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Table of Contents
DRUG REVIEW
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 335-346

Olaparib: A narrative drug review


1 Department of Medical Oncology, Hemat-Oncology and Bone Marrow Transplant, Paras Hospital, Gurugram, Haryana, India
2 Department of Medical Oncology, Dr. B.R.A. IRCH, AIIMS, New Delhi, India

Date of Submission15-May-2021
Date of Decision07-Jun-2021
Date of Acceptance14-Jun-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Vibhor Sharma
Department of Medical Oncology, Paras Hospital, C-1, Sushant Lok 1, Sector 43, Gurugram - 122 002, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_107_21

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  Abstract 


Olaparib is an oral anticancer drug that inhibits the poly adenosine diphosphate-ribose polymerase protein (PARP). It is approved for use in advanced ovarian, breast, pancreatic, and prostate cancers. For this review, we comprehensively searched the PubMed database and Google for randomized trials and meta-analyses using the keywords “breast cancer,” “pancreatic cancer,” “ovarian cancer,” “prostate cancer,” and “olaparib.” A total of 78 randomized studies, meta-analyses, and other studies were identified, of which 70 were finally included. In this review, we have attempted to elucidate the history, pharmacokinetics, pharmacodynamics, adverse event profile, and special scenarios nvolving the use of olaparib. In addition, we have briefly reviewed the existing literature for its use in ovarian, pancreatic, breast, and prostate cancers.

Keywords: Breast cancer mutations, homologous recombination deficiency, olaparib, poly adenosine diphosphate-ribose polymerase inhibitors, PARP


How to cite this article:
Sharma V, Sharma A. Olaparib: A narrative drug review. Cancer Res Stat Treat 2021;4:335-46

How to cite this URL:
Sharma V, Sharma A. Olaparib: A narrative drug review. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Jul 24];4:335-46. Available from: https://www.crstonline.com/text.asp?2021/4/2/335/320161




  Introduction Top


Hereditary breast and ovarian cancer (HBOC) syndrome is characterized by an increased risk of breast and ovarian cancers, including Fallopian tube and primary peritoneal cancers. Patients with HBOC syndrome may also be at an increased risk of melanoma, pancreatic cancer, and prostate cancer. Breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) are the most commonly implicated genes in HBOC syndrome. As per a retrospective analysis of the results of BRCA testing in cancer patients and their relatives fulfilling the criteria for testing for BRCA mutations, the prevalence of pathogenic BRCA1 or BRCA2 mutations was 31.9% in the Indian population.[1],[2] The risk of malignancy depends on whether HBOC syndrome is caused by a mutation in BRCA1 or BRCA2. This knowledge has opened up new avenues of targeted anticancer therapies for these malignancies. Olaparib (AZD2281) is a small-molecule inhibitor of the poly (adenosine diphosphate-ribose) polymerase (PARP) family of proteins, including PARP1, PARP2, and PARP3. The chemical formula of olaparib is C24H23FN4O3 [Figure 1].[3] Olaparib is effective in patients with cancer harboring BRCA1 and BRCA2 germline mutations and in those with homologous recombination deficiency. Initially, olaparib was used in relapsed ovarian cancers only. In the recent years, the use of olaparib has been approved for many new indications. Unlike some of the other newer targeted agents, olaparib is available in India.[4] In view of the ever-increasing indications and settings for olaparib use, we performed a review of the published literature on olaparib. We have focused on the history, chemistry, pharmacology, presently approved indications, and key clinical trials pertaining to olaparib. [Table 1] depicts an overview of the key features of olaparib.
Figure 1: Chemical structure of olaparib (C24H23FN4O3) (Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 23725625, Olaparib. Available from: https://pubchem. ncbi.nlm.nih. gov/compound/Olaparib.)

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Table 1: Key features of olaparib

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  Methods Top


We performed a PubMed and Google search for meta-analyses, randomized controlled trials, and other articles published on olaparib in the English language using the keywords, “breast cancer,” “pancreatic cancer,” “ovarian cancer,” “prostate cancer,” and “olaparib.” A total of 78 records were identified; after removing the duplicates and articles for which a full-text version was not available, 70 randomized controlled trials, meta-analyses, and other articles were included in this review [Figure 2].
Figure 2: Flow diagram for identification of studies to be included in the review

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  History Top


The PARP enzyme was discovered over 50 years ago in Paul Mendel's laboratory.[5] By 1980, it was established that DNA damage activates the PARP1 enzyme, and that it plays a vital role in repairing single-strand DNA breaks.[6] Studies have shown that the inhibition of PARP can lead to an increase in the cytotoxic effects of methylating agents in leukemic mouse cells.[7] This suggested that PARP inhibitors could serve as chemosensitizers. A total of 17 members of the PARP superfamily have been identified to date, of which PARP1 and PARP2 are known to be involved in DNA repair.[8] Initially, the potential of PARP inhibitors as chemo- and radiosensitizers was explored,[9] however, later, they were evaluated as single agents, with selective toxicity in cells with abnormalities in their DNA repair pathways, such as those harboring BRCA1 and BRCA2 mutations. Olaparib was the first PARP inhibitor to get approval from the United States Food and Drug Administration (USFDA).


  Developmental Timeline for Olaparib Top


In June 2014, the USFDA advisory committee sanctioned the accelerated approval of olaparib. In December 2014, the USFDA approved olaparib for the treatment of advanced ovarian cancer. In August 2017, olaparib was approved for the maintenance treatment of ovarian cancer. In January 2018, it was approved for use in metastatic breast cancer with germline BRCA mutations. In December 2018, the USFDA approved olaparib for maintenance treatment in BRCA-mutated advanced ovarian cancer in the first-line setting. In December 2019, olaparib was approved for use as first-line maintenance treatment in metastatic pancreatic cancer with germline BRCA mutations. In May 2020, it was approved as maintenance treatment for homologous recombination deficiency-positive advanced ovarian cancer in the first-line setting in combination with bevacizumab and as a single agent for metastatic castration-resistant prostate cancer with mutations in the homologous recombination repair genes.[10]


  Mechanism of Action Top


Olaparib inhibits the PARP enzymes, including PARP1, PARP2, and PARP3. The nucleotide base excision repair pathway plays an important role in the repair of single-strand DNA breaks. PARP is a vital component of this pathway.[8],[11] Inhibition of PARP reduces the ability of the base excision repair pathway to repair the single-strand DNA breaks, thus leading to double-strand DNA breaks. These double-strand DNA breaks are then usually repaired either by homologous recombination or non-homologous end joining, thus overcoming the loss of function of base excision repair. In tumors with homologous recombination deficiency, such as those with BRCA1 and BRCA2 mutations,[12],[13] inhibition of PARP does not allow the cells to repair the DNA damage, thus resulting in cell death, a concept referred to as synthetic lethality [Figure 3].[14],[15] Moreover, the inhibition of the enzymatic activity of PARP with an increased formation of PARP-DNA complexes can also lead to cell death.
Figure 3: Mechanism of action of olaparib

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  Mechanism of Resistance Top


The mechanisms of resistance to olaparib[16],[17] include:

  • Increased drug efflux due to increased expression of the P-glycoprotein transporter
  • Reduced expression of the p53-binding protein 1, a critical component of the double-strand DNA breaks signaling and repair pathway
  • Reversion mutations in BRCA1 or BRCA2 which result in the restoration of BRCA function
  • Loss of Rev7 expression and function leading to the restoration of homologous recombination.



  Absorption Top


Absorption of orally ingested olaparib is rapid. Olaparib achieves peak plasma concentrations between 1 and 3 hours after administration. Fatty food can decrease the rate of absorption of olaparib but does not affect the systemic exposure.[18] The effect of food on olaparib pharmacokinetics is not deemed clinically significant.[19]


  DistributioN Top


About 82% of the drug binds to the plasma proteins. Steady-state blood levels are achieved in 3–4 days with daily dosing.


  Metabolism Top


Olaparib is metabolized mainly in the liver by the cytochrome P450 3A4 (CYP3A4) microsomal enzymes. The drug is largely metabolized by oxidation reactions, with several of the metabolites subsequently undergoing glucuronide or sulfate conjugation. The half-life of olaparib is 5–7 hours.[18] A Phase I study showed that the mean maximal extent of PARP inhibition in the mononuclear cells of the peripheral blood was 50.6% and in the tumor tissue was 70%.[20] Around 90% of the drug is excreted, 42% in the feces and 44% in the urine, mainly in the form of metabolites.


  Indications Top


  • Treatment of germline BRCA-mutated advanced epithelial ovarian cancer after three or more prior lines of chemotherapy
  • Maintenance treatment of recurrent platinum-sensitive epithelial ovarian, Fallopian tube, or primary peritoneal cancer with complete or partial response to platinum-based chemotherapy
  • Treatment of germline BRCA mutation-positive, HER2-negative metastatic breast cancer that has already been treated with chemotherapy
  • Maintenance treatment of metastatic pancreatic cancer with germline BRCA1 or BRCA2 mutations in those who have not progressed on first-line platinum-based chemotherapy
  • Treatment of castration-resistant metastatic prostate cancer in those with defects in the homologous recombination repair pathway and those who have progressed on either enzalutamide or abiraterone.



  Dosage and Administration Top


  • 300 mg twice daily orally for olaparib tablets
  • 400 mg twice daily for olaparib capsules



  Drug Interactions Top


Drugs inducing the CYP3A4 microsomal enzymes may increase the metabolism of olaparib, resulting in potentially reduced clinical activity. Drugs that inhibit the liver microsomal CYP3A4 enzymes can reduce the metabolism of olaparib, resulting in potentially increased toxicity.


  Special Considerations Top


  1. Dose modification is not required in patients with mild hepatic impairment. No data are available for olaparib use in patients with moderate-to-severe hepatic impairment
  2. Dose modification is not needed in patients with mild renal impairment (creatinine clearance [CrCl]: 50–80 ml/min). In those with moderate renal dysfunction (CrCl: 31–50 ml/min), reduce the dose to 200 mg twice daily. Olaparib has not been studied in those with severe renal dysfunction (CrCl <30 ml/min or patients on dialysis)
  3. Closely monitor for new-onset pulmonary symptoms, and if pneumonitis is confirmed, olaparib therapy should be stopped
  4. Pregnancy category D, i.e., there is evidence of risk to the human fetus. However, the potential benefits may outweigh the risks and therefore, an individualized decision is recommended
  5. Close monitoring of blood counts at monthly intervals is needed. In case of prolonged hematologic toxicities, stop the therapy and monitor the complete blood count weekly until recovery. If blood counts do not normalize in 4 weeks, cytogenetic and bone marrow analyses should be performed to rule out myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML).



  Toxicities Top


Toxicities associated with olaparib include the following:

  1. Fatigue, anorexia, and asthenia
  2. Increased risk of infections, especially pharyngitis and upper respiratory tract infections
  3. Pneumonitis – fever, dyspnea, cough, and wheezing
  4. Arthralgia and myalgia
  5. Nausea, vomiting, constipation, diarrhea, and abdominal pain
  6. Myelosuppression with anemia, thrombocytopenia, and neutropenia
  7. Risk of MDS and AML.


In a meta-analysis evaluating the occurrence of fatigue and anemia in patients receiving olaparib for various cancer types, all-grade fatigue was seen in 40% and high-grade fatigue in 3.7% of the patients. The relative risk of all-grade fatigue was 1.24 and that of high-grade fatigue was 1.71. The relative risk of all-grade anemia was 2.10 and that of high-grade anemia was 3.15.[21]

Another meta-analysis assessed the risk of gastrointestinal toxicities in patients receiving PARP inhibitors for ovarian cancer.[22] This analysis showed that the use of PARP inhibitors was associated with an increased risk of high-grade nausea and vomiting. A safety meta-analysis examined the risk of AML and MDS in patients exposed to PARP inhibitors for various indications. It concluded that PARP inhibitors significantly increased the risk of AML and MDS (Peto odds ratio, 2.63; 95% confidence interval [CI], 1.13–6.14; P = 0.026). The incidence of MDS and AML was 0.73% in the PARP inhibitor group and 0.47% in the placebo group. The median latency period after the first exposure to a PARP inhibitor was 17.8 months. This delayed adverse effect has important implications, especially in the setting of first-line maintenance treatment.[23]


  Olaparib Capsules and Tablets Top


Olaparib in a capsule formulation dosed at 400 mg twice daily was approved in 2014. Olaparib in a tablet formulation dosed at 300 mg twice daily was approved in 2018. A study showed that the 300 mg twice daily tablet dose provided a statistically superior efficacy compared to the 200 mg twice daily capsule dose, and that the risk of adverse effects was similar for the two doses.[24] The pharmacokinetics of olaparib capsule and tablet formulations were compared in a meta-analysis. This meta-analysis showed that the relative exposure of the tablet formulation (300 mg) was 13% higher than that of the capsule formulation (400 mg), thereby providing a key evidence to support the approval of the 300 mg tablet formulation of olaparib.[25]


  Olaparib in Ovarian Cancer Top


Olaparib was first used in the treatment of carcinoma of the ovary in the platinum-sensitive relapsed setting, post multiple lines of chemotherapy. Study 19 was a Phase II randomized trial that evaluated the role of olaparib as maintenance in platinum-sensitive relapsed carcinoma of the ovary.[26] It included patients who had been treated with a minimum of two lines of platinum-based chemotherapy and had achieved at least a complete or partial response to the latest regimen. This trial showed that a 400 mg twice daily maintenance dose of olaparib capsules led to a significant prolongation of the progression-free survival (PFS) (median PFS, 8.4 months vs. 4.8 months) compared to the placebo (hazard ratio [HR], 0.35; P < 0.001). Patients in the olaparib arm experienced greater adverse events (nausea, vomiting, fatigue, and anemia) compared to those in the placebo arm. No significant difference in the overall survival (OS) was observed between the two arms (HR, 0.94; P = 0.75) in the first interim analysis of OS (at 38% maturity).[26] However, notably, olaparib maintenance did not result in any detrimental impact on the health-related quality of life (HRQoL) of the patients.[27]

In addition, in the Study 19 trial, patients with BRCA1 or BRCA2 mutations (approximately 21% of the study population) had significantly better PFS outcomes with olaparib as compared to placebo (median PFS, 11.2 vs. 4.3 months; HR, 0.18; P < 0.0001).[28] The second interim analysis of OS in this trial (at 58% maturity) also showed no significant difference in the OS between the two groups (HR, 0.88; P = 0.44).[28] Even in patients with BRCA1 or BRCA2 mutations, the OS was not significantly different between the olaparib and placebo arms (HR, 0.73; P = 0.19). However, in the placebo arm, a significant proportion of the patients with BRCA mutations received PARP inhibitors after progression. Upon excluding such patients, an improvement in the HR for the OS was observed (HR, 0.52; 95% CI, 0.28–0.97).[29] The updated results of the OS from the Study 19 trial (at 77% data maturity) showed that patients with BRCA mutations receiving olaparib maintenance appeared to have a longer OS (olaparib maintenance – 34.9 months, placebo – 30.2 months; HR, 0.62; 95% CI, 0.41–0.94; P = 0.025) though the difference did not cross the prespecified significance threshold. Long-term exposure to olaparib was not associated with any new safety signals.[30]

The SOLO2 study evaluated the efficacy of olaparib maintenance in patients with platinum-sensitive, relapsed, high-grade serous, or endometrioid carcinoma of the ovary (including primary peritoneal carcinoma and Fallopian tube cancer) with germline or somatic BRCA1 or BRCA2 mutation who had received two or more prior lines of chemotherapy. In this Phase III randomized study, the tablet formulation of olaparib was used at a dose of 300 mg twice daily. The PFS was longer in the olaparib maintenance arm than in the placebo arm (median PFS, 19.1 vs. 5.5 months; HR, 0.30; P < 0.0001). The incidence of fatigue (Grade 3/4) and anemia was higher in the olaparib maintenance arm.[31] In the SOLO2 study, patients in the olaparib maintenance arm did not experience detrimental effects on their quality of life (QoL) when compared to those in the placebo arm. Moreover, there were clinically meaningful patient-reported benefits despite the side effects of olaparib.[32]

The SOLO1 trial evaluated the efficacy of olaparib as maintenance therapy in patients with advanced ovarian cancer in the first-line setting. In this randomized Phase III trial, patients with advanced ovarian cancers (Stage 3/4 high-grade serous or endometrioid ovarian cancer, including primary peritoneal and Fallopian tube cancers) with somatic or germline mutations in BRCA1 and BRCA2 who had a partial or complete response to platinum-based chemotherapy were randomized to receive either maintenance therapy with olaparib at a dose of 300 mg twice daily or placebo. The primary endpoint of the SOLO1 trial was PFS. At a median follow-up of 41 months, the risk of progression or death in the olaparib arm was 70% lower than that in the placebo arm. The 3-year PFS was 60% in the olaparib arm and 27% in the placebo arm (HR, 0.3; 95% CI, 0.23–0.41; P < 0.001). The median duration of olaparib treatment was 24.6 months. The most common and serious side effect in the olaparib arm was anemia. The safety profile of olaparib in the SOLO1 trial was similar to that seen in the SOLO2 trial.[33]

The cost-effectiveness of olaparib maintenance treatment in BRCA1- or BRCA2-mutant carcinomas of the ovary after first-line platinum-based chemotherapy was studied in Italy. These authors reported that maintenance therapy with olaparib could be considered to provide value by virtue of a significant benefit in health. Using the base case scenario, the incremental cost-effectiveness ratio was €9,515 per life-year gained, the incremental cost-utility ratio was €11,345 per quality-adjusted life-year gained, and the incremental net monetary benefit was €12,104.[34]

Patients with carcinoma of the ovary with germline BRCA mutations receiving maintenance olaparib should be evaluated for disease status by contrast-enhanced computed tomography scan rather than cancer antigen 125 (CA125) alone. In the SOLO2 trial, around 50% percent of the patients who did not have disease progression as per the CA125 status had progression as per the Response Evaluation Criteria in Solid Tumors.[35]

Another study showed that long-term response to maintenance olaparib in relapsed ovarian cancer was correlated with complete response to chemotherapy, germline or somatic BRCA1 and BRCA2 mutations, and homologous recombination repair deficiency (Myriad score >42). In addition, the study found that most of the long-term responders had BRCA2 mutations.[36]

Olaparib in combination with chemotherapy has also been used in relapsed carcinoma of the ovary. A randomized Phase II study in patients with platinum-sensitive relapsed carcinoma of the ovary (with either wild-type or mutant BRCA) compared the combination of olaparib + paclitaxel + carboplatin followed by olaparib maintenance, with paclitaxel + carboplatin chemotherapy alone. Remarkable improvement was observed in the PFS in the combination arm (median PFS, 12.2 vs. 9.6 months; HR, 0.51; P = 0.0012). The benefit of olaparib was greater in the BRCA-mutant subset of patients (HR, 0.21; P = 0.0015).[37]

Olaparib in combination with antiangiogenic targeted therapy has been used in ovarian cancers. The PAOLA-1 trial evaluated the efficacy of olaparib and bevacizumab maintenance in advanced ovarian cancers in the first-line setting. In this randomized Phase III trial, patients with high-grade ovarian cancers, with or without homologous recombination deficiency, and with wild-type or mutant BRCA, who had responded to first-line taxane + platinum + bevacizumab combination, were enrolled. After the completion of treatment with the platinum + taxane + bevacizumab combination, the patients were randomized to receive either bevacizumab plus placebo maintenance or bevacizumab plus olaparib maintenance. The PAOLA-1 study showed significantly improved PFS in the bevacizumab plus olaparib maintenance arm (median PFS, 22.1 vs. 16.6 months, HR, 0.59; P < 0.001). Patients with homologous recombination deficiency, who also had a BRCA mutation, received the maximum benefit from the addition of olaparib (median PFS, 37.2 vs. 17.7 months; HR, 0.33). Likewise, patients with homologous recombination deficiency who had wild-type BRCA also benefited from the addition of olaparib (median PFS, 28.1 vs. 16.6 months; HR, 0.43). Fatigue, nausea, and anemia were more frequent in the olaparib + bevacizumab arm, whereas hypertension was more frequent in the bevacizumab + placebo arm.[38]

Another study compared the efficacy of the combination of olaparib plus cediranib with that of olaparib alone in relapsed platinum-sensitive ovarian cancers. The median PFS was found to be significantly longer in the olaparib plus cediranib arm (17.7 vs. 9.0 months; HR, 0.42; P = 0.005). Patients with BRCA mutations (19.4 vs. 16.5 months; P = 0.16) as well as those with wild-type BRCA or unknown BRCA status (16.5 vs. 5.7 months; P = 0.008) benefited from the combination therapy.[39] A Phase II trial in patients with relapsed platinum-sensitive ovarian cancers compared the efficacy of the combination of cediranib plus olaparib with that of single-agent olaparib.[40] The median PFS was found to be significantly longer in the cediranib plus olaparib arm (16.5 vs. 8.2 months; P = 0.007). There was no statistically significant difference in the OS between the two arms. However, both PFS and OS were significantly longer in the combination arm in the subset of patients with wild-type BRCA or unknown BRCA status. Contrarily, the PFS and OS were not significantly different between the two arms in the subset of patients with germline BRCA mutations. This study concluded that the combination of cediranib plus olaparib resulted in a better PFS in platinum-sensitive relapsed ovarian cancer and this improvement was driven by the patients with wild-type or unknown BRCA status.[40]

Non-platinum single-agent chemotherapy is commonly used in patients with extensively pretreated relapsed carcinoma of the ovary, as platinum-based chemotherapy has been shown to confer a survival advantage only in the first- and second-line settings in these patients. In patients with a germline BRCA mutation and carcinoma of the ovary, who have relapsed within 1 year of platinum-based chemotherapy, a study showed no statistically significant difference in the PFS between those who received olaparib and liposomal doxorubicin.[41]

SOLO3 was a Phase III randomized trial in patients with a germline BRCA mutation and relapsed carcinoma of the ovary who had received a minimum of two prior lines of platinum-based chemotherapy. This trial compared the efficacy of olaparib with that of non-platinum chemotherapy in the above setting. Patients enrolled in this trial received either olaparib at a dose of 300 mg twice daily or physician's choice single-agent non-platinum chemotherapy (gemcitabine, liposomal doxorubicin, paclitaxel, or topotecan). The objective response rate (ORR) and PFS were found to be significantly better in the olaparib arm (ORR, 72.2% vs. 51.4%, P = 0.002; median PFS, 13.4 vs. 9.2 months, P = 0.013). The incidence of Grade 3/4 anemia and fatigue was higher in the olaparib arm. Treatment discontinuation resulting from adverse events was greater in the chemotherapy arm.[42]

The Cochrane database review of PARP inhibitors in ovarian cancer showed that in comparison to placebo, adding olaparib to conventional treatment or using it as maintenance treatment led to an improvement in the PFS (HR, 0.42; 95% CI, 0.29–0.60) but not in the OS (HR, 1.05; 95% CI, 0.79–1.39) of patients with platinum-sensitive ovarian cancers. Olaparib maintenance treatment resulted in a higher incidence of adverse events of Grade 3/4 as compared to the placebo (risk ratio, 1.74; 95% CI, 1.22–2.49). Anemia and fatigue were the most frequent serious adverse events in the olaparib arm.[43]

A meta-analysis on the use of PARP inhibitors in ovarian cancers showed that PARP inhibitors resulted in an improvement in the PFS in both primary and recurrent ovarian cancers.[44] In this meta-analysis, 12 Phase II/III randomized clinical studies on a total of 5171 patients were included. In patients with platinum-sensitive recurrent ovarian cancers, PARP inhibitors led to an improvement in the PFS as compared to the placebo, irrespective of their BRCA mutation and/or homologous recombination deficiency status (HR, 0.37). Patients with BRCA mutations (HR, 0.29) and homologous recombination deficiency (HR, 0.34) benefitted more from the addition of PARP inhibitors. In patients with platinum-sensitive relapsed ovarian cancers, the combination of chemotherapy with PARP inhibitors led to better PFS as compared to chemotherapy alone, irrespective of their BRCA mutation and homologous recombination deficiency status (HR, 0.50), with greater benefit in patients with BRCA mutations (HR, 0.19). The addition of PARP inhibitors to antiangiogenic drugs (cediranib or bevacizumab) in patients with platinum-sensitive relapsed ovarian cancers also led to an improvement in the PFS, irrespective of the BRCA mutation and homologous recombination deficiency status (HR, 0.38). In the first-line setting in patients with ovarian cancers, after the completion of standard treatment, maintenance with PARP inhibitors improved the PFS in those with BRCA mutations (HR, 0.33). However, this improvement in the PFS with PARP inhibitors came at the cost of higher rates of severe anemia and fatigue.[44]

Olaparib is also being evaluated in patients with relapsed platinum-resistant carcinoma of the ovary. A study to evaluate biomarker-driven therapy in platinum-resistant carcinoma of the ovary is currently ongoing (AMBITION trial). In this study, patients with homologous recombination deficiency-positive tumors will be randomized to receive either olaparib plus cediranib or olaparib plus durvalumab. Those with homologous recombination deficiency-negative tumors will be randomized according to the programmed death-ligand 1 status.[45]


  Olaparib in Breast Cancer Top


Germline mutations in BRCA1 and BRCA2 are seen in 5%–10% of the patients with breast cancer.[46] Triple-negative breast cancer (TNBC) constitutes about 80% of such cases.[47] The ICEBERG 1 study assessed the utility of olaparib in patients with germline BRCA-mutant metastatic breast cancers. In this study, pretreated patients with metastatic breast cancer harboring germline BRCA1 or BRCA2 mutations had an ORR of 41% for olaparib at a dose 400 mg twice daily.[48]

Study 42, a multicentric, Phase II study, examined the efficacy of olaparib in a spectrum of advanced solid cancers (ovarian, breast, pancreatic, and prostate cancers) in patients with germline BRCA mutations. Patients with breast cancer included in this study had received three or more prior lines of chemotherapy for metastatic disease. The ORR in patients with breast cancer was 12.9%, and an additional 47% of the patients achieved stable disease for ≥8 weeks.[49]

The OlympiAD study[50] was a Phase III randomized trial that compared olaparib monotherapy (300 mg oral tablets twice daily) with standard therapy (vinorelbine, eribulin, or capecitabine) in patients with HER2-negative metastatic breast cancer with germline BRCA mutations. Patients included in this study had to have received up to two lines of chemotherapy for metastatic breast cancer, including anthracyclines and taxanes. Patients with hormone receptor-positive breast cancer had to have progressed on at least one line of endocrine therapy. The median PFS was longer with olaparib than with chemotherapy (7.0 vs. 4.2 months; HR, 0.58; 95% CI, 0.43–0.80; P < 0.001).[50] In addition, the response rate was better with olaparib (59.9% for olaparib versus 28.8% for standard therapy). The benefit in patients with TNBC (HR, 0.43; 95% CI, 0.29–0.63) was greater than in those with hormone receptor-positive breast cancer (HR, 0.82; 95% CI, 0.55–1.26). No statistically significant difference in the OS (secondary endpoint) was observed between the two groups (P = 0.51). At 64% data maturity, the median OS in the olaparib arm was 19.3 months compared to 17.1 months in the chemotherapy arm (HR, 0.90; 95% CI, 0.66–1.23; P = 0.513).[51] Adverse events of Grade 3/4 were noted in 36.6% of the patients in the olaparib arm and 50.5% of the patients who received standard therapy. The most common adverse event overall for patients who received olaparib was nausea; anemia was the most frequent Grade 3 adverse event (observed in 16% of the patients). Most of the adverse events caused by olaparib could be managed by supportive care or dose modification. About 4.9% of the patients in the olaparib arm and 7.7% in the standard therapy arm discontinued the treatment because of adverse events. Patients in the olaparib arm had an improvement in their QoL, which was maintained for longer than those receiving standard therapy. A clinically meaningful reduction in the QoL occurred at a median of 15.3 months in the standard therapy arm compared to not reached the olaparib arm (HR, 0.44; 95% CI, 0.25–0.77; P = 0.004).[52] Thus, the OlympiAD study demonstrated a meaningful improvement in the PFS, with less treatment-related toxicity and improved QoL in patients with germline BRCA-mutant metastatic breast cancers, who had relapsed on chemotherapy.[53]

A subgroup analysis of Asian patients in the OlympiAD study[54] showed that this subgroup attained a longer median PFS with olaparib than with chemotherapy (5.7 vs. 4.2 months; HR, 0.53; 95% CI, 0.29–0.97). This was similar to the trend observed in the global OlympiAD study population. The safety data of the Asian patients were also consistent with those of the overall population. Although the OlympiAD study was not powered to detect ethnic differences, the findings of the subgroup analysis suggest that the results of the OlympiAD study are generalizable to the Asian patients.[54]

Following the success of olaparib in metastatic breast cancer, it is now being studied in germline BRCA-mutant breast cancers as neoadjuvant and adjuvant therapy. The OlympiA study[55] was a randomized Phase III trial evaluating the efficacy and safety of olaparib as adjuvant therapy for 12 months in patients with high-risk germline BRCA-mutant HER2-negative breast cancer who had completed local treatment and six cycles of neoadjuvant chemotherapy containing anthracyclines and taxanes. This study enrolled patients with TNBC (≥ pT2 or ≥pN1 in the adjuvant setting or non-pathological complete response in the neoadjuvant setting) or high-risk hormone receptor-positive breast cancers (≥4 axillary nodes in the adjuvant setting or non-pathological complete response and clinical-pathologic stage-estrogen/grade [CPS-EG] score ≥3 in the neoadjuvant setting). Invasive disease-free survival was the primary endpoint of this study.[55] A planned interim analysis revealed that the 3-year invasive disease-free survival was significantly better in the olaparib arm than placebo (85.9% vs. 77.1%, respectively; HR, 0.58; 95% CI, 0.41–0.82; P < 0.001). The 3-year distant disease-free survival was also significantly better in the olaparib arm at 87.5% than in the placebo arm at 80.4% (HR, 0.57; 95% CI, 0.39–0.83; P < 0.001).[56]

A clinical trial on the combination of olaparib plus chemotherapy (carboplatin) in the treatment of BRCA1- and BRCA2-mutant metastatic breast cancers is ongoing.[57] This study is planned in two phases. In the second phase, patients with germline BRCA mutations and HER2-negative metastatic breast cancers will be randomized to receive either capecitabine or two cycles of olaparib plus carboplatin combination therapy followed by olaparib monotherapy at a dose of 300 mg twice daily.

A meta-analysis showed that olaparib significantly improved the PFS (HR, 0.43; 95% CI, 0.29–0.64) and ORR (HR, 2.57; 95% CI, 1.31–5.09) of patients with TNBC as compared to chemotherapy. Olaparib was noted to lead to a greater benefit over all the other therapies, as per a treatment rank probability analysis.[58] This could have resulted from the similarities in the gene expression profiles of patients with BRCA1-deficient breast cancers and sporadic TNBCs.


  Olaparib in Pancreatic Cancer Top


Germline mutations in BRCA1 and BRCA2 were seen in a small subset (4%–7%) of patients with metastatic pancreatic cancers.[59],[60] The POLO trial[61] was a randomized Phase III study that assessed the efficacy of olaparib as maintenance therapy in patients with metastatic carcinoma of the pancreas harboring germline mutations in BRCA1 and BRCA2 genes, who had not progressed on first-line platinum-based chemotherapy. The subjects were randomly allocated to receive either olaparib at a dose of 300 mg twice daily or placebo. The endpoint of the study was PFS. The median PFS in the olaparib arm was significantly longer than that in the placebo arm (7.4 vs. 3.8 months; HR, 0.53; 95% CI, 0.35–0.82; P = 0.004). The HRQoL was not significantly different between the olaparib and placebo arms. Adverse events of Grade ≥3 were seen in 40% of the patients in the olaparib arm and 23% of those in the placebo arm. Adverse events led to treatment discontinuation in 5% and 2% of the patients in the olaparib and placebo arms, respectively. The POLO trial showed that in patients with germline BRCA-mutant metastatic pancreatic cancers, who have not progressed on first-line platinum-based chemotherapy, maintenance olaparib provided a significant PFS benefit.[61]

The final data of the POLO study showed no significant difference in the OS between the olaparib and placebo arms (median OS, 19.0 vs. 19.2 months, respectively; HR, 0.83 favoring olaparib; 95% CI, 0.56–1.22; P = 0.3487). The 3-year OS was 33.9% for the olaparib arm and 17.8% for the placebo arm.[62] The median PFS2 (time from randomization to second disease progression or death) was 16.9 months in the olaparib arm and 9.3 months in the placebo arm (HR, 0.66; 95% CI, 0.43–1.02; P = 0.0613).


  Olaparib in Prostate Cancer Top


Deleterious aberrations in the genes involved in DNA repair are seen in up to 30% of the patients with metastatic castration-resistant prostate cancer.[63],[64],[65] BRCA1 and BRCA2 repair the DNA damage through the homologous recombination repair pathway.

The PROfound trial[66] was a Phase III study that evaluated the efficacy of olaparib in patients with metastatic castration-resistant prostate cancer, harboring alterations in one of the genes involved in homologous recombination repair. The primary endpoint of the study was imaging-based PFS. Eligible patients who had progressed on abiraterone or enzalutamide were included. Those who had received previous taxane-based chemotherapy were also included. There were two cohorts of patients in this trial. Cohort A included patients with alterations in the BRCA1, BRCA2, or ataxia–telangiectasia-mutated genes. Cohort B included patients who had alterations in any of the other 12 prespecified genes involved in homologous recombination repair. Patients were randomized to receive either olaparib or abiraterone/enzalutamide as per the physician's choice (control arm). The PROfound trial showed that the median PFS was significantly longer in the olaparib arm as compared to the control arm (7.4 vs. 3.6 months; HR = 0.34; 95% CI, 0.25–0.47; P < 0.001) in cohort A. For the cohorts A and B combined, the median PFS was 5.8 months and 3.5 months in the olaparib and control arms, respectively (HR, 0.49; 95% CI, 0.38–0.63; P < 0.001). The ORR was significantly better in the olaparib than in the control arm. In cohort A, the patients in the olaparib arm achieved pain control for a significantly longer duration than those in the control arm (HR, 0.44; 95% CI, 0.2–0.91; P = 0.02). Anemia, nausea, and fatigue were the most frequent adverse effects in the olaparib arm. Anemia was the most common Grade ≥3 adverse effect in the olaparib arm. This study concluded that in patients with metastatic castration-resistant prostate cancer who had progressed on enzalutamide or abiraterone and who had genetic defects in the homologous recombination repair pathway, olaparib led to a longer PFS, better response, and longer pain control as compared to enzalutamide or abiraterone.[66]

The OS in the PROfound study[67] was also significantly longer in the olaparib arm in cohort A. In cohort A, the median OS was 19.1 months and 14.7 months in the olaparib and control arms, respectively (HR, 0.69; 95% CI, 0.50–0.97; P = 0.02). This improvement in the OS was noted despite a substantial crossover from the control arm to the olaparib arm.

A Phase II randomized study[68] on patients with metastatic castration-resistant prostate cancer who had progressed on docetaxel compared the combination of olaparib tablets dosed at 300 mg twice daily plus abiraterone with abiraterone plus placebo. Patients enrolled in this study did not necessarily have mutations in the genes involved in the homologous recombination repair pathway. This study showed significantly improved radiological PFS in the olaparib plus abiraterone arm (PFS, 13.8 vs. 8.2 months; HR, 0.65; 95% CI, 0.44–0.97; P = 0.034). Adverse events of Grade ≥3 were more frequent in the olaparib plus abiraterone arm than in the abiraterone plus placebo arm (54% vs. 28%, respectively).

Another Phase II study[69] evaluated the response rates for olaparib in patients with metastatic castration-resistant prostate cancer, who had progressed on taxanes and had aberrations in the genes involved in DNA damage response. Patients were randomized to receive either 400 mg or 300 mg twice daily dose of olaparib. The composite response rate in those who received the 400 mg dose was 54.3% compared to 39.1% in those who received the 300 mg dose of olaparib. In this study, olaparib showed antitumor activity in patients with metastatic castration-resistant prostate cancer who had alterations in the genes involved in DNA damage response.

[Table 2] depicts the key trials of olaparib for various indications.
Table 2: Key clinical trials of olaparib

Click here to view



  Ongoing Clinical Trials of Olaparib Top


A large number of clinical trials are studying the utility of olaparib in various kinds of malignancies.[70] Ongoing trials of olaparib include:

  1. Olaparib in combination with pembrolizumab in metastatic pancreatic cancer
  2. Olaparib maintenance in resected pancreatic cancer
  3. The combination of olaparib with durvalumab and cediranib in relapsed ovarian cancer
  4. Olaparib in combination with temozolomide in advanced neuroendocrine cancers
  5. Olaparib with or without atezolizumab in unresectable or metastatic non-HER2 positive breast cancer
  6. Olaparib in patients with cholangiocarcinoma, advanced glioma, and isocitrate dehydrogenase (IDH) 1 and 2 mutant solid tumors
  7. Olaparib in combination with ramucirumab in metastatic or recurrent gastric or gastroesophageal junction cancers
  8. Olaparib in combination with radium-223 in metastatic castration-resistant prostate cancer with bone metastases
  9. Olaparib in combination with abiraterone and prednisolone in metastatic castration-resistant prostate cancer
  10. Olaparib in combination with ceralasertib in IDH mutant cholangiocarcinoma
  11. Olaparib in combination with cediranib combination in advanced metastatic solid tumors, including non-small -ell lung cancer, small cell lung cancer, pancreatic cancer, and breast cancer
  12. Olaparib in previously treated homologous recombination repair mutation or homologous recombination deficiency-positive advanced cancer
  13. Olaparib in relapsed refractory AML or MDS with IDH mutations
  14. Olaparib in combination with durvalumab in non-metastatic prostate cancer.



  Conclusion Top


Olaparib is rapidly emerging as a part of the treatment armamentarium in clinically difficult scenarios of metastatic solid tumors such as ovarian, breast, prostate, and pancreatic cancers. With the increasing application of next-generation sequencing and improved understanding of the molecular pathways of carcinogenesis, olaparib may find its use in other tumors with defects in the homologous recombination repair pathways.

Acknowledgments

I wish to acknowledge the help provided by the technical support team at Paras Hospital, Gurugram. I wish to thank my parents for their support and encouragement.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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