Risk of severe hematologic toxicities in cancer patients treated with PARP inhibitors: results of monotherapy and combination therapy trials.
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ABSTRACT:
SUBMITTER: Alecu I
PROVIDER: S-EPMC5826089 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Risk of severe hematologic toxicities in cancer patients treated with PARP inhibitors: results of monotherapy and combination therapy trials.
Alecu Iulian I Milenkova Tsveta T Turner Simon R SR
Drug design, development and therapy 20180221
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Project description:ObjectiveNearly 5% of patients with breast cancer carry germline BRCA mutations, which are more common in triple-negative breast cancer (TNBC). Previous clinical trials demonstrated the therapeutic efficacy of poly (ADP-ribose) polymerase inhibitors (PARPis) against BRCA-mutated metastatic breast cancer. The current study conducted a systemic review and meta-analysis of the clinical efficiency and safety of PARPis, either alone or combined with chemotherapy, in patients with TNBC.MethodsWe searched PubMed, EMBASE, and ClinicalTrials.gov to identify randomized controlled trials comparing PARPi therapy with chemotherapy, and comparisons of chemotherapy plus PARPis with chemotherapy alone were included. The study endpoints included the clinical response, progression-free survival, and adverse event rates.ResultsPARPi therapy was revealed to improve progression-free survival in patients with advanced breast cancer, either alone or in combination with chemotherapy. Subgroup analysis illustrated that patients with mutant BRCA1 and mutant BRCA2 and those who had not been treated with platinum-based agents could specifically benefit from PARPis.ConclusionPARPi monotherapy can significantly improve clinical outcomes in patients with advanced breast cancer, especially those with TNBC, those who had not previously received platinum therapy, and those with mutant BRCA1/2. PARPis combined with chemotherapy represent new treatment options for patients with advanced cancer.
| S-EPMC8164563 | biostudies-literature
Project description: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.
| S-EPMC9428566 | biostudies-literature
Project description:BackgroundPoly ADP-ribose polymerase inhibitors (PARPis) are an important class of therapeutics for metastatic castration-resistant prostate cancer (mCRPC). Unlike hormone-based treatments for mCRPC, PARPis are not without drug-related hematological adverse events.ObjectiveTo review the evidence on hematological toxicities, including anemia, thrombocytopenia, and neutropenia from PARPis in prostate cancer.Study methodologyA systematic review and meta-analysis using the PRISMA guidelines was performed for phase II and III randomized controlled trials (RCTs) of PARPis in prostate cancer. PubMed, Embase, and Ovid All EBM reviews-Cochrane were queried from inception to 9 June 2023. The Mantel-Haenszel method was used to report risk ratios (RR) and 95% confidence intervals (CI) for all-grade and high-grade anemia, thrombocytopenia, and neutropenia toxicities.ResultsThe systematic review retrieved eight phase II and III RCTs; specifically, eight were included in the anemia, five in the all-grade thrombocytopenia and neutropenia, and four in the high-grade thrombocytopenia and neutropenia outcomes. Compared to a placebo and/or other non-PARPi treatments, PARPi use was associated with an increased risk of all-grade anemia (RR, 3.37; 95% CI, 2.37-4.79; p < 0.00001), thrombocytopenia (RR, 4.54; 95% CI, 1.97-10.44; p = 0.0004), and neutropenia (RR, 3.11; 95% CI, 1.60-6.03; p = 0.0008). High-grade anemia (RR, 6.94; 95% CI, 4.06-11.86; p < 0.00001) and thrombocytopenia (RR, 5.52; 95% CI, 2.80-10.88; p < 0.00001) were also associated with an increased risk, while high-grade neutropenia (RR, 3.63; 95% CI, 0.77-17.23; p = 0.10) showed no significant association. Subgroup stratification analyses showed differences in various all-grade and high-grade toxicities.ConclusionPARPis were associated with an increased risk of hematological AEs. Future studies with more pooled RCTs will enhance this understanding and continue to inform patient-physician shared decision-making. Future studies may also have a role in improving the current management strategies for these AEs.
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| S-EPMC5777210 | biostudies-literature
Project description:Despite recent improvements in survival, metastatic castration-resistant prostate cancers (mCRPCs) remain lethal. Alterations in genes involved in the homologous recombination repair (HRR) pathway are associated with poor prognosis. Poly-ADP-ribose polymerase (PARP) inhibitors (PARPis) have demonstrated anti-tumoral effects by synthetic lethality in patients with mCRPCs harboring HRR gene alterations, in particular BRCA2. While both olaparib and rucaparib have obtained government approvals for use, the selection of eligible patients as well as the prescription of these treatments within the clinical urology community are challenging. This review proposes a brief review of the rationale and outcomes of PARPi treatment, then a pragmatic vision of PARPi use in terms of prescription and the selection of patients based on molecular screening, which can involve potential genetic counseling in the case of associated germinal alterations.
| S-EPMC8952857 | biostudies-literature
Project description: Not available
| S-EPMC10644043 | biostudies-literature
Project description:Poly (ADP-ribose) polymerase inhibitors (PARPi) have demonstrated activity across a broad spectrum of molecular backgrounds and tumor types, with the greatest activity observed in patients with aberrations in the homologous recombination DNA damage repair pathway. Despite remarkable responses in a subset of patients, the response is usually modest and transient due to the almost inevitable emergence of resistance. Tumors develop resistance through rapid adaptation to the effects of PARPi as well as by generation or selection of genomic aberration. Although adaptive responses results in drug resistance, it also induces therapeutic vulnerabilities that could be exploited with rational combination therapies. To fulfill this role, we established the combinatorial adaptive response therapy (CART) platform by performing reverse-phase protein arrays to characterize adaptive responses, and develop rational combination therapies. Our series of studies strongly support the efficacy of this strategy, wherein targeting the emerging adaptive responses to PARPi with MEK/ERK inhibitors, WEE1/ATR inhibition (inhibitors of S-phase and G2 DNA damage checkpoint), and PI3K/AKT/mTOR inhibition, and showed promising anti-tumor activity in various preclinical models. Importantly, this approach has been proven highly efficient, and several combinational therapies developed from the CART platform are being evaluated in ongoing clinical trials (NCT03801369, NCT03586661, NCT03162627, NCT03544125, NCT02659241, NCT02208375, NCT02316834, and NCT03637491).
| S-EPMC7329579 | biostudies-literature
Project description:The use of PARP inhibitors (PARPi) in patients with epithelial ovarian cancer is expanding, with the transition from use in recurrent disease to the first-line setting. This is accompanied with an increasing population of patients who develop acquired PARPi resistance. Coupled with those patients with primary PARPi resistance, there is an urgent need to better understand mechanisms of resistance and identify means to overcome this resistance. Combination therapy offers the potential to overcome innate and acquired resistance, by either working synergistically with PARPi or by restoring homologous recombination deficiency, targeting the homologous recombination repair pathway through an alternate strategy. We discuss mechanisms of PARPi resistance and data on novel combinations which may restore PARPi sensitivity.
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Project description:Ataxia telangiectasia and Rad3-related (ATR) kinase protects genome integrity during DNA replication. RP-3500 is a novel, orally bioavailable clinical-stage ATR kinase inhibitor (NCT04497116). RP-3500 is highly potent with IC50 values of 1.0 and 0.33 nmol/L in biochemical and cell-based assays, respectively. RP-3500 is highly selective for ATR with 30-fold selectivity over mammalian target of rapamycin (mTOR) and more than 2,000-fold selectivity over ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and phosphatidylinositol 3-kinase alpha (PI3Kα) kinases. In vivo, RP-3500 treatment results in potent single-agent efficacy and/or tumor regression in multiple xenograft models at minimum effective doses (MED) of 5 to 7 mg/kg once daily. Pharmacodynamic assessments validate target engagement, with dose-proportional tumor inhibition of phosphorylated checkpoint kinase 1 (pCHK1) (IC80 = 18.6 nmol/L) and induction of phosphorylated H2A.X variant histone (γH2AX), phosphorylated DNA-PK catalytic subunit (pDNA-PKcs), and phosphorylated KRAB-associated protein 1 (pKAP1). RP-3500 exposure at MED indicates that circulating free plasma levels above the in vivo tumor IC80 for 10 to 12 hours are sufficient for efficacy on a continuous schedule. However, short-duration intermittent (weekly 3 days on/4 days off) dosing schedules as monotherapy or given concomitantly with reduced doses of olaparib or niraparib, maximize tumor growth inhibition while minimizing the impact on red blood cell depletion, emphasizing the reversible nature of erythroid toxicity with RP-3500 and demonstrating superior efficacy compared with sequential treatment. These results provide a strong preclinical rationale to support ongoing clinical investigation of the novel ATR inhibitor, RP-3500, on an intermittent schedule as a monotherapy and in combination with PARP inhibitors as a potential means of maximizing clinical benefit.
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