Phase I study of olaparib (O), in combination with oral cyclophosphamide (C), in patients (pts) with metastatic triple negative breast cancer (TNBC) and recurrent high grade serous ovarian cancer (OVCA).
Chee Khoon LeeClare L. ScottGeoffrey John LindemanEmma GibbsHeath BadgerRobin PatersonL. T. MacnabEdmond M. KwanFrances BoyleMichael Friedlander
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Abstract:
1104 Background: Poly (ADP-ribose) polymerase (PARP) inhibitors can potentiate chemotherapy induced DNA damage, through synthetic lethality, leading to increased tumor death. We hypothesized that O+C would increase antitumor activity of O through increased DNA damage induced by C. This study ( ANZCTR N12613000924752) evaluated the safety and activity of O+C. Methods: Eligible patient (pts) had performance status 0-2, with ≤3 lines of therapy (including platinum for OVCA and anthracycline and taxane for BC). Pts received O+C with a dose escalations strategy using a 3+3 design with cohort expansions once maximal tolerated dose (MTD) was determined. Dose level 1 (DL1); O, 300 mg bid continuously, C, 50mg on days 1,3 and 5 weekly, 21 day cycle. Dose level 2 (DL2); O, 300 mg bid continuously, C, 50mg days 1-5 weekly 21 day cycle. Dose limiting toxicity was evaluated during 1st two cycles. Safety was assessed by CTCAEv4.0 and efficacy with RECISTv1.1 and GCIC criteria. Results: Of the 32 pts (median age 56, 9 had BC ( BRCA1 22%, BRCA2 44%) and 23 had HGSOC ( BRCA1 39%, BRCA2 26%). 4 pts were treated at DL1 and 28 pts at DL2. DL2 was the MTD. At the time of analysis, 16 of 29 pts had 8 cycles of O+C, with 14 of 16 pts continued with O beyond the 8 th cycle. One pt stopped because of adverse events (AEs) and the remaining 12 stopped due to disease progression. The median treatment duration of O+C was 4.3 months (0.7-23.5). Common AEs were nausea (Grade (Gr) 1/2: 88%, Gr 3: 3%), fatigue (Gr 1/2: 81%), constipation (Gr 1/2: 38%, Gr 3: 3%), and vomiting (Gr 1/2: 38%, Gr 3: 3 %). There were no grade (Gr) 4 or 5 AE. 50% required blood transfusion for anemia. Unconfirmed disease control rate (DCR) was 73% (N = 30; CR = 1, PR = 9, SD = 12). DCR for BC and HGSOC were 56% and 81% respectively. In the BRCA cohort (N = 19), DCR was 79%. GCIG CA125 response rates were 70% and 92% for all HGSOC and BRCA cohort respectively. Conclusions: In HGSOC and BC pts, the recommended phase II dose (O 300 mg bid continuously, C 50mg on days 1-5 weekly) is tolerable and active, particularly in those with germline BRCA mutation, supporting our hypothesis. A randomised phase II study in BRCA mutant HGSOC is planned. Clinical trial information: ACTRN12613000924752.Keywords:
Olaparib
Taxane
PARP inhibitor
Abstract Background: The poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib, has been found to have a therapeutic potential for treating cancers that have an impaired DNA repair ability. However, some cancer presents acquired resistance to PARP inhibitor or platinum. Histone deacetylases (HDACs) are important to enable functional homologous recombination (HR) by regulating the expression of HR-related genes and promoting the accurate assembly of HR-directed subnuclear foci. Thus, HDAC inhibitors have emerged recently as a class of therapeutic agents for the treatment of cancer by inhibiting DNA repair. For this mechanism, HDAC inhibition would enhance the anti-tumor effect of PARP inhibitor in cancer cells by blocking DNA repair pathway. Materials and Methods: We determined whether SAHA, a HDAC inhibitor could enhance the growth inhibition of olaparib on breast cancer cell lines using MTT assay. We examined whether exposure to SAHA affects the expression level of genes involved in HR. The accumulation of DNA double strand breaks (DSBs) induced by combination treatment was accessed by the comet assay. Cell cycle analysis and molecular changes induced by combination of olaparib plus SAHA were also performed. These in vitro data were validated in the in vivo xenograft model as well. Results: Triple-negative breast cancer cell lines showed heterogeneous response to dual inhibition of PARP and HDACs. SAHA enhanced olaparib-induced cell death of MDA-MB-157 and HCC1143 but not of HCC70 and MDA-MB-468. Combination of olaparib plus SAHA caused a greater decrease of pAKT, pERK, and pSTAT3 in MDA-MB-157 and HCC1143 cells compared with monotherapy either olaparib or SAHA. Furthermore, inhibition of PARP increased the accumulation of DNA DSBs induced by SAHA in these two cell lines, MDA-MB-157 and HCC1143. There was no change in proliferative pathway activation in HCC70 and MDA-MB-468 cells with combination of olaparib plus SAHA. Our findings showed that triple-negative breast cancer cells are differentially effective to combination of SAHA plus olaparib which increased levels of unrepaired DNA DSBs. Conclusion: HDAC inhibitor SAHA enhances growth inhibitory activity of PARP inhibitor olaparib in several triple-negative breast cancer cells with increased accumulation of DNA DSBs. Our results provide a rationale for the future clinical trials of olaparib combined with SAHA in the treatment of cancers that have an impaired DNA repair ability. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-16-06.
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PARP inhibitors were recently introduced as a novel targeted therapy for biomarker positive metastatic castration resistant prostate cancer (mCRPC) patients, a population that inevitably acquires resistance to existing standard care regimens. Olaparib and rucaparib are now FDA-approved for mCRPC, while talazoparib and niraparib are advancing through the clinical stage of development. We highlight the recent results of the GALAHAD trial testing the efficacy of niraparib in mCRPC patients with DNA damage repair gene defects and compare its performance to key PARP inhibitor trials (PROFOUND, olaparib; TRITON2, rucaparib; TALAPRO-1, talazoparib). Finally, we briefly discuss recent updates on emerging PARP inhibitor and androgen receptor targeting combination trials as a novel treatment strategy for upfront treatment of mCRPC and in earlier disease settings.
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Abstract Olaparib is a potent oral inhibitor of PARP 1 & 2 with biological activity in various solid tumours for patients with germline and/or sporadic BRCA mutations. The aim of this review is to present the results of the various studies which show Olaparib’s efficacy in ovarian cancer
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Abstract Five PARP inhibitors (PARPi) are approved for cancer treatment, they exploit cancer-specific defects in homologous recombination repair (HRR) to selectively kill tumour cells. Continuous PARP inhibition is required for single-agent anticancer activity. PARPi are also being investigated with ATR inhibitors clinically. We previously showed rucaparib caused prolonged PARP inhibition. Here we aimed to determine if this property was unique to rucaparib or common to other PARPis and the implications for scheduling with an ATR inhibitor (VE-821). Durability of PARP inhibition was determined at 0, 1, 24, 48 and 72 h after a 1 h pulse of 1μM of rucaparib, olaparib, niraparib, talazoparib or pamiparib in IGROV-1 (human ovarian cancer) cells. Inhibition of PARP was sustained to a variable degree with all inhibitors, but reduced with time. Rucaparib caused the most persistent inhibition of PARP activity, which was maintained at ≥75% for 72 h after drug withdrawal. In contrast, only 12% inhibition remained at this time with talazoparib and pamiparib and no detectable inhibition with olaparib and niraparib. Rucaparib enhanced VE-821 cytotoxicity to a similar extent in a sequential schedule as in co-exposure studies (PF 50 : 2.6 vs. 2.7) and there was even an approx. 2-fold enhancement after a 24 h delay between rucaparib and VE-821. Olaparib and niraparib produced similar enhancement of VE-821 cytotoxicity if co-exposed but were ineffective in sequential exposures. These data have clinical implications for both schedules of current PARPi monotherapy and the scheduling of PARPi in combination with ATRi and other cytotoxic drugs. Novelty and Impact PARPi are a new class of anticancer agent. We demonstrate for the first time that 5 PARPi continue to suppress cellular PARP activity after drug removal to a variable extent. Rucaparib caused the most durable PARP inhibition, olaparib and niraparib the least. Rucaparib enhanced ATR inhibitor cytotoxicity in sequential and co-exposures, olaparib and niraparib were only active in co-exposure settings. These data have implications for the clinical use of PARPi, particularly in combination with other drugs.
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e17045 Background: Our previous in vitro work has demonstrated that HSP90-inhibition suppresses homologous recombination (HR) DNA repair and sensitizes HR-proficient ovarian cancer lines to platinum and PARP-inhibitors(PARPis). In this study, we evaluated the combination of PARPi olaparib and the HSP90-inhibitor AT13387 in vivo, in a panel of molecularly characterized high grade serous ovarian cancer patient derived xenograft (PDX) mouse models. Methods: PDX models were established from fresh human ascites samples from patients with either newly diagnosed or recurrent ovarian cancer through an IRB approved protocol. High grade serous ovarian cancer (HGSOC) cells were implanted intraperitoneally into immunocompromised mice and these models were luciferized thereby providing the ability to follow tumor growth and response to therapy by non-invasive bioluminescent imaging technology. Response to therapy was also evaluated by CA125 levels. Olaparib and AT13387 combination tolerability studies were performed prior to the initiation of combination efficacy studies. Results: Tolerability studies demonstrated that doses of olaparib up to 100mg/kg po daily x 3 weeks and AT13387 up to 45mg/kg po for 2 days on / 5 days off x 3 weeks (Days 1, 2, 8, 9, 15, 16) were well tolerated without weight loss in the mice or gross changes in normal tissue histology. Preclinical evaluation of efficacy of treatments (vehicle vs AT13387 vs olaparib vs olaparib plus AT13387) was subsequently performed in one mouse per treatment arm in each PDX model. The combination of AT13387 and olaparib inhibited tumor growth in 8 of 14 PDX models including one BRCA1-mutated/PARPi-resistant model, 2 models with CDKN2A loss and 1 model with CCNE1 amplification. Of these 8 models, 4 were clinically platinum resistant, 2 platinum sensitive, and 2 unknown. Of 11 models with measurable CA125, CA125 responses were seen in 7 models. Pharmacodynamic studies are ongoing. Conclusions: PARPi olaparib and HSP90i AT13387 exhibit synergistic activity in vivo, in a number of high grade serous ovarian cancer PDX models, including HR proficient models. A phase I clinical trial of this combination in HGSOC is planned.
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