.5% or 14.4% of cases, respectively. In a context of extensive assessment of niraparib in combination, these data reinforce the need of a close monitoring of this adverse event to preserve its clinical benefit on patients' survival.

AGO-OVAR 28/ENGOT-ov57. Niraparib alone versus niraparib in combination with bevacizumab in patients with carboplatin-taxane-based chemotherapy in advanced ovarian cancer: a multicenter randomized phase III trial

BackgroundPhase III trial data have shown a significant benefit by the addition of a maintenance treatment with niraparib, irrespective of BRCA or HRD status, in patients with advanced high-grade ovarian...

A Combined Phase 0/2 "Trigger" Trial of Niraparib in Combination with Radiation in Patients with Newly-Diagnosed Glioblastoma

Poly ADP-ribose (PAR) polymerase (PARP) mediates DNA damage response. Niraparib is an investigational PARP1/2-selective inhibitor. We conducted a combined phase 0/2 study to evaluate niraparib pharmacokinetics (PK) and pharmacodynamics (PD) in patients with newly-diagnosed glioblastoma (GBM), graduating patients to a phase 2 study evaluating a therapeutic regimen of niraparib with concurrent conventionally-fractionated radiotherapy (RT) in O6-methylguanine methyltransferase (MGMT) unmethylated tumors exceeding a prespecified PK threshold in non-enhancing tumor. Patients with presumed newly-diagnosed GBM were enrolled in a phase 0 study receiving 4 days of niraparib (300 or 200 mg QD) prior to planned resection 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after 10 Gy ex vivo irradiation in surgical tissue compared to non-irradiated control tissue. A PK 'trigger' determined eligibility for the therapeutic phase 2 expansion portion of the study. This was defined as unbound [niraparib] > 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors exceeding this PK threshold were eligible for expansion phase dosing of niraparib with concurrent RT followed by a maintenance phase of niraparib. Patients with MGMT methylated tumors were not eligible for the expansion phase and proceeded with temozolomide (TMZ) plus RT followed by maintenance TMZ. RT dose was 60 Gy in 30 fractions using volumetric-modulated arc therapy (VMAT). All 29 patients enrolled in the phase 0 portion of the study met the PK threshold. In non-enhancing regions, the mean unbound concentration of niraparib was 258.2 nM. The suppression of PAR levels after ex vivo RT was observed in 79% of the patients (17/22). Sixteen patients had unmethylated tumors, and of those, 11 patients enrolled in phase 2. Five of the 6 initial patients enrolled in phase 2 experienced thrombocytopenia related to niraparib, and 3/5 cases were deemed serious and life-threatening. Consequently, starting dose in both phases was lowered to 200 mg, and no serious AEs were observed thereafter. At a median follow-up of 8.1 months [range: 6.0-12.9 months], 6-month PFS was 64% with 4 patients remaining on treatment and 5 patients ongoing survival follow-up. Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor. When delivered with concurrent RT, niraparib was well-tolerated, with low rates of grade 3+ toxicity. Initial clinical efficacy data are encouraging.

Efficacy and safety of niraparib in combination with anlotinib based on CA 125 level in newly diagnosed ovarian cancer: An open-label, single arm, multicenter, prospective phase II trial (1279)

Efficacy and safety of niraparib in combination with anlotinib based on CA 125 level in newly diagnosed ovarian cancer: An open-label, single arm, multicenter, prospective phase II trial (1279)

A phase 1 evaluation of the safety and tolerability of niraparib in combination with everolimus in advanced ovarian and breast cancers.

Phase 1 trial to determine the safety and tolerability of everolimus and niraparib in patients with advanced ovarian and breast malignancies. Fourteen heavily pretreated patients were enrolled (12 high-grade serous ovarian cancer, 1 clear cell ovarian cancer, and 1 triple negative breast cancer). All patients were PARP naïve and received comprehensive genomic profiling prior to enrollment. Two DLTs were experienced in cohort 2 (niraparib 200 mg daily and everolimus 5 mg 3 days per week) with one patient experiencing prolonged thrombocytopenia and the other experiencing severe hypertension. Four additional patients were enrolled after dose de-escalation with one patient again experiencing severe hypertension leading to conclusion of the study. The most frequent grade 3 or greater adverse events were thrombocytopenia, hypertension, anemia, fatigue, neutropenia, and elevated alkaline phosphatase. Two patients had a PR and five patients had SD. ORR was 18% and the CBR was 45% in 11 evaluable patients. Median PFS was 6 months, and median OS is approximately 18 months with three patients still alive at the data cutoff. The combination of everolimus and niraparib demonstrated significant toxicity at lower doses and is not feasible due to rapid onset and severe hypertension. This limitation possibly blunted the efficacy of the combination as PFS was modest, but OS was surprisingly robust due to three patients with ovarian cancer remaining alive with platinum refractory disease. Further investigation of multiagent blockade of the PI3K pathway combined with PARP is warranted.

A combination of niraparib plus anlotinib in patients with platinum-resistant ovarian clear cell carcinoma: Results of a single-arm phase II study (CC-ANNIE study).

e17552 Background: Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer with distinct biological and molecular characteristics. Patients with platinum-resistant OCCC have a poor prognosis and their treatment represents a significant unmet medical need. Studies have suggested potential efficacy of targeting DNA damage response pathways and inhibition of angiogenesis in OCCC. We hypothesised that patients with platinum-resistant OCCC might benefit from a combination of the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib and the anti-angiogenic agent anlotinib. Methods: This was a phase II, single-arm, two-stage study with a Simon’s two-stage optimal design. The trial could continue to stage 2 if ≥1 responses were observed in the first 6 patients. Eligible patients had histologically confirmed OCCC that was platinum resistant, defined as progression within 6 months after their most recent platinum-based chemotherapy. Use of prior bevacizumab was permitted but prior PARP inhibitor or tyrosine kinase inhibitor treatments were not. Patients received niraparib (300 mg/day or 200 mg/day [baseline body weight &lt; 77 kg, platelet count &lt; 150,000/μL], orally) plus anlotinib (10 mg/day, orally, 2 weeks on and 1 week off, every 3 weeks) until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) assessed by investigators according to the RECIST V.1.1. Secondary endpoints included disease control rate (DCR), time to response (TOR), duration of response (DOR), safety and investigator-assessed progression-free survival (PFS) and overall survival (OS). Results: Between January 2022 and August 2022, 6 eligible patients were enrolled and included in the analyses. The median duration of treatment was 9.8 (range, 6.5 to 19.0) weeks. Of the 6 patients, 0 patients (0%) achieved an objective response, resulting in a confirmed ORR of 0%. The DCR was 50% (0 complete response, 0 partial response, 3 stable disease). With a median follow-up time of 7.5 (range, 3.5 to 10.0) months, all patients experienced disease progression, with a median PFS of 12.0 (95% confidence interval [CI], 3.6 to 20.4) weeks. Frequent treatment-related adverse events (AEs) included hypertension (33.3%), thrombocytopenia (33.3%), and hand-foot syndrome (16.6%). Conclusions: The phase 2 CC-ANNIE study did not meet the primary efficacy endpoint. The combination of niraparib and anlotinib did not show activity in patients with platinum-resistant OCCC. Clinical trial information: NCT05130515 .

Clinical outcome and biomarker assessments of a multi-centre phase II trial assessing niraparib with or without dostarlimab in recurrent endometrial carcinoma

This multi-centre, non-randomized, open-label, phase II trial (NCT03016338), assessed niraparib monotherapy (cohort 1, C1), or niraparib and dostarlimab (cohort 2, C2) in patients with recurrent serous or endometrioid endometrial carcinoma. The primary endpoint was clinical benefit rate (CBR), with ≥5/22 overall considered of interest. Secondary outcomes were safety, objective response rate (ORR), duration of response, progression free survival and overall survival. Translational research was an exploratory outcome. Potential biomarkers were evaluated in archival tissue by immunohistochemistry and next generation sequencing panel. In C1, 25 patients were enrolled, and CBR was 20% (95% CI: 9–39) with median clinical benefit duration of 5.3 months. The ORR was 4% (95% CI: 0–20). In C2, 22 patients were enrolled, and the CBR was 31.8% (95% CI: 16–53) with median clinical benefit duration of 6.8 months. The ORR was 14% (95% CI: 3–35). No new safety signals were detected. No significant association was detected between clinical benefit and IHC markers (PTEN, p53, MMR, PD-L1), or molecular profiling (PTEN, TP53, homologous recombination repair genes). In conclusion, niraparib monotherapy did not meet the efficacy threshold. Niraparib in combination with dostarlimab showed modest activity.

Anti-tumour and radiosensitising effects of PARP inhibitor on cervical cancer xenografts

This study evaluated the radiosensitising effect of niraparib; a poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor on HeLa cervical cancer cells in nude mice and explored its possible mechanism. Twenty-four 3–5-week-old female BALB/c nude mice, inoculated with HeLa cells into the right hind leg, were randomly assigned into eight groups with three mice per group and treated. The tumour volume was significantly reduced under niraparib + radiotherapy combination as compared to monotherapy and untreated mice. The tumour growth was significantly delayed by 23.33–39 days when treated with combination therapy (p<.05). Further, univariate analysis revealed prolonged time for tumour growth when radiotherapy was followed by niraparib (I.G.) rather than niraparib (I.P.) (p=.003). Combination therapy reduced levels of PARP-1 precursor, PARP-1 splicer, PAR and RAD51 protein with high expression of γ-H2AX/CC3 and low expression of Ki-67. Niraparib in combination with radiotherapy can enhance the formation of DNA double strand breaks in HeLa cells and up regulate the expression of γ-H2AX/CC3. IMPACT STATEMENT What is already known on this subject? Asia has the highest incidence of cervical cancer (58.2%). Poly(adenosine diphosphate-ribose) polymerases (PARPs) are family of enzymes involved in single-strand break (SSB) and double-strand break (DSB) repair pathways. Niraparib is an effective inhibitor of both PARP-1 and PARP-2 and has the ability to cross the blood–brain barrier. What the results of this study add? Our study demonstrated that the combination of niraparib and radiotherapy can significantly enhance the cytotoxicity induced by radiotherapy. The inhibition effect of radiotherapy combined with niraparib on the tumour growth of mice was prominent, thereby establishing the radio-sensitisation activity of niraparib. What are the implications of these findings for clinical practice and/or further research? Niraparib can improve the cytotoxic effect of radiotherapy by increasing the formation of DSBs and up regulating the expression of apoptotic protein in HeLa cells.

A novel combination of niraparib and anlotinib in platinum-resistant ovarian cancer: Efficacy and safety results from the phase II, multi-center ANNIE study

Patients with platinum-resistant recurrent ovarian cancer (PROC) face poor prognosis and limited treatment options. Single-agent antiangiogenics and poly (ADP-ribose) polymerase (PARP) inhibitors both show some activities in platinum-resistant diseases. The ANNIE study aimed to evaluate the efficacy and safety of the novel combination of the PARP inhibitor niraparib and the antiangiogenic anlotinib in patients with PROC. ANNIE is a multicentre, single-arm, phase 2 study (ClinicalTrials.gov identifier NCT04376073) conducted at three hospitals in China. Eligible patients had histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal cancer that recurred within 6 months of last platinum-based chemotherapy. Patients with prior PARP inhibitor exposure were excluded. The enrolled patients received oral niraparib 200mg or 300mg (baseline body weight-directed) once daily continuously and anlotinib 10mg (12mg before protocol amendment) once daily on days 1-14 of each 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR). Between May 22, 2020, and April 22, 2021, 40 patients were enrolled and treated. Thirty-six patients underwent post-baseline tumour assessments. By data cut-off (January 31, 2022), median follow-up was 15.4 months (95% CI 12.6-17.7). Intention-to-treat ORR was 50.0% (95% CI 33.8-66.2), including one complete response and 19 partial responses. Median (95% CI) progression-free survival and overall survival were 9.2 months (7.4-11.9) and 15.3 months (13.9-not evaluable), respectively. Drug-related, grade ≥3 TEAEs were reported in 26 (68%) patients. There were no treatment-related deaths. Niraparib plus anlotinib showed promising antitumour activity in patients with PROC. This oral combination warrants further investigation as a potential novel, convenient treatment option for patients with PROC. Zai Lab (Shanghai) Co., Ltd; Jiangsu Chia Tai-Tianqing Pharmaceutical Co., Ltd; the National Natural Science Foundation of China (No. 82102783).

A novel combo of niraparib and anlotinib in platinum-resistant ovarian cancer, the final efficacy and safety report of ANNIE study, a phase II, multi-center trial (LBA 2)

<b>Objectives:</b> Patients with platinum-resistant ovarian cancer have a poor prognosis. Effective treatment options for these patients are limited. In this study (ANNIE), we evaluated the efficacy and safety of niraparib combined with anlotinib in patients with platinum-resistant recurrent (PRR) epithelial ovarian, fallopian tubal, or primary peritoneal cancer. <b>Methods:</b> The ANNIE trial (ClinicalTrials.gov identifier NCT04376073) was a multicentre, single-arm, phase 2 study. The patients with PRR and the measurable disease were given oral niraparib 300mg/200mg once daily continuously and anlotinib 12mg/10mg/8mg on day 1-14 of each 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR) according to RECIST version 1.1. An exploratory analysis of archival peripheral blood was conducted in an attempt to analysis the correlation between circulating tumor markers and prognosis. <b>Results:</b> Between May 22, 2020, and April 22, 2021, 40 patients were finally enrolled. The subjects had previously received a median 4 lines (range, 1-9) of chemotherapy. Only 5 subjects had a deleterious germline <i>BRCA</i>1/2 mutation. At the cutoff date of analysis on December 31, 2021, 7 subjects were still on treatment. Thirty-six subjects underwent imaging evaluation. The confirmed best overall response showed 1 case with complete responses, 19 with partial responses, yielding the ORR of 55.6% (95% CI, 38.1%~ 72.1%). The median progression-free survival was 8.3 (95% CI, 5.86~ 10.81) months. The median overall survival was not reached. The most common drug-related adverse events were hypertension (55.0%), leucopenia (45.0%) and hand-foot syndrome (42.5%), and the most common Grade 3/4 events were neutropenia (17.5%), hypertension (12.5%) and anemia (12.5%). No treatment-related death was recorded. Preliminary analysis showed that patients with wild-type <i>PPM1D</i> had more significant changes in tumor size than those with <i>PPM1D</i> mutation (<i>P</i> =0.048). Further analysis of biomarkers and treatment prognostic results is ongoing and released soon. <b>Conclusions:</b> Niraparib in combination with anlotinib showed promising antitumor activity and tolerable toxicity in patients with platinum-resistant recurrent ovarian cancer.Fig. 1

Abstract 2606: ZN-c3, a potent and selective Wee-1 inhibitor demonstrates anti-tumor activities in combination with other targeted therapies and overcomes PARP inhibitor resistance

Abstract Inhibition of the DNA damage response (DDR) pathway is an attractive approach to target cancers cells. Unlike normal cells which relay on two cell cycle checkpoints to repair DNA damage, most tumor cells only depend on the G2 checkpoint because their G1 checkpoint is defective. Wee1 regulates the G2/M checkpoint and abrogating the G2 checkpoint by inhibiting Wee-1 in cancer cells with DNA damage can preferentially sensitize cancer cells to undergo mitotic catastrophe. We have developed and characterized ZN-c3, a potent and selective Wee-1 inhibitor with a differentiated kinase selectivity and pharmacokinetics profile. ZN-c3 was evaluated in ER-positive, triple negative, triple negative PARP inhibitor resistant, and Her-2 positive trastuzumab resistant breast cancers. In the ER-positive MCF-7 efficacy model, ZN-c3 demonstrated anti-tumor activity as a single agent as well as in combinations with a CDK4/6 inhibitor (Palbociclib) or ZN-c5, a selective estrogen receptor degrader (SERD). In the MDA-MB-436, a triple negative breast cancer tumor xenograft model, ZN-c3 demonstrated efficacy as a single agent and in combination with the PARP inhibitors Olaparib or Niraparib. We extended these combination studies by evaluating the efficacy of Niraparib in combination with ZN-c3 in patient-derived xenograft (PDX) triple negative breast tumors. ZN-c3 was efficacious as a single agent and the efficacy was enhanced in the combination with Niraparib. PARP inhibitors are effective and have been approved for treatment of some cancer types. However, most patients develop resistance to these agents. We sought to investigate whether ZN-c3 can overcome the acquired resistance to PARP inhibitors (Olaparib and Niraparib). We generated PARP inhibitor resistant breast tumor xenograft models. A significant tumor growth inhibition was observed in these resistant tumor xenograft models when treated with ZN-c3. These data suggest that ZN-c3 as a single agent can overcome the acquired PARP inhibitor resistance. Finally, we also evaluated ZN-c3 activity in a HER-2 positive trastuzumab resistant breast tumor xenograft model (JIMT-1) and ZN-c3 showed anti-tumor activity alone and in combination with trastuzumab. In summary, these results demonstrate that ZN-c3 is effective as a single agent and in combination with other targeted therapies in breast cancer models. Moreover, ZN-c3 can overcome the acquired resistance to PARP inhibitors and trastuzumab. ZN-c3 is currently in clinical trials for several indications and has demonstrated promising clinical activity and good tolerability. Citation Format: Jiali Li, Jianhui Ma, Petrus R. de Jong, Hooman Izadi, Tiffany Hoang, Noah Ibrahim, Brant Boren, Sayee Hegde Hegde, Fernando Doñate, Ahmed A. Samatar. ZN-c3, a potent and selective Wee-1 inhibitor demonstrates anti-tumor activities in combination with other targeted therapies and overcomes PARP inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2606.

Abstract 52: Analytical validation of the Resolution HRD plasma assay used to identify mCRPC patients with mutations, including homozygous deletions, in DNA repair genes as a companion diagnostic for niraparib

Abstract Tumor cells of metastatic castration-resistant prostate cancer (mCRPC) patients with homologous recombination deficiency (HRD) are highly sensitive to the blockade of DNA single-strand break repair via the inhibition of the poly(adenosine diphosphate-ribose) polymerase (PARP) family of nuclear proteins. Niraparib is a highly selective PARP inhibitor, with activity against PARP-1/2 DNA-repair polymerases, and the Resolution HRD assay is being developed as a companion diagnostic for niraparib. Detection of HRD in cell free DNA (cfDNA) isolated from blood is minimally invasive and is of special benefit to mCRPC patients, many without accessible lesions. The Resolution HRD assay identifies patients with substitutions, insertions, deletions, and homozygous deletions of the ATM, BRCA1, BRCA2, BRIP1, CDK12 (except homozygous deletions), CHEK2, FANCA, HDAC2, and PALB2 genes by targeted NGS sequencing of cfDNA isolated from plasma. Analytical performance of the Resolution HRD assay was validated using cfDNA from mCRPC patient plasma, cfDNA from healthy donor plasma, and contrived samples with a wide spectrum of technically challenging genetic aberrations along with CRISPR-engineered human cell lines with ATM and BRCA2 gene deletions. The LOD95 was established for substitutions, insertions, deletions, and homozygous deletions for genes represented in the HRD panel with variant types including complex indels, long indels, and challenging genomic settings including homopolymeric and GC-rich regions. mCRPC specimens were used to confirm an acceptable level of precision near 1X LOD and 2-3X LOD concentrations for all 4 variant types. No false-positives were detected in any samples from healthy donors. Resolution HRD has been validated to give consistent results across the 15-30 ng input range. Studies to confirm accuracy of the Resolution HRD test results using a validated orthogonal method will be presented. The Resolution HRD assay offers highly sensitive, specific, and robust test results, and meets analytical requirements for clinical applications. It is intended as a companion diagnostic to niraparib in combination with abiraterone acetate plus prednisone (AAP) for the treatment of mCRPC patients. Citation Format: Julia Pollak, Kristy Potts, PuiYee Chan, Chen-Hsun Tsai, Angela Liao, Carly Garrison, Taylor Brown, Paul Stull, Zhen Li, Christine Baker, Kavita Garg, Ira Pekker, Michael Farabaugh, Michael Gormley, Lesley Farrington, Katherine Bell, Usha Singh. Analytical validation of the Resolution HRD plasma assay used to identify mCRPC patients with mutations, including homozygous deletions, in DNA repair genes as a companion diagnostic for niraparib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 52.

Abstract 5720: Niraparib enhances radiosensitivity of glioblastoma cells with proficient BRCA1/2 through proliferation-related nucleolar protein DDX21

Abstract Background Intrinsic resistance to irradiation is one of important factors leading to recurrence of glioblastoma (GBM) patients underwent standard treatment. The radiosensitization by various poly-(ADP-ribose)-polymerase (PARP) inhibitors have been intensively investigated in many solid tumor models especially harboring deficient BRCA1/2. However, the impact of a PARP1/2 inhibitor niraparib on radiosensitivity of glioblastoma cell lines with proficient BRCA1/2 and underling mechanisms has yet not been fully elucidated. Methods GDSC dataset with IC50 of PARP inhibitors and transcriptome profiles as well as NCI-60 cell lines with known survival fraction at 2 Gy (SF2) were used to deduce potential pathways by which PARP inhibitors suppress cell viability and confer radiosensitization through linear regression and reactome gene set enrichment analysis. Two GBM cell lines with proficient BRCA1/2, A172 and U-87-MG were used to evaluate IC50 and radiation dose enhancement factor DEF37 of niraparib by CCK8 experiment and clonogenicity assay. Changes in the distribution of cell cycle and DDX21 protein expression were analyzed with flow cytometry and western blot respectively. The involvement of DDX21 in the mechanism mediating radiosensization of niraparib was performed with small inference RNA experiment. Results Pathways relevant to ribosome biosynthesis and functions such as eukaryotic translation initiation, rRNA processing was found to be responsible for cytotoxicity of niraparib in 519 tumor cell lines. Moreover, mRNA expression of PARP1/2, genes participated in ribosome biosynthesis and homologous recombination (HR) were all significantly negatively associated with SF2 in 44 NCI-60 cell lines. The IC50 of niraparib in A172 and U-87-MG cell lines were 10.77±3.31 and 32.37±2.84 μM respectively. The DEF37 was established as 1.99 at 348 nM, 2.17 at 1044 nM for A172 cell line and 1.10 at 1056 nM, 1.44 at 3169 nM for U-87-MG cell line, respectively. Treatment with niraparib alone and in the combination with radiation (4 Gy) resulted in significant increase in fraction of G2 phase in both cell lines. Treatment with niraparib alone did not change protein expression level of DDX21 in both cell lines. However, knockdown of DDX21 with siRNA significantly reduced proliferation in U-87-MG cells. Niraparib at 1056 nM further decreased clonogenic number in the combination with 4 Gy radiation in U-87-MG cells compared with those treated with radiation alone. Importantly, knockdown of DDX21 resulted in significant increasing in clonogenic number of U-87-MG cells treated with radiation alone or the combination of niraparib and radiation compared with control cells. Conclusions Niraparib has radiosensitization effect for GBM cells with proficient BRCA1/2 at low concentration. DDX21 may be involved in the radiosensitization mechanism of niraparib. Citation Format: Jia Luo, He Xiao, Qian Chen, Yanlan Li, Chuan Chen, Mingying Geng. Niraparib enhances radiosensitivity of glioblastoma cells with proficient BRCA1/2 through proliferation-related nucleolar protein DDX21 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5720.

AGO-OVAR 28/ENGOT-ov57: Niraparib versus niraparib in combination with bevacizumab in patients with carboplatin-taxane based chemotherapy in advanced ovarian cancer—A multicenter, randomized, phase III trial.

TPS5612 Background: Standard of care chemotherapy in patients (pts) with advanced ovarian cancer (AOC) is the combination of carboplatin and paclitaxel. Data from the PRIMA trial has shown a significant benefit in pts by the addition of a maintenance treatment (MT) with niraparib irrespective of BRCA or HRD-status in high-grade ovarian cancers (OC). The PAOLA-1 trial evaluated MT in pts with AOC with the combination of olaparib and bevacizumab and has also shown a significant benefit compared to bevacizumab monotherapy. However, it is unclear if a PARP-inhibitor (PARPi) MT monotherapy is sufficient or if the addition of bevacizumab is needed. Therefore, we investigate, if the treatment strategy of carboplatin / paclitaxel / bevacizumab / PARPi is superior to the treatment of carboplatin / paclitaxel / PARPi in an all-comer population. Methods: AGO-OVAR 28/ ENGOT-ov57 (NCT05009082; EudraCT Number: 2021-001271-16) is an Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Study Group led, international, multicenter, randomized, prospective phase III trial within the ENGOT trial network. The trial population is composed of adult pts with newly diagnosed, advanced high-grade epithelial OC, primary peritoneal cancer or fallopian tube cancer FIGO III/IV (except FIGO IIIA2 without nodal involvement). All pts should have completed the first cycle of chemotherapy (carboplatin and paclitaxel) as part of Study Run-In-Period. Prior to day1 of cycle2, pts with a valid central tumor BRCA ( tBRCA) test result will be randomized 1:1 into either Arm1 and will receive 5 additional cycles of carboplatin and paclitaxel, q21d followed by niraparib for up to 3 years; or into Arm2 where pts will receive 5 additional cycles of carboplatin and paclitaxel plus bevacizumab, q21d followed by bevacizumab, q21d (for up to 1 year) and niraparib for up to 3 years. Patients who are scheduled for neoadjuvant chemotherapy and interval debulking surgery are also allowed to be included in the trial. The primary objective is progression free survival (PFS). Secondary objectives include but are not limited to: PFS according to tBRCA-status, overall survival, PFS2, safety and tolerability, and quality of life. The trial will start in Q1/2022 with First Patient First Visit expected in Q2/2022. It is planned to recruit 970 patients. Clinical trial information: NCT05009082.

A single-arm, phase II study of niraparib and bevacizumab maintenance therapy in patients with platinum-sensitive, recurrent ovarian cancer previously treated with a PARP inhibitor: Korean Gynecologic Oncology Group (KGOG 3056)/NIRVANA-R trial.

TPS5610 Background: Given the expanding clinical use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPis), there is a significant need for optimal strategies with which to treat patients whose cancer progresses while using a PARPi. However, the treatment consensus after PARPi has not been established. The aim of the Korean Gynecologic Oncology Group (KGOG) 3056/NIRVANA-R trial is to investigate the efficacy of niraparib in combination with bevacizumab as a maintenance therapy in platinum-sensitive ovarian cancer patients who were previously treated with a PARPi. Methods: The KGOG 3056/NIRVANA-R is a multi-centre, investigator-initiated, single-arm, phase II trial of patients with platinum-sensitive recurrent ovarian cancer recruited from seven KGOG sites. This study included patients with platinum-sensitive recurrent epithelial ovarian cancer who received at least 2 previous courses of platinum-containing therapy and had been treated with a PARPi. Mucinous histology type was excluded. Patients who had responded to the last platinum regimen (either complete or partial response) were eligible to participate in this study. Forty-four patients will be recruited. All enrolled patients are treated with niraparib and bevacizumab for maintenance therapy until disease progression, unacceptable toxicity, or withdrawal of patient consent. The primary endpoint of the study is 6-month progression-free survival rate and 4 of planned 44 patients have been enrolled. Clinical trial information: NCT04734665.

Abstract P2-07-13: High-dimensional, single-cell analysis and transcriptional profiling reveal novel correlatives of response to PARP inhibition plus PD-1 blockade in triple-negative breast cancer

Abstract Background: TOPACIO was a phase I/II study evaluating the PARP inhibitor (PARPi) niraparib in combination with the anti-PD-1 antibody pembrolizumab in patients with locally advanced and metastatic triple-negative breast cancer (TNBC, n=55) and ovarian cancer irrespective of BRCA mutation status. In the efficacy-evaluable population (n=47) the objective response rate (ORR) was 21% and disease control rate (DCR) 49%. Although activity was greater in patients with BRCA mutations (7/15, ORR=47% and 12/15, DCR=80%), durable clinical benefit was seen in patients with wild-type BRCA tumors (3/27, ORR=11% and 9/27, DCR=33%). In a limited cohort of 20 patients with durable clinical benefit, there were 8 BRCA wildtype patients, four of whom had mutations in genes associated with the homologous recombination repair and other DNA damage repair pathways. Pre-treatment tissues were collected and evaluated for tumor PD-L1 status. Patients with PD-L1 positive tumors (28/47, 60%) had a higher response rate (9/28, ORR=32%) than those with PD-L1 negative tumors (1/13, ORR=8%; 6 tumors had unknown PD-L1 status). It remains unstudied whether the tumor’s gene expression profile or immune status in baseline biospecimens is predictive of treatment response. In this study we conducted exploratory biomarker analyses to test the hypothesis that gene expression patterns and immune status are associated with treatment response. Methods: Transcriptional profiling of baseline samples was performed using the BC360 (n=41) and PanCancer IO360 (n=42) panels (Nanostring) and multigene signatures were used to measure tumor and immune activities as well as relative immune cell abundance. Transcriptional analysis was paired with high-dimensional, single-cell cyclic immunofluorescence (CyCIF) of samples that had adequate tissue for analysis (n=19) to characterize the composition and topology of the immune microenvironment at single-cell resolution. Results: Nanostring transcriptional analysis revealed that PAM50 genes stratified tumor samples into 4 subgroups with distinct histology as determined by CyCIF. Each subgroup was capable of responding to niraparib plus pembrolizumab. Multiple genes involved in WNT signaling (WNT5B, TANKS1, TANKS2, PARP4, and NET02) were associated with favorable clinical responses. Low neuropilin and tolloid-like protein 2 (NETO2) gene expression was strongly correlated with favorable progression free survival (PFS; R=-0.61, p=0.0008, Spearman’s correlation), suggesting it may be a predictive biomarker of therapeutic response. Nanostring gene expression signatures for tumor inflammation, apoptosis, and inflammatory chemokines also distinguished responders from non-responders (p&amp;lt;0.05). CyCIF analysis performed on whole tissue sections accounting for 2.97 million single cells revealed 43 distinct cell-states comprising the tumor microenvironment. PD1+CD4+ T cells were significantly correlated with extended PFS (R=0.65, p=0.006, Spearman’s correlation). However, PD1+CD4+ T cells were less abundant in patients who continue to respond to the therapy (2.7-fold reduced, p=0.004), suggesting two groups of responders. Conclusion: WNT signaling, NETO2 and PD1+CD4 T cells are candidate biomarkers for predicting response to niraparib plus pembrolizumab. Further studies are underway to characterize the biological underpinnings of these correlative findings. Citation Format: Jennifer L Guerriero, Gregory J Baker, Jia-Ren Lin, Yu-An Chen, Ricardo Pastorello, Tuulia Vallius, Janae Davis, Clarence Yapp, Sarah E Church, Eric Miller, Anniina Färkkilä, Shaveta Vinayak, Melinda L Telli, Giulia Fulci, Alan D'Andrea, Geoffrey I Shapiro, Sara M Tolaney, Sandro Santagata, Peter K Sorger, Elizabeth A Mittendorf. High-dimensional, single-cell analysis and transcriptional profiling reveal novel correlatives of response to PARP inhibition plus PD-1 blockade in triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-07-13.

A phase II study of niraparib and dostarlimab with radiation in patients with metastatic pancreatic cancer.

564 Background: PARP inhibitors have activity as monotherapy in BRCA1/2 mutated metastatic pancreatic cancer; however, several other genes and associated proteins exist in the homologous recombination repair (HRR) pathway promoting resistance to chemotherapy and radiation-induced damage. Tumors with HRR deficiency have an impaired ability to repair themselves and are susceptible to PARP inhibition, but ionizing radiation can also induce DNA breaks. Ongoing research suggests that PARP inhibitors may cause radio-sensitization and may also enhance sensitivity to immunotherapy. We conducted a phase 2 study of niraparib and dostarlimab with radiation in a biomarker unselected PDAC population given PARP inhibitors' immunomodulatory and radiosensitizing effects. Methods: In this open-label, single-arm, phase-2 study, eligible patients had histologically confirmed MSS PDAC, ECOG PS 0-1, and progressed on at least one line of jm. Treatment consisted of niraparib 200 mg daily on a 21-day cycle, dostarlimab 500 mg every 3 weeks every 4 weeks for the first four doses, then 1000 mg every 6 weeks, and 3 fractions of 8 Gy at Cycle 2. Treatment continued until progressive disease, discontinuation, or withdrawal. The primary endpoint was DCR by RECIST 1.1 with radiological evaluations every 3 months. Secondary endpoints included DCR by irRECIST, PFS, OS, and safety. Responses were defined as disease control outside the radiation field. We obtained serial tumor biopsies, including pre-treatment. A two-stage design was used, requiring disease control in at least one of the first 15 patients before proceeding to the full accrual of 25 patients. Intention to treat analysis included all patients receiving at least one dose of any study agent. Results: We enrolled and treated 15 pts (median age 60 years [range 37-77], 53% male) from 08/2020 to 05/2021. Overall, DCR was 0/15 (95% CI: 0-22%), median PFS was 1.6 months (95% CI: 1.1-2.7), and median OS 3.1 months (95% CI: 1.5-7.7). Among 27 treatment-related serious adverse events, 15 (56%) were grade 3, including decreased CD4 lymphocytes, thrombocytopenia, anemia, and fatigue being the most common. Conclusions: The combination of niraparib and dostarlimab with radiation did not meet the pre-specified criteria for expansion to full accrual. Further analyses of dose intensity in this heavily pretreated and evaluation of in-field responses are underway. Further investigation of the combination with biomarker selection is warranted. Clinical trial information: NCT04409002.

824TiP An open-label, single arm, phase II trial of niraparib in combination with anti-PD1 antibody in recurrent/advanced stage endometrial cancer patients

Endometrial carcinoma is the most common malignancy of the female reproductive tract. Most cases are diagnosed at an early stage due to the appearance of symptoms such as postmenopausal bleeding. However, endometrial carcinoma carries a poor prognosis when it recurs after previous definitive treatment or when diagnosed at an advanced stage.The 5-year survival rate for FIGO III is approximately 57-66% and for FIGO IV is approximately 10-20%.The combination of PARP inhibitors and PD1/PD-L1 has the theoretical support of preclinical molecular biology.