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Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, Leuven Cancer Institute, Catholic University Leuven, Herestraat 49, 3000 Leuven, Belgium, European Union
Several biomarker tests are available to determine patient selection for PARPis.
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These tests identify tumours with HRD and help determine sensitivity to PARPis.
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We reviewed biomarker tests to assess HRD and their relevance for PARPi treatment.
Abstract
Poly (ADP-ribose) polymerase inhibitors (PARPis) have demonstrated clinical activity in patients with BRCA1 and/or BRCA2 mutated breast, ovarian, prostate, and pancreatic cancers. Notably, BRCA mutations are associated with defects in the homologous recombination repair (HRR) pathway. This homologous recombination deficiency (HRD) phenotype can also be observed as genomic instability in tumour cells. Accordingly, PARPi sensitivity has been observed in various tumours with HRD, independent of BRCA mutations. Currently, four PARPis are approved by regulatory agencies for the treatment of cancer across multiple tumour types. Most indications are specific to tumours with a confirmed BRCA mutation, mutations in other HRR-related genes, HRD evidenced by genomic instability, or evidence of platinum sensitivity. Regulatory agencies have also approved companion and complementary diagnostics to facilitate patient selection for each PARPi indication. This review aims to summarise the biological basis, clinical validation, and clinical relevance of the available diagnostic methods and assays to assess HRD.
]. In the past decade, PARP inhibitors (PARPis) have emerged as a new class of anticancer drugs in multiple cancers, including ovarian (niraparib, olaparib and rucaparib), metastatic castration-resistant prostate (mCRPC; olaparib and rucaparib), breast (olaparib and talazoparib) and metastatic pancreatic (olaparib) [
]. Predicting benefit from PARPis is critical for optimal clinical use, and several biomarker tests are available to determine patient selection for PARPis across treatment settings, with more tests in development [
]. These tests identify tumours with defects in DNA repair pathways, most specifically the homologous recombination repair (HRR) pathway, which make them vulnerable to PARPis. Choice of the appropriate biomarker test depends on tumour type and may even differ by line of therapy for the same tumour type, thereby presenting challenges for the clinician. This review aims to enhance the understanding of different biomarker tests to assess homologous recombination deficiency (HRD) and their relevance for PARPi treatment selection in different tumour types.
2. HRD in cancer
Numerous genes have been implicated in the HRR pathway, including those encoding sensor proteins involved in DSB detection (i.e. γH2AX, ATM and ATR), signal mediator proteins (i.e. BRCA1, BRCA2 and PALB2), and an effector protein (RAD51) that promotes strand invasion and replication fork stabilisation (Fig. 1) [
]. The best-characterised HRR genes in relation to cancer are BRCA1 and BRCA2, which have been associated with breast, ovarian, pancreatic and prostate cancers [
Fig. 1Measuring HRD. (A) The identification of mutations in BRCA and other HRR-related genes and detecting genomic instability are two principal ways to detect HRD. (B) Notably, LOH, TAI and LST are all measures of genomic instability. Abbreviations: HRD, homologous recombination deficiency; HRR, homologous recombination repair; LOH, loss of heterozygosity; LST, large-scale state transitions; TAI, telomeric allelic imbalance.
HRD is characterised by an inability to repair DNA DSBs through the HRR pathway. Causes of HRD are not always known but include loss-of-function mutations and epigenetic modifications in HRR-related genes, particularly BRCA1 and/or BRCA2 [
], which may manifest as loss of heterozygosity (LOH; existence of a single allele resulting from a cross-chromosomal event that leads to the loss of entire genes and the surrounding chromosomal region [
In 2014, olaparib became the first PARPi approved by the US Food and Drug Administration (FDA) specifically for treating germline BRCA-mutated metastatic ovarian cancer after ≥3 lines of chemotherapy [
FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy.
]. Currently, four PARPis (olaparib, rucaparib, talazoparib and niraparib) are approved by regulatory agencies for the treatment of multiple tumour types. Most indications are specific to tumours with a confirmed BRCA mutation, other HRR mutation, or HRD genomic instability (Supplementary Table 1), but PARPi therapy is also broadly indicated for patients with platinum-sensitive disease relapse [
]. The prevalence of BRCA mutations have been reported to range from 1% to 15% (BRCA1) and 2%–6% (BRCA2) in advanced/metastatic breast cancer, 12%–15% (BRCA1) and 5%–7% (BRCA2) in ovarian cancer, 0.3%–1% (BRCA1) and 5%–6% (BRCA2) in metastatic prostate cancer and 0.3%–2.3% (BRCA1) and 0.7%–5.7% (BRCA2) in pancreatic cancer [
]. However, clinical data have shown that PARPi therapy can be efficacious for patients who test negative with existing HRD diagnostics as well as for patients whose tumours are driven by other HRR mutations or HRD genomic instability that is unrelated to BRCA mutations [
Efficacy and safety of niraparib as maintenance treatment in patients with newly diagnosed advanced ovarian cancer using an individualized starting dose (PRIME study): a randomized, double-blind, placebo- controlled, phase 3 trial.
]. Accordingly, PARPi biomarker tests that are currently available can be categorised into three approaches depending on how they aim to detect the presence of HRD in tumour cells, which include identifying the presence of a mutation that causes HRD (e.g. BRCA mutations), detecting genomic instability (indicative of HRD) or directly testing HRR function in a cellular assay [
The first approach is evaluating tumour mutation status by gene sequencing of a panel of specified genes known to cause HRD. BRCA1 and BRCA2 are the most well-characterised HRR genes in terms of their relationship to cancer and should always be evaluated. This approach can be expanded to include multiple other genes related to the HRR pathway, but, in some diseases, such as first-line ovarian cancer, non-BRCA HRR mutations do not predict PARPi response, while HRD genomic instability has been predictive (Fig. 1) [
Homologous recombination repair mutation gene panels (excluding BRCA) are not predictive of maintenance olaparib plus bevacizumab efficacy in the first-line PAOLA-1/ENGOT-ov25 trial.
]. Emerging evidence suggests that other HRR gene alterations may be associated with different PARPi sensitivity.
The second approach investigates whether the consequences of HRD, namely genomic instability, are present by identifying chromosomal aberrations (i.e. genomic scars), which are changes in the genome as a consequence of the dysfunctional HRR pathway (both direct and indirect) including LOH, TAI and LST [
]. Given the recognition of BRCA mutations as an archetypal cause of HRD, BRCA testing is invariably conducted. As such, some assays combine the measurement of both the HRR mutations (i.e. BRCA) and HRD genomic instability approaches.
The third approach directly evaluates HRR function in tumour cells to determine if there is proficiency. An example of a functional assay is the RAD51 foci assay, which measures the capacity of tumour cells to recruit nuclear RAD51 foci during the S/G2 cell cycle phase in the presence of DSBs using immunofluorescence [
]. Functional assays provide a measure of HRR competency, which may be important when, for example, a reversion mutation results in a tumour switching from HRD status to being HRR proficient [
] summarises the HRD diagnostics for various PARPi indications. These assays use a variety of sample types (blood or tumour tissue). Other tests for HRR mutations and HRD genomic instability, including locally developed tests, are being established, validated and commercialised.
Table 1HRD diagnostics for PARPis.
Diagnostic
Sample used
Biomarkers evaluated
Cancer type (regulatory-approved PARPi)
Test category
FoundationOne®CDx is a comprehensive genomic profiling test that detects substitutions, insertion and deletion alterations and copy number alterations in 324 genes and select gene rearrangements, including a number of HRR genes, as well as genomic signatures including MSI and TMB. LOH is evaluated for patients with ovarian cancer. FoundationOne CDx defines positive HRD status as a BRCA mutation in the tumour and/or LOH-high. On this device, assessment of LOH is designated by the FDA as a complementary, not companion, diagnostic [
A number of BRCA1/BRCA2 tests are also designated CE-IVD.
Diagnostic
Sample used
Biomarkersevaluated
Cancer type
Test category
Myriad MyChoice®CDx PLUS is a next-generation sequencing based in vitro diagnostic device that provides sequencing and large rearrangement analyses on a panel of genes and/or detects genomic instability [
HRR gene panel analysis of this test is not covered by the CE-IVD claim.
is a deep learning–powered diagnostic application leveraging low-pass whole genome sequencing in conjunction with a convolutional neural network–based deep-learning algorithm to produce the Genomic Integrity Index. This score measures the extent of genomic scarring across the genome as a result of mutations within genes associated with HRR, yielding HRD impact on tumour samples [
PPP2R2A, PTEN, RAD51B, RAD51C, RAD51D, RAD54L and TP53
Ovarian cancer
HRR mutation test and HRD genomic instability test
AmoyDx® HRD Focus Panel is a next-generation sequencing-based in vitro diagnostic assay intended for qualitative determination of HRD status via detection and classification of single nucleotide variants and insertions and deletions in protein coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes and the determination of the Genomic Scar Score, which is an algorithmic measurement of genomic instability status [
5. Clinical validity and utility of HRR mutations and tests for HRD in various cancers
In the first-line maintenance treatment setting of ovarian cancer, the benefit of PARPis in BRCA-mutated tumours was demonstrated in randomised phase 3 trials (Table 2 [
Homologous recombination repair mutation gene panels (excluding BRCA) are not predictive of maintenance olaparib plus bevacizumab efficacy in the first-line PAOLA-1/ENGOT-ov25 trial.
Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.
Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial.
A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45).
Rucaparib versus chemotherapy in patients with advanced, relapsed ovarian cancer and a deleterious BRCA mutation: efficacy and safety from ARIEL4, a randomized phase III study.
Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial.
Newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal or fallopian tube cancer; complete or partial response after platinum-taxane chemotherapy plus bevacizumab
Deleterious germline BRCA1 or BRCA2 mutation (MyChoice® HRD Plus assay) HRD-positive defined as HRD score ≥42
PFS Overall: 22.1 versus 16.6 mo (HR 0.59; 95% CI: 0.49–0.72) BRCA-mutated HRD-positive: 37.2 versus 17.7 mo (HR 0.33; 95% CI: 0.25–0.45) Non-BRCA HRD-positive: 28.1 versus 16.6 mo (HR 0.43; 95% CI: 0.28–0.66)
Newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal or fallopian tube cancer; complete or partial response after platinum-based chemotherapy without bevacizumab
Deleterious or suspected deleterious germline or somatic BRCA1 and/or BRCA2 mutation (BRACAnalysis test)
PFS NR versus 13.8 mo (HR 0.30; 95% CI: 0.23–0.41) PFS rate at 3 years 60% versus 27%
Niraparib 300 mg/day (200 mg/day if bodyweight <77 kg; n = 487) versus placebo (n = 246)
Newly diagnosed, advanced high-grade serous or endometrioid ovarian, peritoneal or fallopian tube cancer; complete or partial response after platinum-based chemotherapy
HRD-positive defined as HRD score ≥42 and/or a deleterious BRCA mutation (MyChoice test)
PFS Overall: 13.8 versus 8.2 mo (HR 0.62; 95% CI: 0.50–0.76) HRD-positive: 21.9 versus 10.4 mo (HR 0.43; 95% CI: 0.31–0.59)
A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45).
Homologous recombination repair mutation gene panels (excluding BRCA) are not predictive of maintenance olaparib plus bevacizumab efficacy in the first-line PAOLA-1/ENGOT-ov25 trial.
Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial.
Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.
Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial.
Rucaparib versus chemotherapy in patients with advanced, relapsed ovarian cancer and a deleterious BRCA mutation: efficacy and safety from ARIEL4, a randomized phase III study.
HRD positivity (defined as a tumour with a BRCA mutation or a genomic instability score above a specified threshold for the HRD assay used) was also associated with a PFS benefit with PARPis in randomised phase 3 trials in the first-line maintenance treatment setting in advanced ovarian cancer (Table 2 [
Homologous recombination repair mutation gene panels (excluding BRCA) are not predictive of maintenance olaparib plus bevacizumab efficacy in the first-line PAOLA-1/ENGOT-ov25 trial.
Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.
Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial.
A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45).
Rucaparib versus chemotherapy in patients with advanced, relapsed ovarian cancer and a deleterious BRCA mutation: efficacy and safety from ARIEL4, a randomized phase III study.
Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial.
]). A recent exploratory analysis evaluating HRR mutations other than BRCA demonstrated that only a small percentage (4%) of patients with HRD-positive tumours without a BRCA mutation harbour other non-BRCA HRR mutations commonly included in the HRR mutation testing panel [
Homologous recombination repair mutation gene panels (excluding BRCA) are not predictive of maintenance olaparib plus bevacizumab efficacy in the first-line PAOLA-1/ENGOT-ov25 trial.
]. A PFS benefit with olaparib plus bevacizumab versus placebo plus bevacizumab was not observed in the subgroup of patients with non-BRCA HRR mutations; however, in a small number of these patients, HRD-positive status by genomic instability testing was predictive of a PFS benefit [
Homologous recombination repair mutation gene panels (excluding BRCA) are not predictive of maintenance olaparib plus bevacizumab efficacy in the first-line PAOLA-1/ENGOT-ov25 trial.
In patients with relapsed platinum-sensitive ovarian cancer, HRR mutation, HRD status and response to immediate platinum chemotherapy are all predictive of a PFS benefit with PARPis, as demonstrated by the findings from four clinical trials (Table 2 [
Homologous recombination repair mutation gene panels (excluding BRCA) are not predictive of maintenance olaparib plus bevacizumab efficacy in the first-line PAOLA-1/ENGOT-ov25 trial.
Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.
Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial.
A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45).
Rucaparib versus chemotherapy in patients with advanced, relapsed ovarian cancer and a deleterious BRCA mutation: efficacy and safety from ARIEL4, a randomized phase III study.
Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial.
The European Society for Medical Oncology Translational Research and Precision Medicine Working Group recently assessed evidence of predictive biomarkers in high-grade serous ovarian cancer and recommended the use of germline or somatic BRCA mutation testing and a validated scar-based (genomic instability) test for HRD to select patients for PARPi treatment in the first-line maintenance and in the platinum-sensitive relapsed settings [
]. This group concluded that evidence is currently insufficient to determine the clinical validity of non-BRCA HRR mutation, next-generation sequencing-based mutational signature, BRCA1 or RAD51C promoter methylation and functional assays for predicting a PARPi response [
]. Data on the clinical validity of somatic BRCA mutations, HRR mutations and HRD genomic instability tests in other cancers besides mCRPC are limited.
Olaparib, rucaparib and niraparib have demonstrated antitumour activity in people with BRCA-mutated mCRPC [
Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial.
Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial.
Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: analysis from the phase ii TRITON2 study.
]. PROfound was a randomised, open-label phase 3 trial evaluating olaparib versus physician's choice of hormone therapy (enzalutamide or abiraterone) in mCRPC with a qualifying alteration in any one of 15 HRR genes [
]. In patients with ≥1 alteration in BRCA1, BRCA2 or ATM, PFS was significantly prolonged for the olaparib versus the control group (median, 7.4 versus 3.6 months; hazard ratio [HR] 0.34; 95% CI: 0.25–0.47) and with statistically significant OS benefit (median, 19.1 versus 14.7 months; HR 0.69; 95% CI: 0.50–0.97; p = 0.0175) [
Final overall survival (OS) analysis of PROfound: olaparib vs physician’s choice of enzalutamide or abiraterone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.
]. A PFS benefit was also observed in the overall population (any HRR mutation) with an HR of 0.49 (95% CI: 0.38–0.63), and a trend toward improved OS was also seen (HR 0.79; 95% CI: 0.61–1.03; nominal p = 0.0515). The HR for PFS in patients with HRR mutations other than BRCA1, BRCA2 or ATM was 0.88. In the phase 2 TRITON2 trial, rucaparib was evaluated in patients with mCRPC and a non-BRCA HRR mutation. The trial found limited radiographic and prostate-specific antigen responses to rucaparib in patients with an alteration in ATM, CDK12 or CHEK2; patients with alterations in other HRR mutations (e.g. PALB2) may benefit from rucaparib, but the patient subgroup sizes were too small to make definitive conclusions; further investigation was deemed warranted [
Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: analysis from the phase ii TRITON2 study.
In advanced/metastatic breast cancer, olaparib has demonstrated a PFS benefit versus chemotherapy in patients with a germline BRCA mutation in two randomised, open-label phase 3 clinical trials [
]. In OlympiAD, olaparib significantly prolonged median PFS versus chemotherapy (7.0 versus 4.2 months; HR 0.58; 95% CI: 0.43–0.80) in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2-negative metastatic breast cancer treated with ≤2 previous chemotherapies. Olaparib has also been associated with a median PFS of 6.3 months (90% CI: 4.4–not available) in 16 patients with metastatic breast cancer and a somatic BRCA mutation [
]. In the EMBRACA study, talazoparib significantly prolonged median PFS versus chemotherapy in patients with a germline BRCA mutation and advanced breast cancer treated with ≤3 previous chemotherapies (8.6 versus 5.6 months; HR 0.54; 95% CI: 0.41–0.71) [
Approval of olaparib maintenance therapy for pancreatic cancer was based on results from the pivotal phase 3 POLO trial in patients with a germline BRCA1 or BRCA2 mutation and metastatic disease that had not progressed during first-line platinum-based chemotherapy. A PFS benefit in favour of olaparib versus placebo was reported (median, 7.4 versus 3.8 months; HR 0.53; 95% CI: 0.35–0.82) [
Patients with HRD tumours caused by a BRCA mutation represent the subgroup with the best-documented clinical benefit from a PARPi, and whether non-BRCA HRR mutations or HRD genomic instability tests best predict PARPi response by disease site requires further research in many indications. BRCA mutations remain the best-characterised measure of HRD and should always be assessed regardless of other assays that might be used (e.g. assessment of other HRR-related genes or HRD genomic instability). However, patients with HRD tumours without a BRCA mutation can benefit from PARPis in first-line ovarian cancer. HRD is a phenotype that can be measured in different ways, such as by identifying genomic scars or mutational signatures or by measuring HRR function. Further, HRD genomic instability gives a historical rather than a functional view of the genome, hence the interest in functional assays such as that for RAD51 foci. However, varying degrees of evidence exist for the predictive value of these different measures. Inconsistent use of terminology adds to the confusion over these tests. The regulatory-approved companion diagnostics are specific to each PARPi, tumour type, and treatment setting. HRR mutations and HRD genomic instability tests have different predictive power in different clinical settings and are not interchangeable. In newly diagnosed advanced ovarian cancer, HRD positivity by genomic instability tests, but not non-BRCA HRR mutations, are predictive of benefit from PARPi maintenance treatment after response to first-line platinum chemotherapy. In the relapsed setting, selection for benefit from PARPi is based on platinum sensitivity. HRR mutation tests have been validated in patients with prostate cancer whereas there are few data on the clinical validity of HRD genomic instability testing. Future clinical and translational studies are needed to further elucidate the mechanisms by which PARPis interact with HRD to inform treatment strategies and patient selection.
Funding
This work was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and AstraZeneca, Cambridge, UK.
Data sharing
Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD) is committed to providing qualified scientific researchers access to anonymised data and clinical study reports from the company's clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the US and EU or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses.
Author contributions
Thomas J. Herzog: Formal analysis; validation; draft writing; other – critically reviewing or revising the manuscript for important intellectual content and final approval.
Ignace Vergote: conceptualisation; validation; draft writing; other – critically reviewing or revising the manuscript for important intellectual content and final approval.
Leonard G. Gomella: conceptualisation; validation; other – critically reviewing or revising the manuscript for important intellectual content and final approval.
Tsveta Milenkova: conceptualisation; validation; other – critically reviewing or revising the manuscript for important intellectual content and final approval.
Tim French: conceptualisation; formal analysis; validation; draft writing; other – critically reviewing or revising the manuscript for important intellectual content and final approval.
Raffi Tonikian: formal analysis; other – critically reviewing or revising the manuscript for important intellectual content and final approval.
Christian Poehlein: conceptualisation; data curation; formal analysis; validation; draft writing; other – critically reviewing or revising the manuscript for important intellectual content and final approval.
Maha Hussain: other – critically reviewing or revising the manuscript for important intellectual content and final approval.
Conflict of interest statement
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TH reports scientific advisory boards for AstraZeneca, Caris, Clovis, Eisai, Epsilogen, Genentech, GSK, Immunogen, J&J, Merck, Mersana, and Seagen.
IV reports consulting for Agenus, Akesobio China, Amgen (Europe) GmbH, AstraZeneca, Bristol Myers Squibb, Clovis Oncology Inc., Carrick Therapeutics, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, F. Hoffmann-La Roche Ltd, Genmab, GSK, Immunogen Inc., Jazzpharma, Karyopharm, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Novartis, Octimet Oncology NV, Oncoinvent AS, Seagen, Sotio a.s., Verastem Oncology and Zentalis; contracted research (via KU Leuven) for Oncoinvent AS and Genmab; grant (i.e. corporate sponsored research) for Amgen and Roche and accommodations and/or travel expenses for Amgen, MSD, Tesaro, AstraZeneca and Roche.
LGG reports scientific advisory boards for AstraZeneca, Merck, Lantheus and Exelixis.
TM is an employee of AstraZeneca.
TF is an employee and stockholder of AstraZeneca.
RT is a former employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and stockholder of Merck & Co., Inc., Rahway, NJ, USA.
CP is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and stockholder of Merck & Co., Inc., Rahway, NJ, USA.
MH reports scientific advisory boards for Astra Zeneca, Merck, Janssen, Novartis, TEMPUS, Bayer, GSK, Pfizer and BMS.
Acknowledgements
This work was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and AstraZeneca LTD, Cambridge, UK, which are codeveloping olaparib. The funders participated in study design, data analysis and interpretation, and article writing. All authors had full access to the data and had final responsibility for the decision to submit the article for publication. Medical writing and/or editorial assistance was provided by Lei Bai, PhD, Max Chang, PhD, Holly C. Cappelli, PhD, CMPP, and Christina Vitolo of ApotheCom (Yardley, PA) and was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and AstraZeneca LTD, Cambridge, UK, which are codeveloping olaparib.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy.
Efficacy and safety of niraparib as maintenance treatment in patients with newly diagnosed advanced ovarian cancer using an individualized starting dose (PRIME study): a randomized, double-blind, placebo- controlled, phase 3 trial.
(SGO Annual Meeting on Women’s cancer. Abstract 244. Presented March 19, 2022) XX,
2022
Homologous recombination repair mutation gene panels (excluding BRCA) are not predictive of maintenance olaparib plus bevacizumab efficacy in the first-line PAOLA-1/ENGOT-ov25 trial.
Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.
Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial.
A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45).
Rucaparib versus chemotherapy in patients with advanced, relapsed ovarian cancer and a deleterious BRCA mutation: efficacy and safety from ARIEL4, a randomized phase III study.
(SGO Virtual Annual Meeting on Women's cancer; 2021; Virtual: March 19-25)2021
Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial.
Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial.
Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial.
Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: analysis from the phase ii TRITON2 study.
Final overall survival (OS) analysis of PROfound: olaparib vs physician’s choice of enzalutamide or abiraterone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.
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