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Targeted Oncology May 2021Loss-of-function mutations in BRCA1 and BRCA2 are detected in at least 5% of unselected patients with breast cancer (BC). These BC susceptibility genes encode proteins... (Review)
Review
Loss-of-function mutations in BRCA1 and BRCA2 are detected in at least 5% of unselected patients with breast cancer (BC). These BC susceptibility genes encode proteins critical for DNA homologous recombination repair (HRR). This review provides an update on oral poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of BC. Olaparib and talazoparib are PARP inhibitors approved as monotherapies for deleterious/suspected deleterious germline BRCA-mutated, HER2-negative BC. Olaparib is approved in the USA for metastatic BC and in Europe for locally advanced/metastatic BC. Talazoparib is approved for locally advanced/metastatic BC in the USA and Europe. In phase 3 trials, olaparib and talazoparib monotherapies demonstrated significant progression-free survival benefits compared with chemotherapy. Common toxicities were effectively managed by supportive treatment and dose interruptions/reductions. Veliparib combined with platinum-based chemotherapy has also shown promise for locally advanced/metastatic BC in a phase 3 trial. Differences in efficacy and safety across PARP inhibitors (olaparib, talazoparib, veliparib, niraparib, rucaparib) may relate to differences in potency of PARP trapping on DNA and cytotoxic specificity. PARP inhibitors are being investigated in early BC, in novel combinations, and in patients without germline BRCA mutations, including those with somatic BRCA mutations and other HRR gene mutations. Ongoing phase 2/3 studies include PARP inhibitors combined with immune checkpoint inhibitors for the treatment of triple-negative BC. Wider access to testing for BRCA and other mutations, and to genetic counseling, are required to identify patients who could benefit from PARP inhibitor therapy. The advent of PARP inhibitors has potential benefits for BC treatment beyond the locally advanced/metastatic setting.
Topics: Breast Neoplasms; Female; Humans; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 33710534
DOI: 10.1007/s11523-021-00796-4 -
Pharmacological Research Sep 2021Glioblastoma multiforme (GBM) is a WHO grade IV glioma and the most common malignant, primary brain tumor with a 5-year survival of 7.2%. Its highly infiltrative nature,...
Glioblastoma multiforme (GBM) is a WHO grade IV glioma and the most common malignant, primary brain tumor with a 5-year survival of 7.2%. Its highly infiltrative nature, genetic heterogeneity, and protection by the blood brain barrier (BBB) have posed great treatment challenges. The standard treatment for GBMs is surgical resection followed by chemoradiotherapy. The robust DNA repair and self-renewing capabilities of glioblastoma cells and glioma initiating cells (GICs), respectively, promote resistance against all current treatment modalities. Thus, durable GBM management will require the invention of innovative treatment strategies. In this review, we will describe biological and molecular targets for GBM therapy, the current status of pharmacologic therapy, prominent mechanisms of resistance, and new treatment approaches. To date, medical imaging is primarily used to determine the location, size and macroscopic morphology of GBM before, during, and after therapy. In the future, molecular and cellular imaging approaches will more dynamically monitor the expression of molecular targets and/or immune responses in the tumor, thereby enabling more immediate adaptation of tumor-tailored, targeted therapies.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Drug Resistance, Neoplasm; Glioblastoma; Humans
PubMed: 34302977
DOI: 10.1016/j.phrs.2021.105780 -
Clinical Cancer Research : An Official... Nov 2019Irinotecan and topotecan have been widely used as anticancer drugs for the past 20 years. Because of their selectivity as topoisomerase I (TOP1) inhibitors that trap... (Review)
Review
Irinotecan and topotecan have been widely used as anticancer drugs for the past 20 years. Because of their selectivity as topoisomerase I (TOP1) inhibitors that trap TOP1 cleavage complexes, camptothecins are also widely used to elucidate the DNA repair pathways associated with DNA-protein cross-links and replication stress. This review summarizes the basic molecular mechanisms of action of TOP1 inhibitors, their current use, and limitations as anticancer agents. We introduce new therapeutic strategies based on novel TOP1 inhibitor chemical scaffolds including the indenoisoquinolines LMP400 (indotecan), LMP776 (indimitecan), and LMP744, and on tumor-targeted delivery TOP1 inhibitors using liposome, PEGylation, and antibody-drug conjugates. We also address how tumor-specific determinants such as homologous recombination defects (HRD and BRCAness) and Schlafen 11 (SLFN11) expression can be used to guide clinical application of TOP1 inhibitors in combination with DNA damage response inhibitors including PARP, ATR, CHEK1, and ATM inhibitors.
Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; DNA Topoisomerases, Type I; Humans; Irinotecan; Molecular Targeted Therapy; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Precision Medicine; Topoisomerase I Inhibitors; Topotecan
PubMed: 31227499
DOI: 10.1158/1078-0432.CCR-19-1089 -
The New England Journal of Medicine Dec 2019Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma.
METHODS
In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the -mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the -mutation cohort), and the intention-to-treat population.
RESULTS
A total of 1140 patients underwent randomization. In the -mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall.
CONCLUSIONS
Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.).
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carboplatin; Combined Modality Therapy; Cystadenocarcinoma, Serous; Double-Blind Method; Female; Genes, BRCA1; Genes, BRCA2; Humans; Intention to Treat Analysis; Maintenance Chemotherapy; Middle Aged; Mutation; Ovarian Neoplasms; Paclitaxel; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Quality of Life
PubMed: 31562800
DOI: 10.1056/NEJMoa1909707 -
Annals of Oncology : Official Journal... Sep 2020In recurrent ovarian cancer, poly(ADP-ribose) polymerase (PARP)-inhibiting agents have transformed the treatment of platinum-sensitive disease. New data support use of... (Review)
Review
BACKGROUND
In recurrent ovarian cancer, poly(ADP-ribose) polymerase (PARP)-inhibiting agents have transformed the treatment of platinum-sensitive disease. New data support use of PARP inhibitors earlier in the treatment algorithm.
DESIGN
We review results from recent phase III trials evaluating PARP inhibitors as treatment and/or maintenance therapy for patients with newly diagnosed ovarian cancer. We discuss the efficacy and safety of these agents in the all-comer and biomarker-selected populations studied in clinical trials, and compare the strengths and limitations of the various trial designs. We also consider priorities for future research, with a particular focus on patient selection and future regimens for populations with high unmet need.
RESULTS
Four phase III trials (SOLO-1, PAOLA-1/ENGOT-OV25, PRIMA/ENGOT-OV26 and VELIA/GOG-3005) demonstrated remarkable improvements in progression-free survival with PARP inhibitor therapy (olaparib, niraparib or veliparib) for newly diagnosed ovarian cancer. Differences in trial design (treatment and/or maintenance setting; single agent or combination; bevacizumab or no bevacizumab), patient selection (surgical outcome, biomarker eligibility, prognosis) and primary analysis population (intention-to-treat, BRCA mutated or homologous recombination deficiency positive) affect the conclusions that can be drawn from these trials. Overall survival data are pending and there is limited experience regarding long-term safety.
CONCLUSIONS
PARP inhibitors play a pivotal role in the management of newly diagnosed ovarian cancer, which will affect subsequent treatment choices. Refinement of testing for patient selection and identification of regimens to treat populations that appear to benefit less from PARP inhibitors are a priority.
Topics: Carcinoma, Ovarian Epithelial; Clinical Trials as Topic; Female; Humans; Neoplasm Recurrence, Local; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 32569725
DOI: 10.1016/j.annonc.2020.06.004 -
Cell Nov 2020Strategies for installing authentic ADP-ribosylation (ADPr) at desired positions are fundamental for creating the tools needed to explore this elusive post-translational...
Strategies for installing authentic ADP-ribosylation (ADPr) at desired positions are fundamental for creating the tools needed to explore this elusive post-translational modification (PTM) in essential cellular processes. Here, we describe a phospho-guided chemoenzymatic approach based on the Ser-ADPr writer complex for rapid, scalable preparation of a panel of pure, precisely modified peptides. Integrating this methodology with phage display technology, we have developed site-specific as well as broad-specificity antibodies to mono-ADPr. These recombinant antibodies have been selected and characterized using multiple ADP-ribosylated peptides and tested by immunoblotting and immunofluorescence for their ability to detect physiological ADPr events. Mono-ADPr proteomics and poly-to-mono comparisons at the modification site level have revealed the prevalence of mono-ADPr upon DNA damage and illustrated its dependence on PARG and ARH3. These and future tools created on our versatile chemical biology-recombinant antibody platform have broad potential to elucidate ADPr signaling pathways in health and disease.
Topics: ADP-Ribosylation; Amino Acid Sequence; Antibodies; Benzimidazoles; Carrier Proteins; Cell Line, Tumor; Cell Surface Display Techniques; DNA Damage; Glycoside Hydrolases; Histones; Humans; Nuclear Proteins; Phosphates; Phosphoric Monoester Hydrolases; Phthalazines; Piperazines; Poly (ADP-Ribose) Polymerase-1; Recombinant Proteins; Serine; Tyrosine
PubMed: 33186521
DOI: 10.1016/j.cell.2020.09.055 -
Journal of Clinical Oncology : Official... May 2020Five percent to 9% of pancreatic ductal adenocarcinomas (PDACs) develop in patients with a germline or (g+) mutation. Phase IB data from a trial that used cisplatin,... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Five percent to 9% of pancreatic ductal adenocarcinomas (PDACs) develop in patients with a germline or (g+) mutation. Phase IB data from a trial that used cisplatin, gemcitabine, and veliparib treatment demonstrated a high response rate (RR), disease control rate (DCR), and overall survival (OS) in this population. We designed an open-label, randomized, multicenter, two-arm phase II trial to investigate cisplatin and gemcitabine with or without veliparib in g+ PDAC.
PATIENTS AND METHODS
Eligible patients had untreated g PDAC with measurable stage III to IV disease and Eastern Cooperative Oncology Group performance status of 0 to 1. Treatment for patients in arm A consisted of cisplatin 25 mg/m and gemcitabine 600 mg/m intravenously on days 3 and 10; treatment for patients in arm B was the same as that for patients in arm A, and arm A also received veliparib 80 mg orally twice per day on days 1 to 12 cycled every 3 weeks. The primary end point was RRs of arm A and arm B evaluated separately using a Simon two-stage design. Secondary end points were progression-free survival, DCR, OS, safety, and correlative analyses.
RESULTS
Fifty patients were evaluated by modified intention-to-treat analysis. The RR for arm A was 74.1% and 65.2% for arm B ( = .55); both arms exceeded the prespecified activity threshold. DCR was 100% for arm A and 78.3% for arm B ( = .02). Median progression-free survival was 10.1 months for arm A (95% CI, 6.7 to 11.5 months) and 9.7 months for arm B (95% CI, 4.2 to 13.6 months; = .73). Median OS for arm A was 15.5 months (95% CI, 12.2 to 24.3 months) and 16.4 months for arm B (95% CI, 11.7 to 23.4 months; = .6). Two-year OS rate for the entire cohort was 30.6% (95% CI, 17.8% to 44.4%), and 3-year OS rate was 17.8% (95% CI, 8.1% to 30.7%). Grade 3 to 4 hematologic toxicities for arm A versus arm B were 13 (48%) versus seven (30%) for neutropenia, 15 (55%) versus two (9%) for thrombocytopenia, and 14 (52%) versus eight (35%) for anemia.
CONCLUSION
Cisplatin and gemcitabine is an effective regimen in advanced g+ PDAC. Concurrent veliparib did not improve RR. These data establish cisplatin and gemcitabine as a standard approach in g/+ PDAC.
Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; Benzimidazoles; Cisplatin; Constipation; Deoxycytidine; Fanconi Anemia Complementation Group N Protein; Female; Germ-Line Mutation; Humans; Hypertension; Kaplan-Meier Estimate; Male; Middle Aged; Nausea; Outcome Assessment, Health Care; Pancreatic Neoplasms; Gemcitabine
PubMed: 31976786
DOI: 10.1200/JCO.19.02931 -
Journal of Hematology & Oncology Jan 2022The members of the Poly(ADP-ribose) polymerase (PARP) superfamily are involved in several biological processes and, in particular, in the DNA damage response (DDR). The... (Review)
Review
The members of the Poly(ADP-ribose) polymerase (PARP) superfamily are involved in several biological processes and, in particular, in the DNA damage response (DDR). The most studied members, PARP1, PARP2 and PARP3, act as sensors of DNA damages, in order to activate different intracellular repair pathways, including single-strand repair, homologous recombination, conventional and alternative non-homologous end joining. This review recapitulates the functional role of PARPs in the DDR pathways, also in relationship with the cell cycle phases, which drives our knowledge of the mechanisms of action of PARP inhibitors (PARPi), encompassing inhibition of single-strand breaks and base excision repair, PARP trapping and sensitization to antileukemia immune responses. Several studies have demonstrated a preclinical activity of the current available PARPi, olaparib, rucaparib, niraparib, veliparib and talazoparib, as single agent and/or in combination with cytotoxic, hypomethylating or targeted drugs in acute leukemia, thus encouraging the development of clinical trials. We here summarize the most recent preclinical and clinical findings and discuss the synthetic lethal interactions of PARPi in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Despite the low frequency of genomic alterations of PARP and other DDR-related genes in acute leukemia, selective vulnerabilities have been reported in several disease subgroups, along with a "BRCAness phenotype." AML carrying the RUNX1-RUNX1T1 or PML-RARA fusion genes or mutations in signaling genes (FLT3-ITD in combination with TET2 or TET2 and DNMT3A deficiency), cohesin complex members (STAG2), TP53 and BCOR as co-occurring lesions, IDH1/2 and ALL cases expressing the TCF3-HLF chimera or TET1 was highly sensitive to PARPi in preclinical studies. These data, along with the warning coming from the observation of cases of therapy-related myeloid malignancies among patients receiving PARPi for solid tumors treatment, indicate that PARPi represents a promising strategy in a personalized medicine setting. The characterization of the clonal and subclonal genetic background and of the DDR functionality is crucial to select acute leukemia patients that will likely benefit of PARPi-based therapeutic regimens.
Topics: Animals; Antineoplastic Agents; DNA Damage; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases
PubMed: 35065680
DOI: 10.1186/s13045-022-01228-0 -
Expert Opinion on Investigational Drugs Jun 2022Poly (ADP-ribose) polymerase inhibitors (PARPis) are an exciting class of agents that have shown efficacy, particularly for BRCA-mutant triple-negative breast cancer... (Review)
Review
PARP inhibitors as single agents and in combination therapy: the most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers.
INTRODUCTION
Poly (ADP-ribose) polymerase inhibitors (PARPis) are an exciting class of agents that have shown efficacy, particularly for BRCA-mutant triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC). However, most patients who receive PARPi as their standard of care therapy inevitably develop resistance and this underscores the need to identify additional targets that can circumvent such resistance. Combination treatment strategies have been developed in preclinical and clinical studies to address the challenges of efficacy and resistance.
AREAS COVERED
This review examines completed or ongoing clinical trials of PARPi mono- and combination therapies. PARPi monotherapy in HER2 negative breast (HR+ and TNBC subtypes) and ovarian cancer is a focal point. The authors propose potential strategies that might overcome resistance to PARPi and discuss key questions and future directions.
EXPERT OPINION
While the advent of PARPis has significantly improved the treatment of tumors with defects in DNA damage and repair pathways, careful patient selection will be essential to enhance these treatments. The identification of molecular biomarkers to predict disease response and progression is an endeavor.
Topics: Carcinoma, Ovarian Epithelial; DNA Damage; Female; Humans; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Triple Negative Breast Neoplasms
PubMed: 35435784
DOI: 10.1080/13543784.2022.2067527 -
Annals of Oncology : Official Journal... Apr 2022Primary analyses of the phase III BrighTNess trial showed addition of carboplatin with/without veliparib to neoadjuvant chemotherapy significantly improved pathological... (Randomized Controlled Trial)
Randomized Controlled Trial
Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase III trial.
BACKGROUND
Primary analyses of the phase III BrighTNess trial showed addition of carboplatin with/without veliparib to neoadjuvant chemotherapy significantly improved pathological complete response (pCR) rates with manageable acute toxicity in patients with triple-negative breast cancer (TNBC). Here, we report 4.5-year follow-up data from the trial.
PATIENTS AND METHODS
Women with untreated stage II-III TNBC were randomized (2 : 1 : 1) to paclitaxel (weekly for 12 doses) plus: (i) carboplatin (every 3 weeks for four cycles) plus veliparib (twice daily); (ii) carboplatin plus veliparib placebo; or (iii) carboplatin placebo plus veliparib placebo. All patients then received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. The primary endpoint was pCR. Secondary endpoints included event-free survival (EFS), overall survival (OS), and safety. Since the co-primary endpoint of increased pCR with carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel was not met, secondary analyses are descriptive.
RESULTS
Of 634 patients, 316 were randomized to carboplatin plus veliparib with paclitaxel, 160 to carboplatin with paclitaxel, and 158 to paclitaxel. With median follow-up of 4.5 years, the hazard ratio for EFS for carboplatin plus veliparib with paclitaxel versus paclitaxel was 0.63 [95% confidence interval (CI) 0.43-0.92, P = 0.02], but 1.12 (95% CI 0.72-1.72, P = 0.62) for carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel. In post hoc analysis, the hazard ratio for EFS was 0.57 (95% CI 0.36-0.91, P = 0.02) for carboplatin with paclitaxel versus paclitaxel. OS did not differ significantly between treatment arms, nor did rates of myelodysplastic syndromes, acute myeloid leukemia, or other secondary malignancies.
CONCLUSIONS
Improvement in pCR with the addition of carboplatin was associated with long-term EFS benefit with a manageable safety profile, and without increasing the risk of second malignancies, whereas adding veliparib did not impact EFS. These findings support the addition of carboplatin to weekly paclitaxel followed by doxorubicin and cyclophosphamide neoadjuvant chemotherapy for early-stage TNBC.
Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carboplatin; Cyclophosphamide; Doxorubicin; Female; Follow-Up Studies; Humans; Neoadjuvant Therapy; Paclitaxel; Triple Negative Breast Neoplasms
PubMed: 35093516
DOI: 10.1016/j.annonc.2022.01.009