Combination Of Olaparib Research Articles

Phase I feasibility study of Olaparib in combination with loco-regional radiotherapy in head and neck squamous cell carcinoma

PurposePARP-inhibitors have potent radiosensitizing properties in pre-clinical models. To identify the maximum tolerated dose (MTD) of the PARP-inhibitor Olaparib in combination with radiotherapy in patients with head and neck cancer, a single institutional phase-I dose escalation trial was initiated. Patients and methodsThe starting dose of Olaparib was 25 mg BID, combined with radiotherapy (70 Gy in 35 fractions). The MTD was defined as the highest dose-level at which not more than 20 % of patients experience dose-limiting toxicities (DLT) or as the highest reached dose in the absence of DLT’s. ResultsOne week Olaparib‐only treatment (25 mg QD) was administered to all patients prior to the start of radiotherapy. In dose-level I, Olaparib (25 mg BID) was combined with accelerated radiotherapy (70 Gy in 6 weeks). Because of DLT’s in 3 of the 4 treated patients (acute tracheotomy 5 and 7 months and osteoradionecrosis 7 months after treatment), the Olaparib dose was de-escalated to 25 mg QD, and combined with conventional radiotherapy (70 Gy in 7 weeks) (dose-level II). There were no DLT’s observed in 5 patients treated within dose-level II. After a median follow-up of 60 months, the 4-year LRC and OS rates were 77.8 % and 88.9 %, respectively. ConclusionOlaparib 25 mg QD combined with conventionally fractionated radiotherapy was well tolerated and identified as the MTD while severe DLT’s were observed when Olaparib 25 mg BID was combined with accelerated radiation. This combination might be further explored in future Olaparib dose escalation studies in patients with locally-advanced HNSCC unfit for cisplatin-based chemoradiotherapy.

Comparative efficacy of olaparib in combination with or without novel antiandrogens for treating metastatic castration-resistant prostate cancer.

Studies using novel antiandrogens (NAA) in patients with metastatic castration-resistant prostate cancer (mCRPC) have shown overall survival benefit. As patients develop resistance to NAA therapy, the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib in combination with NAA may become a promising therapy. However the overall benefit of olaparib monotherapy or combination therapy still needs to be evaluated. Therefore, we performed a network meta-analysis to assess the efficacy and toxicity between olaparib, olaparib combined with abiraterone and NAA. We searched PubMed, EMBASE, the Cochrane Library and American Society of Clinical Oncology (ASCO) University Meeting abstracts for randomized controlled trials reporting olaparib and NAA from 2010 up to March, 2023. Network meta-analysis using Stata 16.0 and R 4.4.2, hazard ratios (HR) with 95% confidence intervals (CI) were used to assess the results. Four trials reported olaparib, olaparib plus abiraterone and apalutamide plus abiraterone. radiographic progression-free survival (rPFS) was significantly lower in patients on apalutamide plus abiraterone compared to olaparib (HR, 1.43; 95% CI, 1.06-1.93). rPFS was similar for olaparib plus abiraterone and olaparib (HR, 1.35; 95% CI, 0.99-1.84); likewise, olaparib plus abiraterone and apalutamide plus abiraterone were similar (HR, 1.06; 95% CI, 0.83-1.35). In addition, there was no significant difference between the three interventions for OS. But olaparib has the highest probability of being a preferred treatment for improving rPFS and OS. rPFS was in favor of olaparib compared with apalutamide plus abiraterone. But there were no difference between olaparib plus abiraterone and either olaparib or apalutamide plus abiraterone. Apalutamide plus abiraterone might be the most preferred intervention in cases where AEs are involved. https://inplasy.com, identifier INPLASY2023100072.

Synergistic antitumor efficacy of rMV-Hu191 and Olaparib in pancreatic cancer by generating oxidative DNA damage and ROS-dependent apoptosis

BackgroundMalignancies with BRCA1/2 deficiencies are particularly sensitive to PARP inhibitors. Thus, combining PARP inhibitors with agents that impair DNA damage repair to treat BRCA1/2 wild-type PDAC could broaden the clinical use of these promising PARP inhibitors. Here we examined the synergism and mechanism of oncolytic measles virus (rMV-Hu191) with a PARP inhibitor (Olaparib) in vitro and in vivo. MethodsThe cell viability assay, cell cycle analysis, colony formation assay, TCID 50 method, western blotting, flow cytometry, DNA comet assay, Mice bearing PDAC xenografts, IF, IHC and TUNEL assay were performed to explore the antitumor efficacy and underlying mechanisms. ResultsIn this study, we explored the antitumor activities of rMV-Hu191 and Olaparib in two PDAC cell lines harboring wild-type BRCA1/2 genes. Compared to monotherapy, the combination of rMV-Hu191 and Olaparib was able to synergistically cause growth arrest, apoptotic cell death and DNA damage, accompanying with excessive oxidative stress. Mechanistically, the data indicated that the observed synergy depended on the oxidative DNA damage and ROS-dependent apoptosis generating by rMV-Hu191 combined with Olaparib in human PDAC cells. Tumor inhibition and prolonged survival of PDAC mice xenografts in vivo confirmed the synergism of combinational treatment with trivial side-effects. ConclusionsOur findings firstly suggested that combination treatment with rMV-Hu191 and Olaparib had a profound and synergistic therapeutic effect against human PDAC through synthetic lethality. In conclusion, we recommend combining oncolytic rMV-Hu191 with a PARP inhibitor (Olaparib) as a novel therapeutic strategy and provided a potential mechanism for advanced PDAC regardless of BRCA mutation status.

PRIMA-1 synergizes olaparib-induced cell death in p53 mutant triple negative human breast cancer cell line via restoring p53 function, arresting cell cycle, and inducing apoptosis.

This study concerned with assessing the effect of restoring p53 using PRIMA-1 on the anti-cancer activity of olaparib against TP53-mutant triple negative breast cancer (TNBC) cells and exploring the optimum synergistic concentrations and the underlying mechanism. Human BC cell lines, MDA-MB-231 with mutated TP53 gene, and MCF-7 with wild-type TP53 gene were treated with olaparib and/or PRIMA-1. The IC50 value for olaparib was significantly decreased by PRIMA-1 in MDA-MB-231 cells compared to MCF-7 cells. Contrary to MCF-7 cells, co-treatment with olaparib and PRIMA-1 had a synergistic anti-proliferative effect in MDA-MB-231 at all tested concentrations with the best synergistic combination at 45and 8.5µM, respectively, and furthermore PRIMA-1 enhanced olaparib-induced apoptosis. This synergistic apoptotic effect was associated with a significant boost in mRNA expression of TP53 gene, cell cycle arrest at G2/M phase, modulation of BRCA-1, BAX and Bcl2 proteins expressions, and induction of active caspase-3. These results present a clue for the utility of combined olaparib and PRIMA-1 in treatment of TP53-mutant TNBC invitro. PRIMA-1 triggers olaparib-induced MDA-MB-231 cell death in a synergistic manner via restoring TP53, decreasing BRCA-1 expression, cell cycle arrest, and enhancement of apoptosis via p53/BAX/Bcl2/caspase 3 pathway.

Indirubin derivatives as bifunctional molecules inducing DNA damage and targeting PARP for the treatment of cancer

Based on the facts that significant synergistic effect existed between PARP inhibitors and DNA damage agents and the DNA damage caused by indirubin's derivatives, we herein adopted the strategy to combine the pharmacophores of PARP inhibitors and the unique scaffold of indirubin to design a series of bifunctional molecules inducing DNA damage and targeting PARP. After SAR studies, the most potent compound 12a, encoded as KWWS-12a, exhibited improved inhibitory effect against PARP1 compared with PARP1 inhibitor Olaparib (IC50 = 1.89 nM vs 7.48 nM) and enhanced antiproliferative activities than the combination of Olaparib and indirubin-3′-monoxime towards HCT-116 cells (IC50 = 0.31 μM vs 1.37 μM). In the normal NCM-460 cells, 12a showed low toxicity (IC50 > 60 μM). The mechanism research indicated that 12a could increase the levels of γH2AX concentration dependently, arrest the cell cycle in S phase and induce apoptosis in HCT-116 cells. In vivo experiments showed that 12a displayed more significant antitumor potential than that of the positive controls. Our studies demonstrated that 12a could be a promising candidate for cancer therapy.

Germ line variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy

AbstractGrowth factor independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of hematopoiesis. GFI1-36N is a germ line variant, causing a change of serine (S) to asparagine (N) at position 36. We previously reported that the GFI1-36N allele has a prevalence of 10% to 15% among patients with acute myeloid leukemia (AML) and 5% to 7% among healthy Caucasians and promotes the development of this disease. Using a multiomics approach, we show here that GFI1-36N expression is associated with increased frequencies of chromosomal aberrations, mutational burden, and mutational signatures in both murine and human AML and impedes homologous recombination (HR)–directed DNA repair in leukemic cells. GFI1-36N exhibits impaired binding to N-Myc downstream-regulated gene 1 (Ndrg1) regulatory elements, causing decreased NDRG1 levels, which leads to a reduction of O6-methylguanine-DNA-methyltransferase (MGMT) expression levels, as illustrated by both transcriptome and proteome analyses. Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via olaparib, a poly-ADP ribose polymerase 1 inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1-36N, whereas the effects were insignificant in nonmalignant GFI1-36S or GFI1-36N cells. In addition, mice that received transplantation with GFI1-36N leukemic cells treated with a combination of temozolomide and olaparib had significantly longer AML-free survival than mice that received transplantation with GFI1-36S leukemic cells. This suggests that reduced MGMT expression leaves GFI1-36N leukemic cells particularly vulnerable to DNA damage initiating chemotherapeutics. Our data provide critical insights into novel options to treat patients with AML carrying the GFI1-36N variant.

KLF5 Promotes Tumor Progression and Parp Inhibitor Resistance in Ovarian Cancer.

One major characteristic of tumor cells is the aberrant activation of epigenetic regulatory elements, which remodelthe tumor transcriptome and ultimately promotecancer progression and drug resistance. However, the oncogenic functions and mechanisms of ovarian cancer (OC) remain elusive. Here, super-enhancer (SE) regulatory elements that are aberrantly activated in OC are identified and it is found that SEs drive the relative specific expression of the transcription factor KLF5 in OC patients and poly(ADP-ribose) polymerase inhibitor (PARPi)-resistant patients. KLF5 expression is associated with poor outcomes in OC patients and can drive tumor progression in vitro and in vivo. Mechanistically, KLF5 forms a transcriptional complex with EHF and ELF3 and binds to the promoter region of RAD51 to enhance its transcription, strengthening the homologous recombination repair (HRR) pathway. Notably, the combination of suberoylanilide hydroxamic acid (SAHA) and olaparib significantly inhibits tumor growth and metastasis of PARPi-resistant OC cells with high KLF5. In conclusion, it is discovered that SEs-driven KLF5 is a key regulatory factor in OC progression and PARPi resistance;and potential therapeutic strategies for OC patients with PARPi resistance and high KLF5 are identified.

SOLAR: Phase Ib Dose Expansion of Selumetinib (MEK Inhibitor) and OLAparib (PARP Inhibitor) Combination in Solid Tumors with RAS Pathway Alterations and in PARP Inhibitor-Resistant Ovarian Cancer (LBA 9)

SOLAR: Phase Ib Dose Expansion of Selumetinib (MEK Inhibitor) and OLAparib (PARP Inhibitor) Combination in Solid Tumors with RAS Pathway Alterations and in PARP Inhibitor-Resistant Ovarian Cancer (LBA 9)

Triggering pyroptosis enhances the antitumor efficacy of PARP inhibitors in prostate cancer.

PARP inhibitors have revolutionized the treatment landscape for advanced prostate cancer (PCa) patients who harboring mutations in homologous recombination repair (HRR) genes. However, the molecular mechanisms underlying PARP inhibitors function beyond DNA damage repair pathways remain elusive, and identifying novel predictive targets that favorably respond to PARP inhibitors in PCa is an active area of research. The expression of GSDME in PCa cell lines and human PCa samples was determined by western blotting. Targeted bisulfite sequencing, gene enrichment analysis (GSEA), clone formation, construction of the stably transfected cell lines, lactate dehydrogenase (LDH) assay, western blotting as well as a mouse model of subcutaneous xenografts were used to investigate the role of GSDME in PCa. The combinational therapeutic effect of olaparib and decitabine was determined using both in vitro and in vivo experiments. We have found low expression of GSDME in PCa. Interestingly, we demonstrated that GSDME activity is robustly induced in olaparib-treated cells undergoing pyroptosis, and that high methylation of the GSDME promoter dampens its activity in PCa cells. Intriguingly, genetically overexpressing GSDME does not inhibit tumor cell proliferation but instead confers sensitivity to olaparib. Furthermore, pharmacological treatment with the combination of olaparib and decitabine synergistically induces GSDME expression and cleavage through caspase-3 activation, thus promoting pyroptosis and enhancing anti-tumor response, ultimately resulting in tumor remission. Our findings highlight a novel therapeutic strategy for enhancing the long-term response to olaparib beyond HRR-deficient tumors in PCa, underscoring the critical role of GSDME in regulating tumorigenesis.

Durvalumab in Combination With Olaparib Versus Durvalumab Alone as Maintenance Therapy in Metastatic NSCLC: The Phase 2 ORION Study

IntroductionIncreased DNA damage triggered through poly (ADP-ribose) polymerase inhibition may modify tumor immunogenicity, sensitizing tumors to immunotherapy. ORION (NCT03775486) evaluated the combination of olaparib with durvalumab as maintenance therapy in patients with metastatic NSCLC. MethodsORION is a phase 2, randomized, multicenter, double-blind, international study. Patients with metastatic NSCLC (without activating EGFR or ALK aberrations) and Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled to receive initial therapy with durvalumab (1500 mg intravenously; every 3 wk) plus platinum-based chemotherapy for four cycles. Patients without disease progression were then randomized (1:1) to maintenance durvalumab (1500 mg; every 4 wk) plus either olaparib (300 mg orally) or placebo (both twice daily); randomization was stratified by objective response during initial therapy and tumor histologic type. The primary end point was investigator-assessed progression-free survival (PFS) (Response Evaluation Criteria in Solid Tumors version 1.1). ResultsBetween January 2019 and February 2020, 269 of 401 patients who received initial therapy were randomized. As of January 11, 2021 (median follow-up: 9.6 mo), median PFS was 7.2 months (95% confidence interval: 5.3–7.9) with durvalumab plus olaparib versus 5.3 months (3.7–5.8) with durvalumab plus placebo (hazard ratio = 0.76, 95% confidence interval: 0.57–1.02, p = 0.074). Safety findings were consistent with the known profiles of durvalumab and olaparib. Anemia was the most common adverse event (AE) with durvalumab plus olaparib (26.1% versus 8.2% with durvalumab plus placebo). The incidence of grade 3 or 4 AEs (34.3% versus 17.9%) and AEs leading to treatment discontinuation (10.4% versus 4.5%) was numerically higher with durvalumab plus olaparib versus durvalumab plus placebo. ConclusionsMaintenance therapy with durvalumab in combination with olaparib was not associated with a statistically significant improvement in PFS versus durvalumab alone, although numerical improvement was observed.

Transcriptionally regulated miR-26a-5p may act as BRCAness in Triple-Negative Breast Cancer

BackgroundDNA damage and DNA damage repair (DDR) are important therapeutic targets for triple-negative breast cancer (TNBC), a subtype with limited chemotherapy efficiency and poor outcome. However, the role of microRNAs in the therapy is emerging. In this study, we explored whether miR-26a-5p could act as BRCAness and enhance chemotherapy sensitivity in TNBC.MethodsQuantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to detect the expression of miR-26a-5p in breast cancer tissues and cell lines. CCK-8 was used to measure drug sensitivity in concentration gradient and time gradient. Comet assay was used to detect DNA damage. Flow cytometry was performed to examine apoptosis. Moreover, we used western blot and immunofluorescence to detect biomarkers. Luciferase reporter assay was performed to verify the combination of miR-26a-5p and 3’UTR of target gene. Hormone deprivation and stimulation assay were used to validate the effect of hormone receptors on the expression of miR-26a-5p. Chromatin immunoprecipitation (ChIP) assays were used to verify the binding sites of ER-a or PR with the promoter of miR-26a-5p. Animal experiments were performed to the effect of miR-26a-5p on Cisplatin treatment.ResultsThe expression of miR-26a-5p was significantly downregulated in TNBC. Overexpressing miR-26a-5p enhanced the Cisplatin-induced DNA damage and following apoptosis. Interestingly, miR-26a-5p promoted the expression of Fas without Cisplatin stimulating. It suggested that miR-26a-5p provided a hypersensitivity state of death receptor apoptosis and promoted the Cisplatin sensitivity of TNBC cells in vitro and in vivo. Besides, miR-26a-5p negatively regulated the expression of BARD1 and NABP1 and resulted in homologous recombination repair defect (HRD). Notably, overexpressing miR-26a-5p not only facilitated the Olaparib sensitivity of TNBC cells but also the combination of Cisplatin and Olaparib. Furthermore, hormone receptors functioned as transcription factors in the expression of miR-26a-5p, which explained the reasons that miR-26a-5p expressed lowest in TNBC.ConclusionsTaken together, we reveal the important role of miR-26a-5p in Cisplatin sensitivity and highlight its new mechanism in DNA damage and synthetic lethal.

Discovery of dual PARP and CDK6 inhibitors for triple-negative breast cancer with wild-type BRCA

Inhibition of PARP is synthetic lethal with defects in BRCA, which provide effective targeted therapy strategy for BRCA mutation type of TNBC patients. However, approximately 80% of TNBC patients do not have BRCA mutations. Recent studies have shown that CDK4/6 inhibitors can increase the sensitivity of wild-type BRCA cells to PARP inhibitors. We designed a series of dual PARP and CDK6 inhibitors, and the most promising compound, P4i, showed good inhibitory activity against PARP1 and CDK6 and good inhibitory effects on MDA-MB-231 (IC50 = 1.96 μM), MDA-MB-468 (IC50 = 2.81 μM) and BT-549 (IC50 = 2.37 μM) cells with wild-type BRCA. Compared with Olaparib, the inhibition capacity of the three BRCA wild-type (MDA-MB-231, MDA-MB-468 and BT-549) cells was about 10–20 times higher, and even better than the combination of Olaparib and Palbociclib. As a novel PARP multifunctional molecule, it is a potential compound for the treatment of BRCA wild-type TNBC.

Abstract B061: Updated analysis of “CANCAP03” – A study into the pharmacodynamic biomarker effects of olaparib (PARP inhibitor) ± degarelix (GnRH antagonist) given prior to radical prostatectomy

Abstract Background: PARP inhibition with androgen deprivation is an effective treatment for Prostate Cancer (PC). We investigated the effects of a two-week course of olaparib±degarelix in the “window” before radical prostatectomy (RP). Methods: Primary endpoint: level of PARP inhibition. Secondary endpoints: safety and feasibility of the trial design. Exploratory endpoints: changes in relevant biological pathways after olaparib±degarelix. Participants (Pt) with localised PC (D’Amico intermediate or high risk) were randomly allocated (1:1) to receive olaparib 300mg bid for two weeks ± degarelix (240mg s/c). Recruitment target was twenty evaluable Pts. Compliance (patient diaries) and toxicity (CTCAE v4.03) were assessed. Diagnostic biopsies with subsequent prostatectomy samples were analysed by IHC for PAR protein expression and whole transcriptome gene expression analysis was performed using NovaSeq. Gene mutation profiling was performed using a custom 350 gene panel, sequenced on Illumina NextSeq 2000 and analysed with in-house bioinformatics pipeline. Serum samples for PSA and testosterone were taken at baseline, day 15 and 42 post RP. Results: 24 patients were recruited, 23 evaluable for safety and 20 for primary endpoint (11 olaparib, 9 olaparib+degarelix). All related AE ≤ Grade (Gr) 2, majority Gr 1. Commonest AEs: fatigue, nausea & vomiting (olaparib) or injection site reaction, fatigue & nausea (olaparib+degarelix). No RP was delayed by an AE. PSA declined from baseline in all (8/8) Pt after olaparib+degarelix and 3/9 Pt after olaparib (-11, -17 & -47%). PAR protein expression decreased in both cohorts after treatment, with the mean reduction in PAR expression olaparib > olaparib+degarelix (p=0.01). After olaparib, Pt with greatest PSA change also had greatest reduction in PAR expression compared with other Pt (p=0.008); no correlation between PSA and PAR change was detected in olaparib+degarelix Pt. Pathogenic mutations (in BRCA2/ATM and ATM) were detected in two Pt. Upregulation of gene signatures, including homologous recombination signature, were noted following combined olaparib+degarelix treatment. Conclusions: We have previously reported that toxicities were predictable and manageable, with no drug-related delay in RP for Pt. Updated results confirm PARP inhibition (reduced PAR expression) in PC samples after olaparib and (to a lesser degree) olaparib+degarelix. Up-regulation of homologous recombination deficiency gene signature occurred after olaparib+degarelix. Further assessments of post-treatment tissues are ongoing to establish mechanisms of action of combination therapy across all genetic backgrounds. Citation Format: Harveer Dev, Mark Linch, Howard Kynaston, Greg Shaw, Krishna Narahari, Tatiana Hernández, Anne Warren, Alopa Malaviya, Vincent Gnanapragasam, Elizabeth Harrington, Niedzica Camacho, Silvia Glont, Massimo Sqautrito, Joshua Armenia, Luiza Moore, Robert Hanson, Toby Milne-Clarke, Shubha Anand, Charlie Massie, Nimish Shah, Simon Pacey. Updated analysis of “CANCAP03” – A study into the pharmacodynamic biomarker effects of olaparib (PARP inhibitor) ± degarelix (GnRH antagonist) given prior to radical prostatectomy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B061.

A phase II study of olaparib and durvalumab in patients with IDH-mutated cholangiocarcinoma.

4099 Background: IDH1/2 mutations (m) occur in approximately 25% of cholangiocarcinomas (CCAs) (20% intrahepatic, < 5% extrahepatic) and result in the accumulation of R-2-hydroxyglutarate (R2HG). R2HG, suppresses homologous recombination repair and as a result IDH1/2m are hypothesized to predict PARP inhibitor sensitivity. PARP inhibition upregulates PD-L1 and the combination is thought to be synergistic. We conducted a phase II trial of olaparib with durvalumab for patients with IDH-mutated cholangiocarcinoma. Methods: Patients with advanced IDHm CCA were enrolled in this phase II open-label study (NCT03991832). Patients received olaparib 300 mg twice daily continuously and durvalumab 1500 mg IV every 4 weeks. Simon’s optimal two-stage design was used, with an interim analysis planned for efficacy. 10 patients were accrued in the first stage, with a plan for expansion if ≥2 responses were observed. The primary objective was to determine the overall response rate (RECIST 1.1) and disease control rate (DCR). Secondary objectives included progression-free survival, overall survival, and safety of the olaparib and durvalumab combination. Results: 10 patients with IDH1m were enrolled in this study between January 2020-August 2021. Median age was 63.5 years (range 49-78), and 50% were female. All patients had a baseline ECOG PS of 0-1. 40% of patients had prior surgical resections and subsequently developed recurrent disease. 20% of patients had ³2 lines of prior chemotherapy, with 90% receiving prior platinum. Median duration of treatment was 1.95 months (range 1.8-13.5). There were no treatment-related grade 3-4 toxicities. Any grade toxicities included fatigue (100%), nausea (60%), anemia (20%), hypothyroidism (20%), elevated liver enzymes (20%). We did not observe any complete or partial responses. The DCR was 30% with 3 patients demonstrating stable disease. One patient remained on treatment for 13.5 months, and was eventually taken off study due to clinical progression. The median PFS was 1.97 months (95% CI 1.73-3.93). Given that no responses were seen in the initial 10 patients, the study did not proceed to Stage 2. Conclusions: While the combination of olaparib and durvalumab was well-tolerated, this study was discontinued after Stage I due to lack of efficacy. IDH1/2m may not induce a BRCAness phenotype and further correlative studies are planned to evaluate this. Clinical trial information: NCT03991832 .

Circulating tumor cells (CTCs) in patients with metastatic castration resistant prostate cancer (mCRPC) treated with olaparib plus 177lutetium-prostate specific membrane antigen-617 (177Lu-PSMA-617) in the LuPARP trial.

5064 Background: LuPARP (NCT03874884) is evaluating the safety and efficacy of olaparib in combination with 177Lu-PSMA-617 in patients (pts) with mCRPC who have progressed on an androgen receptor pathway inhibitors and docetaxel. We aim to identify potential prognostic and predictive biomarkers from serial CTC profiling. Methods: Twenty-six pts with high PSMA expression on PSMA-PET received 7.4 GBq of 177Lu-PSMA-617 every 6 weeks (wk) together with an escalating dose-schedule of olaparib (50mg BD – 300mg BD, days 2 to 14 or days -4 to 14) for up to 6 cycles. For CTC analysis, 10 mls of blood was collected at baseline, 12-weekly for 48 wk, and thereafter every 24 wk and at disease progression. CK+, CD45-, and DAPI+ CTCs were enumerated from 3 mls of blood and immunoassayed for PSMA expression using the Epic Sciences platform. Correlations between total and PSMA+ CTC counts and PSA50 response (PSA reduction of ≥ 50%) were evaluated. Low pass whole genome sequencing (lpWGS) was performed on baseline and longitudinal CTC samples to identify copy number alterations. Results: At baseline, 23 of 26 pts (88%) had detectable CTCs (median 2.9 CTC/ml, range 0-30), and of these 23 pts, 17 (74%) had detectable PSMA+ CTCs (median 0.9 CTC/ml, range 0.3-27), indicating heterogeneity of PSMA expression in CTCs. The CTC positivity rates (% of cases ≥1 CTC) at week (w)12, w24, w36, w48 and at disease progression were 57%, 58%, 75%, 36% and 100%, and the PSMA positivity rates (% of cases ≥1 PSMA+ CTC) were 38%, 36%, 22%, 50% and 56%, respectively. Fifteen of 20 (75%) evaluable pts with paired baseline and w12 CTCs had a ≥50% decline in total CTC count, of which 9/15 (60%) pts also achieved a PSA50 response. Five of these 9 (56%) pts had 100% CTC clearance at w12. In terms of PSMA+ CTCs, 14/15 (93%) evaluable pts had ≥50% PSMA+ CTC decline with 13 pts (93%) achieving complete CTC clearance by w12. Six of the 13 pts with complete PSMA+ CTC clearance at w12 also achieved a PSA50 response. Beyond PSMA expression, genomic heterogeneity was evident in baseline and on-treatment CTCs, including recurrent loss of PTEN, TP53, BRCA2, ATM, and RB1, and gain of AR and MYC. lpWGS in 10 baseline samples identified 5 cases with BRCA2 loss and 5 cases with ATM loss. Two pts with BRCA2 loss and 3 pts with ATM loss had a PSA50 response by w12. Conclusions: We observed high rates of total and PSMA+ CTCs in PSMA-expressing mCRPC. Total and PSMA+ CTCs decline with combined olaparib and 177Lu-PSMA-617 treatment. Early declines in total and PSMA+ CTCs including 12w CTC clearance paralleled PSA responses. Notably, total and PSMA+ CTCs rise again in the setting of disease progression. Serial CTC profiling may assist in tracking response to 177Lu-PSMA-617 therapy. Clinical trial information: NCT03874884 .

Neoplastic and blood-based biomarkers of response in patients with advanced endometrial cancer: Results from NRG GY012.

5525 Background: NRG GY012 is a randomized, 3-arm phase II study, comparing olaparib (O) and the combination of cediranib and olaparib (CO) to the reference arm cediranib (C) for metastatic pre-treated, endometrial cancer (EC). The trial found a trend towards benefit for CO and no benefit for O compared to C. Archival tumor and prospective blood samples were collected for biomarker analysis. Methods: Targeted next-generation sequencing (BROCA-GO) was used to detect pathogenic variants (PV) and loss of heterozygosity (LOH) in DNA from paired blood and archival cancers. The LOH cut-off was identified at 11% for HRD based on testing ovarian cancers with known HRD. Plasma samples collected at baseline, cycle 2 day 1, and end-of-treatment were analyzed via multiplex ELISA for 25 angiogenic and inflammatory circulating protein biomarkers (Angiome); IL6 was of specific interest. Prognostic associations with PFS and OS were analyzed using proportional hazards models (PhM) stratified by histology and adjusted for treatment assignment. Predictive associations (PFS and OS) were analyzed using PhM stratified by histology and including main effects for both treatment assignment and biomarker group plus an interaction term. Results: In 97 patients (pts) with evaluable tumor, BROCA-GO identified 370 somatic PV; TP53 (61%) was the most commonly mutated gene. PV in homologous recombination repair (HRR) genes were identified in 5 cases (5%). Somatic PVs were identified in BRCA2, RAD51B and PALB2. 1 pt had a germline BRCA1 PV. 2 cases had somatic PV that might restore HRR: 1 case with a somatic BRCA2 PV had somatic PVs in CHD4 and TP53BP1; the TP53BP1 frameshift PV was present only in the recurrent and not primary cancer. LOH was available for 45 cases. LOH high occurred in 16 (35.6%) cases and was exclusive to EC with TP53 mutations (p=0.0003). LOH was not associated with outcome in any of the arms. For the circulating biomarker analysis (N=96), median IL-6 was 4pg/ml. IL-6 levels >4pg/ml were associated with increased risk of progression (HR: 1.59; 95% CI: (1.04-2.42); p-value=0.032). In predictive analyses, pts with IL-6 > 4 pg/ml receiving C or C+O had increased PFS (3.8 mo vs 1.9 mo) and OS (11.9 mo vs 5.7 mo) compared to pts receiving O, the interaction p value did not reach statistical significance. Conclusions: LOH high status was not associated with outcome to O. There were too few cases with HRR PVs to determine their relationship to PARPi response. The restriction of LOH high to cancers with TP53 mutation may suggest that genomic LOH in ECs correlates better with aneuploidy than with HRR function indicating that at least some biomarkers of PARPi response vary between tumor types. IL-6 levels were prognostic of PFS but were not predictive of either OS or PFS for pts receiving C compared to pts receiving O in this small study. Further analysis of the complete Angiome and integration with the BROCA-GO dataset are ongoing. Clinical trial information: NCT03660826 .

Association of KMT2C loss-of-function mutations in circulating tumor DNA and prolonged response to the combination of PARPi and PI3Ki.

e13003 Background: The emergence of somatic KMT2C mutations has been associated with resistance to various treatments, including chemotherapy and endocrine therapy in patients with estrogen receptor-positive breast cancers. The impact of these mutations in patients treated with poly-ADP ribose polymerase inhibitors (PARPi) and phosphatidylinositol-3-kinase inhibitors (PI3Ki) is unknown. Methods: Circulating tumor DNA (ctDNA) was obtained from plasma and peripheral blood at different time points from 38 patients prior to treatment with the combination of the PARPi olaparib with the alpha-specific PI3Ki alpelisib (NCT01623349). CtDNA was also collected immediately before the first cycle and at the time of disease progression. CtDNA underwent deep targeted sequencing (tumor-normal pairs, 397 genes (2Mb) at 25,000x somatic and 10,000x germline) at the Broad Institute of MIT and Harvard. Variants that were exonic, non-synonymous, and predicted to lead to loss-of-function were considered mutations. Cohorts were stratified according to the presence or absence of the genomic alteration, and progression-free survival was compared with the Kaplan-Meier method and log-rank test. A Cox regression was performed using age, tumor type, germline BRCA1/2 mutation status, performance status, and number of previous lines of treatment as covariates. Results: The KMT2C gene was one of the 3 genes most frequently mutated in our cohort, affecting 5 patients (15%) after the exclusion of those with variants with non-deleterious alterations. The other 2 commonly mutated genes were TP53 (76%) and PIK3CA (15%). In the comparison of patients based on these most common mutations, we identified that patients with somatic KMT2C mutations (n=5) have longer mPFS than those that were wild type (n=28): mPFS 386 vs. 151 days, log-rank p = 0.025. Cox proportional hazards model accounting for age, tumor type, germline BRCA1/2 mutation status, performance status, and number of previous lines revealed a hazard ratio of 0.16; p = 0.007. All somatic KMT2C mutations were proximal to the SET domain critical for methyltransferase activity. Upon progression, the KMT2C-mutated clones were suppressed to below the detection level of mutation calling algorithms. Analysis of the raw files revealed that the clones were suppressed but not eliminated. Conclusions: While the emergence of KMT2C has been reported to be associated with cancer progression and resistance to different therapies, patients with deleterious KMT2C mutations in the ctDNA may benefit from therapy with PARPi and PI3Ki.

Phase 2 trial of pembrolizumab and olaparib (POLAR) maintenance for patients (pts) with metastatic pancreatic cancer (mPDAC): Two cohorts B non-core homologous recombination deficiency (HRD) and C exceptional response to platinum-therapy.

4140 Background: Maintenance olaparib improves PFS in g BRCA1/2m (core HRD) in mPDAC (Golan, NEJM 2019). Whether other HRD indicators, such as gene mutations other than g BRCA1/2m (non-Core HRD, Cohort B) and exceptional platinum responders (Cohort C, response > 6 months) may benefit from PARPi in mPDAC remains unanswered. We hypothesized that pembrolizumab and olaparib (POLAR) combination may improve outcome by immunogenic cell death. Methods: We conducted an open-label, non-randomized, phase 2 trial of POLAR as maintenance therapy for pts with mPDAC whose disease had not progressed for 4 months (m) in Cohort B or 6 m in C. Herein, we report on Cohorts B & C. Eligibility: ECOG 0-1, mPDAC meeting eligibility of B or C. POLAR (Pembrolizumab 200mg IV Q3W+ OLApaRib 300mg BID) until disease progression or limiting toxicity. Objective response rate (ORR), median PFS (mPFS), median overall survival (mOS), disease control rate (DCR), CA 19-9, cfDNA and baseline HRD mutational signature were analyzed. Results: Cohorts B and C enrolled N=15 each. N=25 pts evaluable by RECIST 1.1. Median follow-up 9.9 (1.3-22.8) and 11.3 (5.8-23) m, respectively. Efficacy details are shown. G3-5 AEs related to treatment: 5/14 (36%): 1 diarrhea (7%), 1 hyperglycemia (7%), 2 anemia (14%), 1 lipase increased (7%). Cohort B: 9/15 (60%) ATM, 3 CHEK2, 2 MUTYH, 1 BLM, 1 FANCC. Canonical gene mutations for mPDAC were less common for pts in Cohort B, especially in ATM PA group (n=9) vs C. Median genomic instability score (GIS) was computed and higher 28 (0-38) vs 9 (0-24) in Cohort B vs C, p=0.052. Median tumor mutation burden (TMB) was not different between B and C (3.3 and 4.1). Conclusions: Clinical activity of POLAR maintenance observed in select pts in B and C. Although PFS was modest (mPFS of 4m [2.1-5.4] in B + C), an intriguing survival signal (mOS at 14m [10-NR] from first POLAR dose) was seen in select patients without chemotherapy. Extensive correlative analyses underway to evaluate response and resistance (SPORE: 1P50CA257881-01A1). Cohort A (core HRD) actively accruing. Clinical trial information: NCT04666740 . [Table: see text]

Exactis-03: A phase I trial of the combination of olaparib and navitoclax in women with high grade serous ovarian cancer and triple negative breast cancer.

TPS5623 Background: Identifying new therapeutic options for patients (pts) with high grade serous ovarian cancer (HGSC) and triple negative breast cancer (TNBC) is a priority. For pts with pathogenic variants in BRCA, the PARP inhibitor (PARPi) olaparib is used to treat TNBC and as maintenance for HGSC. PARPi can induce a senescence-like phenotype in cancer cells with cell survival dependent on anti-apoptotic proteins. The intrinsic apoptotic pathway is regulated by the Bcl-2 family composed of anti-apoptotic proteins (including Bcl-2, Bcl-xL), pro-apoptotic effectors and the pro-apoptotic BH3-only proteins. Increased expression of Bcl-xL occurs in 88% of HGSC. Olaparib and navitoclax, a Bcl-2/Bcl-xL inhibitor, are synergistic in pre clinical models of HGSC and TNBC. Exactis- 03 investigates targeting, olaparib-induced sensecence as a treatment strategy for pts with HGSC and TNBC. Methods: Exactis-03 is a multi-centre phase I trial determining if olaparib can be safely combined with navitoclax in pts with TNBC who have somatic or germline mutations in BRCA1/2 or PALB2 and pts with recurrent HGSC who have progressed ≥ 6 months since their last platinum based chemotherapy. Additional eligibility criteria include : ≥3 prior lines of treatment for TNBC (no limit for HGSC); for pts with HGSC prior PARPi is allowed provided there was no progression on or ≤6 months since discontinuation of the PARPi; ECOG PS ≤2; ability to absorb study medication and pts must be willing and able to undergo study related procedures. The primary endpoint is identification of the recommended phase II dose (RP2D) of olaparib combined with navitoclax. Olaparib 200mg bid is administered alone for the first 2 weeks. Tumor biopsies will be performed at baseline and on day 7-12 (prior to navitoclax) to evaluate senescence and apoptosis biomarkers and to create 3D organoids and ex vivo microdissected tumor (MDT) models for functional assessment of drug response. Navitoclax is dose escalated with a fixed dose of olaparib in 28-day cycles with 3 pts initially treated at each dose level. If no dose limiting toxicity (DLT) is observed, the dose level will be escalated until ≥ 1/3 or ≥ 2/6 patients experience DLT. The RP2D will be defined as the dose level below the one where ≥ 1/3 or ≥ 2/6 patients experience DLT. The 2-week lead-in with olaparib alone and one full cycle of the combination (navitoclax/olaparib) must be completed before dose escalation is permitted. Blood samples are collected for pharmacokinetics and serial evaluation of plasma biomarkers. There is an optional tumor biopsy on progression. Exploratory objectives include determining levels of pro- and anti- apoptotic proteins in biopsy samples and evaluation of cell fate decision biomarkers in biopsy tissue and blood (senescence secretome). Patient-derived organoids and ex vivo MDT will be used to explore drug response and sequencing (NCT05358639). Clinical trial information: NCT05358639 .

A phase 1/2 study of combination olaparib and radium-223 in men with metastatic castration-resistant prostate cancer with bone metastases (COMRADE): A trial in progress.

TPS5110 Background: Radium-223, an α-emitting radioisotope inducing DNA double-stranded breaks leading to cell death has demonstrated improvement in overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases. PARP inhibitors prevent the repair of DNA single-stranded breaks and have demonstrated clinical efficacy as monotherapy in mCRPC patients harboring alterations in the homologous recombination repair (HRR) pathway and in combination with androgen receptor signaling inhibitors irrespective of DNA repair mutation status. In preclinical models, PARP inhibitors have shown efficacy as radio sensitizing agents. We designed a phase 1/2 trial to identify the recommended phase 2 dose (RPD2) of olaparib and radium-223 and test the hypothesis that radium-223 + olaparib will demonstrate anti-tumor activity in mCRPC irrespective of homologous recombination repair deficiency (HRD) status (NCT03317392). Methods: This open-label, multicenter, phase 1/2 study evaluates the dosing, safety and efficacy of olaparib with radium-223 in men with mCRPC with bone metastases. The phase 1 component used a 3+3 dose escalation design to determine the olaparib recommended phase 2 dose (RP2D) + fixed dose radium-223 (55 kBq/kg IV every 4 weeks x 6). The phase 1 portion has completed accrual (n = 12) and demonstrated that the RP2D of olaparib is 200 mg by mouth twice daily when combined with standard dose radium-223. The phase 2 component of the study which was activated in 1/2021 is an open-label, randomized trial (1:1) evaluating olaparib + radium-223 compared to radium-223 alone. The inclusion criteria include patients with mCRPC with any number of prior therapy lines for mCRPC and ≥2 bone metastases by imaging and at least 1 lesion which has not been treated with prior radiation. Patients with visceral metastases or malignant lymphadenopathy ( > 4 cm in short diameter) are excluded. The primary endpoint for phase 2 is radiographic progression-free survival (rPFS) per PCWG3 guidelines for bone metastases and RECIST v1.1 for non-bone disease. The integrated biomarker is Oncopanel assay to determine HRR status. A key secondary endpoint will evaluate rPFS in biomarker positive and negative patients. Other secondary endpoints include time to PSA progression, PSA response, time to subsequent therapy, time to first skeletal event, and OS. Exploratory endpoints include WES/WTS of baseline biopsy tissue, assessment of RAD51 IHC and correlation with outcomes, ctDNA assessment and correlation with responses, evaluation of changes in the tumor immune microenvironment, and quality of life assessment. Target accrual is 133 patients. Clinical trial information: NCT03317392 .