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Expert Opinion on Investigational Drugs Jun 2017Basal-like breast cancer is characterized by being triple negative and aggressive. Defects in DNA repair is a promising therapeutic target as BRCA alterations are found... (Review)
Review
Basal-like breast cancer is characterized by being triple negative and aggressive. Defects in DNA repair is a promising therapeutic target as BRCA alterations are found in 11 to 42% of these tumors, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors exploit this deficiency through a synthetic lethality and are considered as promising anticancer therapies, especially in patients harboring BRCA1 or BRCA 2 mutations. Areas covered: Olaparib is one of the most widely investigated PARP inhibitors. Here, the preclinical data, completed clinical trials and ongoing investigations are discussed. Expert opinion: PARP inhibitors show promising results in breast cancer. However, several issues are raised including the identification of biomarkers to predict treatment response and strategies to counteract emerging resistance. Moreover, the results from ongoing phase III trials of olaparib in breast cancer are still awaited.
Topics: Animals; Antineoplastic Agents; BRCA1 Protein; BRCA2 Protein; Biomarkers, Tumor; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Mutation; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 28395540
DOI: 10.1080/13543784.2017.1318847 -
The Lancet. Oncology Jul 2014Maintenance monotherapy with the PARP inhibitor olaparib significantly prolonged progression-free survival (PFS) versus placebo in patients with platinum-sensitive... (Randomized Controlled Trial)
Randomized Controlled Trial
Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial.
BACKGROUND
Maintenance monotherapy with the PARP inhibitor olaparib significantly prolonged progression-free survival (PFS) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer. We aimed to explore the hypothesis that olaparib is most likely to benefit patients with a BRCA mutation.
METHODS
We present data from the second interim analysis of overall survival and a retrospective, preplanned analysis of data by BRCA mutation status from our randomised, double-blind, phase 2 study that assessed maintenance treatment with olaparib 400 mg twice daily (capsules) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more platinum-based regimens and who had a partial or complete response to their most recent platinum-based regimen. Randomisation was by an interactive voice response system, stratified by time to progression on penultimate platinum-based regimen, response to the most recent platinum-based regimen before randomisation, and ethnic descent. The primary endpoint was PFS, analysed for the overall population and by BRCA status. This study is registered with ClinicalTrials.gov, number NCT00753545.
FINDINGS
Between Aug 28, 2008, and Feb 9, 2010, 136 patients were assigned to olaparib and 129 to placebo. BRCA status was known for 131 (96%) patients in the olaparib group versus 123 (95%) in the placebo group, of whom 74 (56%) versus 62 (50%) had a deleterious or suspected deleterious germline or tumour BRCA mutation. Of patients with a BRCA mutation, median PFS was significantly longer in the olaparib group than in the placebo group (11·2 months [95% CI 8·3-not calculable] vs 4·3 months [3·0-5·4]; HR 0·18 [0·10-0·31]; p<0·0001); similar findings were noted for patients with wild-type BRCA, although the difference between groups was lower (7·4 months [5·5-10·3] vs 5·5 months [3·7-5·6]; HR 0·54 [0·34-0·85]; p=0·0075). At the second interim analysis of overall survival (58% maturity), overall survival did not significantly differ between the groups (HR 0·88 [95% CI 0·64-1·21]; p=0·44); similar findings were noted for patients with mutated BRCA (HR 0·73 [0·45-1·17]; p=0·19) and wild-type BRCA (HR 0·99 [0·63-1·55]; p=0·96). The most common grade 3 or worse adverse events in the olaparib group were fatigue (in ten [7%] patients in the olaparib group vs four [3%] in the placebo group) and anaemia (seven [5%] vs one [<1%]). Serious adverse events were reported in 25 (18%) patients who received olaparib and 11 (9%) who received placebo. Tolerability was similar in patients with mutated BRCA and the overall population.
INTERPRETATION
These results support the hypothesis that patients with platinum-sensitive recurrent serous ovarian cancer with a BRCA mutation have the greatest likelihood of benefiting from olaparib treatment.
FUNDING
AstraZeneca.
Topics: Aged; Anemia; Antineoplastic Agents; Disease-Free Survival; Fatigue; Female; Genes, BRCA1; Genes, BRCA2; Germ-Line Mutation; Humans; Maintenance Chemotherapy; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Cystic, Mucinous, and Serous; Ovarian Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Proportional Hazards Models; Retrospective Studies
PubMed: 24882434
DOI: 10.1016/S1470-2045(14)70228-1 -
JAMA Oncology Dec 2022Triple-negative breast cancer (TNBC) cells are sensitive to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors used as radiosensitizers. Whether combining...
IMPORTANCE
Triple-negative breast cancer (TNBC) cells are sensitive to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors used as radiosensitizers. Whether combining PARP inhibitors with radiotherapy in patients with TNBC would enhance the biological effectiveness of the irradiation and improve locoregional control is unclear.
OBJECTIVE
To assess the safety and tolerability of PARP inhibition with olaparib used concurrently with radiotherapy in patients with TNBC with residual disease after neoadjuvant chemotherapy.
DESIGN, SETTING, AND PARTICIPANTS
This phase 1 prospective dose-escalation trial (Olaparib and Radiation Therapy for TNBC [RadioPARP] trial) using a time-to-event continual reassessment method was performed from September 2017 to November 2019, with follow-up until November 2021. Participants had an incomplete pathologic response after neoadjuvant chemotherapy or unresectable TNBC despite previous neoadjuvant chemotherapy, an Eastern Cooperative Oncology Group Performance Status score of 0 or 1, and adequate organ functions.
INTERVENTIONS
Olaparib was administered orally in the form of tablets and given at increasing doses (50 mg, 100 mg, 150 mg, or 200 mg twice daily). Olaparib therapy was started 1 week before radiotherapy and was continued concomitantly with radiotherapy. After breast-conserving surgery, a total dose of 50.4 Gy was delivered to the whole breast, with a 63-Gy simultaneously integrated boost to the tumor bed for patients younger than 60 years. After radical mastectomy or for unresectable tumors despite neoadjuvant chemotherapy, a total dose of 50.0 Gy was delivered to the chest wall (after mastectomy) or to the whole breast (for unresectable tumors). Regional lymph node stations could be treated with a total dose of 50.0 Gy to 50.4 Gy in cases of node-positive disease.
MAIN OUTCOMES AND MEASURES
Main outcomes were the safety and tolerability of PARP inhibition with radiotherapy for early-stage, high-risk TNBC. Secondary outcomes included overall survival (OS) and event-free survival (EFS).
RESULTS
Among the 24 patients included in the trial (100% female; median age, 46 years [range, 25-74 years]), no dose-limiting toxic effects were observed, and olaparib was escalated to 200 mg twice daily without reaching the maximum tolerated dose. No late treatment-related grade 3 or greater toxic effect was observed, and the maximum observed treatment-related toxic effects at the 2-year follow-up were grade 2 breast pain, fibrosis, and deformity in 1 patient (4.2%). Three-year OS and EFS were 83% (95% CI, 70%-100%) and 65% (95% CI, 48%-88%), respectively. Homologous recombination status was not associated with OS or EFS.
CONCLUSIONS AND RELEVANCE
The findings of this phase 1 dose-escalation trial suggest that PARP inhibition with olaparib concurrently with radiotherapy for early-stage, high-risk TNBC is well tolerated and should continue to be evaluated in further clinical trials.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03109080.
Topics: Humans; Female; Middle Aged; Male; Triple Negative Breast Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Prospective Studies; Antineoplastic Combined Chemotherapy Protocols; Mastectomy
PubMed: 36301572
DOI: 10.1001/jamaoncol.2022.5074 -
Annals of Oncology : Official Journal... Oct 2022In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and BRCA mutation significantly... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy of subsequent chemotherapy for patients with BRCA1/2-mutated recurrent epithelial ovarian cancer progressing on olaparib versus placebo maintenance: post-hoc analyses of the SOLO2/ENGOT Ov-21 trial.
BACKGROUND
In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and BRCA mutation significantly improved progression-free survival (PFS) and prolonged overall survival (OS). Following disease progression on olaparib, efficacy of subsequent chemotherapy remains unknown.
PATIENTS AND METHODS
We conducted a post-hoc hypothesis-generating analysis of SOLO2 data to determine the efficacy of different chemotherapy regimens following RECIST disease progression in patients who received olaparib or placebo. We evaluated time to second progression (TTSP) calculated from the date of RECIST progression to the next progression/death.
RESULTS
The study population comprised 147 patients who received chemotherapy as their first subsequent treatment after RECIST progression. Of these, 69 (47%) and 78 (53%) were originally randomized to placebo and olaparib arms, respectively. In the placebo-treated cohort, 27/69 and 42/69 received non-platinum and platinum-based chemotherapy, respectively, compared with 24/78 and 54/78, respectively, in the olaparib-treated cohort. Among patients treated with chemotherapy (N = 147), TTSP was significantly longer in the placebo than in the olaparib arm: 12.1 versus 6.9 months [hazard ratio (HR) 2.17, 95% confidence interval (CI) 1.47-3.19]. Similar result was obtained on multivariable analysis adjusting for prognostic factors at RECIST progression (HR 2.13, 95% CI 1.41-3.22). Among patients treated with platinum-based chemotherapy (n = 96), TTSP was significantly longer in the placebo arm: 14.3 versus 7.0 months (HR 2.89, 95% CI 1.73-4.82). Conversely, among patients treated with non-platinum-based chemotherapy (n = 51), the TTSP was comparable in the placebo and olaparib arms: 8.3 versus 6.0 months (HR 1.58, 95% CI 0.86-2.90).
CONCLUSIONS
Following progression from maintenance olaparib in the recurrent setting, the efficacy of platinum-based subsequent chemotherapy seems to be reduced in BRCA1/2-mutated patients with PSROC compared to patients not previously receiving poly (ADP-ribose) polymerase inhibitors (PARPi). The optimal strategy for patients who relapse after PARPi is an area of ongoing research.
Topics: Adenosine Diphosphate; Antineoplastic Agents; BRCA1 Protein; BRCA2 Protein; Carcinoma, Ovarian Epithelial; Disease Progression; Female; Humans; Maintenance Chemotherapy; Neoplasm Recurrence, Local; Ovarian Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Ribose
PubMed: 35772665
DOI: 10.1016/j.annonc.2022.06.011 -
European Journal of Cancer (Oxford,... May 2023In the Phase III OlympiAD study, olaparib significantly prolonged progression-free survival versus chemotherapy treatment of physician's choice (TPC) in patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
OlympiAD extended follow-up for overall survival and safety: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.
BACKGROUND
In the Phase III OlympiAD study, olaparib significantly prolonged progression-free survival versus chemotherapy treatment of physician's choice (TPC) in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2-negative metastatic breast cancer (mBC). In the final pre-specified analysis (64% maturity), median overall survival (OS) was 19.3 months for olaparib and 17.1 months for TPC (P = 0.513). Post-hoc extended follow-up, 25.7 months longer than previously reported for OS, is reported.
PATIENTS AND METHODS
Patients with gBRCAm, human epidermal growth factor receptor 2-negative mBC, who had received ≤2 lines of chemotherapy for metastatic disease, were randomised 2:1 to olaparib (300 mg bid) or TPC. During extended follow-up, OS was analysed every 6 months using the stratified log-rank test (overall population) and Cox proportional hazards model (pre-specified subgroups).
RESULTS
In the overall population (302 patients; 76.8% maturity), median OS was 19.3 months for olaparib and 17.1 months for TPC (hazard ratio 0.89, 95% confidence interval 0.67-1.18); median follow-up was 18.9 and 15.5 months, respectively. Three-year survival was 27.9% for olaparib versus 21.2% for TPC. With olaparib, 8.8% of patients received study treatment for ≥3 years versus none with TPC. In first-line mBC, median OS was longer for olaparib than TPC (22.6 versus 14.7 months; hazard ratio 0.55, 95% confidence interval 0.33-0.95) and 3-year survival was 40.8% for olaparib versus 12.8% for TPC. No new serious adverse events related to olaparib were observed.
CONCLUSIONS
OS was consistent with previous analyses from OlympiAD. These findings support the possibility of meaningful long-term survival benefit with olaparib, particularly in first-line mBC.
Topics: Female; Humans; Breast Neoplasms; Follow-Up Studies; Germ-Line Mutation; Phthalazines; Physicians; Genes, BRCA1; Genes, BRCA2
PubMed: 36893711
DOI: 10.1016/j.ejca.2023.01.031 -
Expert Review of Clinical Pharmacology Sep 2018Germ line BRCA mutations (gBRCAm) are diagnosed in approximately 5% of unselected breast cancer patients. Olaparib is a new treatment option for patients with a gBRCAm... (Review)
Review
Germ line BRCA mutations (gBRCAm) are diagnosed in approximately 5% of unselected breast cancer patients. Olaparib is a new treatment option for patients with a gBRCAm who have metastatic HER2-negative breast cancer. Areas covered: Olaparib is an oral poly (ADP-ribose) polymerase inhibitor that has been shown in phase I-III clinical trials to have single-agent efficacy in breast cancer patients with gBRCAm. The recent phase III OlympiAD study demonstrated a statistically significant progression-free survival benefit compared with the chemotherapy control arm, although an overall survival benefit has not been demonstrated. The most common adverse events seen with olaparib include nausea, anemia, and vomiting. The most common grade 3 adverse events are anemia and neutropenia. Expert commentary: The US FDA-approved olaparib tablets in January 2018 for the treatment of patients with a gBRCAm and metastatic HER2-negative breast cancer. This is a well-tolerated and effective treatment option for this patient population, particularly in patients with triple-negative breast cancer in which chemotherapy is the only alternative. More data are needed to understand the role of olaparib in combination with endocrine therapy, other targeted agents, and chemotherapy, as well as sequentially with platinum chemotherapy in the metastatic setting.
Topics: Antineoplastic Agents; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Disease-Free Survival; Germ-Line Mutation; Humans; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Triple Negative Breast Neoplasms
PubMed: 30118334
DOI: 10.1080/17512433.2018.1513321 -
Annals of Oncology : Official Journal... Feb 2023In the phase III PAOLA-1 study, the addition of maintenance olaparib to bevacizumab in patients with newly diagnosed high-grade ovarian cancer (HGOC) resulted in...
Association of location of BRCA1 and BRCA2 mutations with benefit from olaparib and bevacizumab maintenance in high-grade ovarian cancer: phase III PAOLA-1/ENGOT-ov25 trial subgroup exploratory analysis.
BACKGROUND
In the phase III PAOLA-1 study, the addition of maintenance olaparib to bevacizumab in patients with newly diagnosed high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for homologous recombination deficiency-positive tumors, including those with a BRCA mutation (BRCAm). The magnitude of benefit from olaparib and bevacizumab according to the location of mutation in BRCA1/BRCA2 remains to be explored.
PATIENTS AND METHODS
Patients with advanced-stage HGOC responding after platinum-based chemotherapy + bevacizumab received maintenance therapy bevacizumab (15 mg/kg q3w for 15 months) + either olaparib (300 mg b.i.d. for 24 months) or placebo. PFS was analyzed in the subgroup of patients with BRCA1m/BRCA2m according to mutation location in the functional domains of BRCA1 [Really Interesting Gene (RING), DNA-binding domain (DBD), or C-terminal domain of BRCA1 (BRCT)] and BRCA2 [RAD51-binding domain (RAD51-BD); DBD].
RESULTS
From 806 randomized patients, 159 harbored BRCA1m (19.7%) and 74 BRCA2m (9.2%). BRCA1m in RING, DBD, and BRCT domains was detected in 18, 40, and 33 patients, and BRCA2m in RAD51-BD and DBD in 36 and 13 patients, respectively. After a median follow-up of 25.5 months, benefit from maintenance olaparib + bevacizumab was observed irrespective of location of BRCAm. The benefit was particularly high for those with BRCA1m located in the DBD, with 24-month PFS estimated to be 89% and 15% [olaparib + bevacizumab versus placebo + bevacizumab hazard ratio = 0.08 (95% confidence interval 0.02-0.28); interaction P = 0.03]. In BRCA2m patients, 24-month PFS rates for those with mutations located in the DBD were 90% and 100% (olaparib + bevacizumab versus placebo + bevacizumab), respectively.
CONCLUSIONS
Advanced-stage BRCA-mutated HGOC patients reported PFS benefit from maintenance olaparib and bevacizumab regardless of mutation location. The benefit is particularly high for patients with mutations located in the DBD of BRCA1. Mutations located in the DBD of BRCA2 are also associated with excellent outcome.
Topics: Humans; Female; Bevacizumab; Antineoplastic Agents; Ovarian Neoplasms; BRCA1 Protein; Phthalazines; Mutation; Maintenance Chemotherapy; BRCA2 Protein
PubMed: 36564284
DOI: 10.1016/j.annonc.2022.11.003 -
Drugs Feb 2015Olaparib (Lynparza™) is an oral, small molecule, poly (ADP-ribose) polymerase inhibitor being developed by AstraZeneca for the treatment of solid tumours. The primary... (Review)
Review
Olaparib (Lynparza™) is an oral, small molecule, poly (ADP-ribose) polymerase inhibitor being developed by AstraZeneca for the treatment of solid tumours. The primary indication that olaparib is being developed for is BRCA mutation-positive ovarian cancer. A capsule formulation of the drug has received approval for use in this setting in the EU and USA, and a tablet formulation is in global phase III trials (including in the USA, EU, Australia, Brazil, Canada, China, Israel, Japan, Russia and South Korea). In addition, phase III trials in breast, gastric and pancreatic cancer are underway/planned, and phase I/II investigation is being conducted in other malignancies, including prostate cancer, non-small cell lung cancer, Ewing's sarcoma and advanced cancer. This article summarizes the milestones in the development of olaparib leading to this first approval for ovarian cancer.
Topics: Administration, Oral; Animals; Antineoplastic Agents; BRCA1 Protein; BRCA2 Protein; Clinical Trials, Phase III as Topic; Drug Approval; Female; Humans; Molecular Structure; Mutation; Ovarian Neoplasms; Phthalazines; Piperazines
PubMed: 25616434
DOI: 10.1007/s40265-015-0345-6 -
British Journal of Clinical Pharmacology Jan 2016Olaparib is used to treat BReast CAncer susceptibility protein (BRCA)-associated, platinum-sensitive ovarian cancer. Olaparib inhibits poly(ADP-ribose) polymerase,...
Olaparib is used to treat BReast CAncer susceptibility protein (BRCA)-associated, platinum-sensitive ovarian cancer. Olaparib inhibits poly(ADP-ribose) polymerase, thereby blocking the repair of single-strand DNA breaks. This results in synthetic lethality in BRCA-associated cancer cells, which have a dysfunction of another DNA repair pathway - homologous recombination.
Topics: Antineoplastic Agents; DNA Repair; Humans; Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 26344419
DOI: 10.1111/bcp.12761 -
Expert Review of Anticancer Therapy Oct 2018Despite treatment strategies which include both surgery and chemotherapy, epithelial ovarian cancer often relapses and survival rates remain poor. There is therefore a... (Review)
Review
Despite treatment strategies which include both surgery and chemotherapy, epithelial ovarian cancer often relapses and survival rates remain poor. There is therefore a need to identify novel treatment targets and develop approaches that improve outcomes. The role of both germ line and somatic mutations in BRCA1 and BRCA2 in the development of ovarian cancer is well established, with mutation in either gene resulting in deficiencies in homologous recombination. Olaparib is an orally active inhibitor of poly(ADP-ribose) polymerase (PARP) which has demonstrated anti-tumor activity in ovarian cancer. Areas covered: This review focuses on the rationale for olaparib therapy in the context of relapsed epithelial ovarian cancer associated with a BRCA1 or BRCA2 mutation and summarizes the existing efficacy and safety data in this context. Ongoing phase III trials will be discussed. Expert commentary: Research regarding the optimal use of olaparib in the context of relapsed epithelial ovarian cancer associated with a BRCA mutation continues, with evidence for its use as maintenance therapy, treatment as a single agent and in combination with other targeted agents. The mechanisms of resistance require further exploration and it remains to be established whether retreatment or combination with other agents are viable treatment strategies.
Topics: Animals; Antineoplastic Agents; BRCA1 Protein; BRCA2 Protein; Carcinoma, Ovarian Epithelial; Female; Humans; Mutation; Neoplasm Recurrence, Local; Ovarian Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 30092674
DOI: 10.1080/14737140.2018.1510323