Olaparib, an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), is an antineoplastic agent.1
First-line Maintenance Treatment of BRCA-mutated Advanced Ovarian Cancer
Olaparib is used for the maintenance treatment of adults with deleterious or suspected deleterious germline or somatic BRCA -mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy.1 The drug has been designated an orphan drug by FDA for the treatment of these cancers.3 An FDA-approved companion diagnostic test is required to confirm the presence of specific biomarkers prior to initiation of olaparib therapy for this indication.1
Efficacy and safety of olaparib for this indication are based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 trial (SOLO-1).1, 15 The SOLO-1 trial enrolled 391 adults with advanced (stage III or IV) high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer who had previously received first-line platinum-based chemotherapy.1, 15 All patients had confirmed or suspected deleterious germline or somatic BRCA 1/2 mutation, as determined by the Myriad BRACAnalysis test or other BRCA 1/2 genetic testing assay.15 Patients were randomized (stratified by clinical response after platinum-based chemotherapy) in a 2:1 ratio to receive olaparib 300 mg orally twice daily or placebo.15 Treatment was continued for up to 2 years or until disease progression or unacceptable toxicity; patients with evidence of disease at 2 years could continue treatment beyond 2 years at the discretion of the treating healthcare provider.1 The primary measure of efficacy was investigator-assessed progression-free survival.1, 15
The median age of patients who received olaparib was 53 years (range: 29-82 years); 85% had primary ovarian cancer, and the Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 77% of patients.1, 15 The median age of patients who received placebo was 53 years (range: 31-84 years); 86% had primary ovarian cancer, and the ECOG performance status was 0 in 80% of patients.1, 15 In the overall study population, 82% were white, and 82% were in complete response to their most recent platinum-based chemotherapy regimen; 389 or 2 patients had germline or somatic BRCA mutations, respectively.1 At a median follow-up of 41 months, the median investigator-assessed progression-free survival rate was 13.8 months in the placebo group, but had not been reached in the olaparib group.1, 15 The estimated rate of freedom from disease progression or death at 3 years was 60% in patients receiving olaparib and 27% in those receiving placebo.15 The results of the progression-free survival analysis based on investigator assessment were consistent with results from an independent blinded central review.1, 15 An interim analysis of overall survival data (data maturity, 21%) produced 3-year overall survival estimates of 84% in patients receiving olaparib and 80% in patients receiving placebo.15 Olaparib treatment did not have a clinically meaningful impact on quality of life at 24 months (assessed using the Functional Assessment of Cancer Therapy-Ovarian Cancer [FACT-O] Trial Outcome Index [TOI] score).15, 16
A post hoc analysis evaluated 5-year progression-free survival rates in the SOLO-1 trial.34 Median follow-up for this analysis was 4.8 years in the olaparib group and 5 years in the placebo group.34 In the olaparib group, median progression-free survival was 56 months compared to 13.8 months in the placebo group.34 The 5-year progression-free survival rate was 48% among patients who received olaparib and 21% among patients who received placebo.34 A prespecified 7-year analysis of overall survival in SOLO-1 was conducted after a median follow-up of 88.9 or 87.4 months for olaparib or placebo, respectively.35 The median overall survival was not reached for olaparib and was 75.2 months for placebo.35 Rates of 7-year survival were 67 or 46.5% among patients given olaparib or placebo, respectively.35 An estimated 45.3 or 20.6% of patients given olaparib or placebo, respectively, were alive at 7 years and had not received a first subsequent treatment.35
First-line Maintenance Treatment of Homologous Recombination Deficiency-positive Advanced Ovarian Cancer
Olaparib is used in combination with bevacizumab for the maintenance treatment of adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status (defined by a deleterious or suspected deleterious BRCA mutation and/or genomic instability).1 The drug has been designated an orphan drug by FDA for the treatment of these cancers.3 An FDA-approved companion diagnostic test is required to confirm the presence of specific biomarkers prior to initiation of olaparib therapy for this indication.1
Efficacy and safety of olaparib for this indication are based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 trial (PAOLA-1).1, 17 The PAOLA-1 trial enrolled a total of 806 adults with advanced (stage III or IV) high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.1, 17 Patients were required to have completely resected tumors or be in complete or partial response following completion of first-line platinum-based chemotherapy plus bevacizumab.1, 17 Patients were randomized (stratified by response to first-line therapy and tumor BRCA status) in a 2:1 ratio to receive olaparib 300 mg tablets orally twice daily in combination with bevacizumab 15 mg/kg IV every 3 weeks or placebo in combination with bevacizumab 15 mg/kg IV every 3 weeks.1, 17 Bevacizumab was initiated in combination with chemotherapy and continued as maintenance therapy for a total duration of up to 15 months.1, 17 Olaparib was initiated 3 to 9 weeks after completion of chemotherapy and continued for up to 2 years, or until disease progression or unacceptable toxicity occurred.1, 17 Patients could continue treatment beyond 2 years at the discretion of the treating healthcare provider.1 The primary measure of efficacy was investigator-assessed progression-free survival.1
Retrospective testing with the Myriad myChoice® HRD Plus tumor test identified 387 patients with HRD-positive tumors within the trial population.1, 17 Among these patients, the median age was 58 years (range: 32-82 years); 87% had primary ovarian cancer.1 The ECOG performance status was 0 in 75% of patients and 1 in 24% of patients.1 Outcomes after first-line treatment with platinum-based chemotherapy and bevacizumab were as follows: 36% had no evidence of disease with complete macroscopic resection at initial debulking surgery, 29% had no evidence of disease or complete response with complete macroscopic resection at interval debulking surgery, 16% had no evidence of disease or complete response after either incomplete resection or no debulking surgery, and 19% had a partial response.1 Deleterious BRCA mutations were present in 62% of patients treated with olaparib-bevacizumab and 58% of patients treated with placebo-bevacizumab.1
In the subgroup of patients with HRD-positive tumors, median investigator-assessed progression-free survival (at a median follow-up of 27 months) was 37.2 months in olaparib-treated patients and 17.7 months in patients assigned to placebo.1, 17 The results of the progression-free survival analysis based on investigator assessment were consistent with results from an independent blinded review.1 At the time of analysis, disease progression or death occurred in 34% of patients with HRD-positive tumors receiving olaparib-bevacizumab and 70% of those receiving placebo-bevacizumab.1
A final analysis of overall survival data was performed 3 years after the primary analysis (55% data maturity).36 Median duration of follow-up was 61.7 or 61.9 months for olaparib-bevacizumab or placebo-bevacizumab, respectively.36 Among patients with HRD-positive tumors, median overall survival was 75.2 months for olaparib-bevacizumab and 57.3 months for placebo-bevacizumab.1, 36 Death occurred in 36% of patients with HRD-positive tumors receiving olaparib-bevacizumab and 52% of those receiving placebo-bevacizumab.1
Maintenance Treatment of BRCA-mutated Recurrent Ovarian Cancer
Olaparib is used for the maintenance treatment of adults with deleterious or suspected deleterious germline or somatic BRCA -mutated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.1 The drug has been designated an orphan drug by FDA for the treatment of these cancers.3 An FDA-approved companion diagnostic test is required to confirm the presence of specific biomarkers prior to initiation of olaparib therapy for this indication.1
Efficacy and safety of olaparib for this indication are based principally on the results of a randomized, double-blind, placebo-controlled trial (SOLO-2).1, 18, 19 The SOLO-2 trial enrolled 295 adults with platinum-sensitive, germline BRCA -mutated, relapsed high-grade ovarian, fallopian tube, or primary peritoneal cancer.1, 18 Patients must have received at least 2 previous lines of chemotherapy and be in complete or partial response to their most recent platinum-based chemotherapy.1, 18 Patients were randomized (stratified by response to last platinum chemotherapy and time to disease progression after the penultimate platinum-based chemotherapy) in a 2:1 ratio to receive olaparib 300 mg tablets orally twice daily or placebo until disease progression or unacceptable toxicity.1, 18 The primary measure of efficacy was investigator-assessed progression-free survival.1, 18
In the SOLO-2 study, the median age of patients who received olaparib was 56 years (range: 28-83 years); the ECOG performance status was 0 in 83%, 17% had received prior bevacizumab therapy, and 44% had received 3 or more lines of platinum-based chemotherapy.1 The median age of patients who received placebo was 56 years (range: 39-78 years); the ECOG performance status was 0 in 78%, 20% had received prior bevacizumab therapy, and 37% had received 3 or more lines of chemotherapy.1 In the overall study population, 89% were white, 47% were in complete response to their most recent platinum-based regimen, and 40% had a progression-free interval of 6-12 months since their penultimate platinum regimen.1 All patients had a confirmed or suspected deleterious germline BRCA mutation detected by a local test or central Myriad CLIA test followed by confirmation by BRACAnalysis CDx®.1 Median investigator-assessed progression-free survival (at a median follow-up of 22 months) was 19.1 months in patients receiving olaparib and 5.5 months in patients receiving placebo.1, 18 The results of the progression-free survival analysis based on investigator assessment were consistent with results from an independent blinded review.1 At 2 years, rates of progression-free survival were 43% in patients receiving olaparib and 15% in patients receiving placebo.18 The final analysis of overall survival did not reach significance.1 Median overall survival at the time of final analysis (at a median follow-up of 65.7 months in patients receiving olaparib and 64.5 months in patients receiving placebo) was 51.7 months in patients receiving olaparib and 38.8 months in patients receiving placebo.1, 19 In an exploratory analysis that adjusted for subsequent PARP inhibitor therapy in the placebo group, median overall survival was 51.7 months in patients receiving olaparib and 35.4 months in patients receiving placebo.19
Newly Diagnosed Ovarian Cancer
Guidelines from the American Society of Clinical Oncology (ASCO) state that patients with newly diagnosed stage III or IV epithelial ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy should be offered PARP inhibitors as maintenance therapy in the presence of high-grade serous or endometroid ovarian cancer.37 Options for patients with germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 include olaparib, niraparib, or rucaparib.37 In the presence of HRD-positive disease, rucaparib and niraparib are options.37
For recurrent ovarian cancer, ASCO states that PARP inhibitor monotherapy may be used for second-line or greater maintenance treatment in PARP inhibitor-naïve patients with epithelial ovarian cancer who have responded to platinum-based regimens, regardless of BRCA mutation status.37 PARP inhibitor options include olaparib, rucaparib, and niraparib; treatment should be continued until disease progression or toxicity.37 In September 2023, the labeled use for olaparib maintenance therapy in recurrent ovarian cancer was restricted to patients with a tumor BRCA mutation only, based on the totality of information from other PARP inhibitors in the second or later line maintenance setting in ovarian cancer.48
Olaparib was previously labeled for use in the treatment of adults with confirmed or suspected deleterious germline BRCA -mutated advanced ovarian cancer previously treated with 3 or more chemotherapy regimens; however, this use was removed from the labeling in August 2022 based on the results of the SOLO-3 trial, which found a decrease in overall survival with olaparib compared to chemotherapy in the subgroup of patients who had received 3 or more prior lines of chemotherapy.37
Adjuvant Treatment of BRCA-mutated, HER2-negative High-risk Early Breast Cancer
Olaparib is used for the adjuvant treatment of adults with deleterious or suspected deleterious germline BRCA -mutated, human epidermal growth factor receptor type 2 (HER2)-negative, high-risk, early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy.1 An FDA-approved companion diagnostic test is required to confirm the presence of specific biomarkers prior to initiation of olaparib therapy for this indication.1
Efficacy and safety of olaparib for this indication are based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 trial (OlympiA).1, 38 The OlympiA trial enrolled 1836 patients with germline BRCA -mutated, HER2-negative high-risk early breast cancer who had received definitive local treatment and neoadjuvant or adjuvant chemotherapy (≥6 cycles containing anthracyclines, taxanes, or both).1 In patients who had received prior neoadjuvant chemotherapy, high-risk early breast cancer was defined as triple-negative breast cancer or hormone receptor-positive breast cancer with residual invasive cancer in the breast and/or resected lymph nodes at the time of surgery; patients with hormone receptor-positive breast cancer also had to have a score ≥3 points based on pre-treatment clinical and post-treatment pathologic stage, estrogen receptor status, and histologic grade.1 In patients who had received prior adjuvant chemotherapy, high-risk early breast cancer was defined as hormone receptor-positive, HER2-negative cancer with ≥4 positive lymph nodes or triple-negative breast cancer with node-positive disease or node-negative disease with a primary tumor ≥2 cm.1
Patients were randomly assigned (in a 1:1 ratio) to receive either olaparib 300 mg or matching placebo twice daily for 52 weeks or until disease recurrence or unacceptable toxicity.1, 38 The primary outcome assessed was invasive disease-free survival; overall survival was also assessed.1
The median age of patients enrolled in the trial was 42 years; 67% percent of patients were white and 29% were Asian.1 Most patients (89%) had an ECOG performance status of 0.1 Only 18% of patients had hormone receptor-positive breast cancer; the remaining 82% had triple-negative breast cancer.1 Half of the enrolled patients had received prior neoadjuvant chemotherapy, and half had received prior adjuvant chemotherapy.1 Prior treatments included anthracycline and taxane chemotherapy in 94% of patients and platinum-based therapies in 26%.1 Among patients with hormone receptor-positive breast cancer, 90% received concurrent endocrine therapy.1 At 3 years, the rate of invasive disease-free survival was 86% in the olaparib group and 77% in the placebo group.1 Overall survival was also greater with olaparib versus placebo, with 3-year overall survival rates of 93 and 89% in the olaparib and placebo groups, respectively.1
BRCA-mutated, HER2-negative Metastatic Breast Cancer
Olaparib is used for the treatment of adults with deleterious or suspected deleterious germline BRCA -mutated, HER2-negative, metastatic breast cancer previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting.1 Patients with hormone receptor-positive breast cancer should have been previously treated with endocrine therapy unless they were not candidates for endocrine therapy.1 An FDA-approved companion diagnostic test is required to confirm the presence of specific biomarkers prior to initiation of olaparib therapy for this indication.1
Efficacy and safety of olaparib for this indication are based principally on the results of a randomized, open-label, phase 3 trial (OlympiAD).1, 24, 25 The OlympiAD trial enrolled 302 adults with HER2-negative metastatic breast cancer and confirmed or suspected deleterious germline BRCA mutation detected on BRACAnalysis CDx® or local genetic testing.1, 24 Patients were required to have received previous therapy with an anthracycline (unless contraindicated) and a taxane in the neoadjuvant, adjuvant, or metastatic setting; patients with hormone receptor-positive breast cancer had to have progressed on at least 1 previous endocrine therapy, unless endocrine therapy was deemed inappropriate for the patient.1, 24 Patients who had previously received platinum chemotherapy were required to have no evidence of disease progression during platinum treatment.1, 24 Patients were randomized (stratified by prior use of chemotherapy for metastatic disease, hormone receptor status, and previous use of platinum-based chemotherapy) in a 2:1 ratio to receive olaparib 300 mg tablets orally twice daily or investigator's choice of chemotherapy (capecitabine, eribulin, or vinorelbine at standard doses) until disease progression or unacceptable toxicity.1, 24 The dosing regimens for capecitabine, eribulin, and vinorelbine were as follows: capecitabine 2.5 g/m2 (in 2 divided doses) orally daily on days 1-13 of each 21-day cycle; eribulin 1.4 mg/m2 IV on days 1 and 8 of each 21-day cycle; and vinorelbine 30 mg/m2 IV on days 1 and 8 of each 21-day cycle.24 The primary measure of efficacy was progression-free survival as assessed by blinded independent central review (BICR).1, 24
The median age of patients who received olaparib was 44 years (range: 22-76 years); 65% were white, 4% were male, 100% had an ECOG performance status of 0 or 1, approximately 50% had triple-negative tumors, and 29.3% received prior platinum-based chemotherapy.24 The median age of patients who received standard chemotherapy was 45 years (range: 24-68 years); 65% were white, 2% were male, 63.9% had an ECOG performance status of 0, 49.5% had triple-negative breast cancer, and 26.8% had received prior platinum-based chemotherapy.24 The median number of previous chemotherapy regimens for metastatic disease was 1 in each treatment arm; approximately 30% of patients had not received prior chemotherapy for metastatic breast cancer.1 Presence of a confirmed or suspected deleterious germline BRCA mutation was confirmed by BRACAnalysis CDx® in 297 of the 299 tested patients.1, 24 Median BICR-assessed progression-free survival (at a median follow-up of 14 months) was 7 months in patients receiving olaparib and 4.2 months in patients receiving standard chemotherapy (hazard ratio, 0.58; 95% confidence interval, 0.43-0.80).1, 24 The results of a progression-free survival analysis based on investigator assessment were consistent with the results from the independent blinded review.1, 24 Results of a subgroup analysis (based on prior use of chemotherapy for metastatic disease, hormone receptor status, and previous use of platinum-based chemotherapy) suggested that the effect of olaparib on progression-free survival was consistent across all subgroups.1 Among patients who had measurable disease at baseline, confirmed objective response rates were 52 or 23% in patients receiving olaparib or standard chemotherapy, respectively; complete responses were achieved in 7.8 and 1.5% of patients, respectively.1 Median overall survival at the time of final analysis (at a median follow-up of 25.3 months in patients receiving olaparib and 26.3 months in patients receiving standard chemotherapy) was 19.3 months in patients receiving olaparib and 17.1 months in patients receiving standard chemotherapy.1, 25 Overall survival was generally consistent across subgroups, with a potentially greater benefit for olaparib compared with standard chemotherapy among patients who had not received prior chemotherapy for metastatic breast cancer.25 Results of OlympiAD were further analyzed in a post-hoc extended follow-up.39 At 3 years, survival rates were 27.9 and 21.2% among patients given olaparib or standard chemotherapy, respectively.39
Treatment of early breast cancer typically involves surgery; systemic therapies may be administered preoperatively (neoadjuvant) or postoperatively (adjuvant), depending on factors such as stage, grade, and molecular status of the tumor.42 Olaparib has been studied as an adjuvant therapy in patients with early breast cancer and germline BRCA1 or BRCA2 mutations; however, its specific role in therapy is not addressed in the ASCO guideline on adjuvant treatment of early breast cancer.42, 43
Guidelines from ASCO state that patients with metastatic hormone receptor-positive, HER2-negative breast cancer with germline BRCA1 or BRCA2 mutations who are no longer benefiting from endocrine therapy may be offered an oral PARP inhibitor in the first- through third-line setting rather than chemotherapy.40, 41 Because PARP inhibitors are associated with fewer adverse events, PARP inhibition is preferable to chemotherapy after 1-2 prior lines of endocrine therapy; however, it is not known whether PARP inhibitors are superior to platinum or taxane chemotherapy in the metastatic setting due to a lack of comparative trial data.41
Patients with metastatic triple-negative breast cancer with germline BRCA1 or BRCA2 mutations who have previously been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting may be offered an oral PARP inhibitor (olaparib or talazoparib) rather than chemotherapy.41 However, it is not known whether PARP inhibitors are superior to platinum, anthracycline, or taxane chemotherapy in the metastatic setting.41
Olaparib is used for the first-line maintenance treatment of adults with deleterious or suspected deleterious germline BRCA -mutated metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.1 The drug has been designated an orphan drug by FDA for the treatment of this cancer.3 An FDA-approved companion diagnostic test is required to confirm the presence of specific biomarkers prior to initiation of olaparib therapy for this indication.1
Efficacy and safety of olaparib for this indication are based principally on the results of a randomized, double-blind, placebo-controlled trial (POLO).1, 26 The POLO trial enrolled 154 adults with pancreatic adenocarcinoma and a confirmed or suspected deleterious germline BRCA mutation detected on central BRACAnalysis CDx testing (Myriad BRACAnalysis® or BRACAnalysis CDx®) or local genetic testing.1, 26 Patients were required to have received at least 16 weeks of first-line platinum-based chemotherapy without evidence of disease progression.1, 26 Patients were randomized in a 3:2 ratio to receive olaparib 300 mg tablets orally twice daily or placebo until disease progression or unacceptable toxicity.1, 26 The primary measure of efficacy was progression-free survival assessed by blinded independent central review (BICR).1, 26
The median age of the overall study population was 57 years (range: 36-84 years); 92% were white, 54% were male, and 67% had an ECOG performance status of 0.1 The median time from initiation of first-line platinum-based chemotherapy to randomization was 5.8 months (range: 3.4-33.4 months), and 49% achieved a complete or partial response to platinum-based chemotherapy.1 Most patients (75%) received FOLFIRINOX, while 8% received FOLFOX or capecitabine plus oxaliplatin (CapeOx, XELOX), 4% received gemcitabine plus oxaliplatin (GEMOX), and 3% received gemcitabine plus cisplatin.1
Median BICR-assessed progression-free survival (at a median follow-up of 9.1 months in patients receiving olaparib and 3.8 months in patients receiving placebo) was 7.4 months in patients receiving olaparib and 3.8 months in patients receiving placebo (hazard ratio, 0.53; 95% confidence interval, 0.35-0.81).1, 26 The results of a progression-free survival analysis based on investigator assessment were consistent with the results from the independent blinded review.26 Results of a subgroup analysis based on relevant patient characteristics suggested that the effect of olaparib on progression-free survival was consistent across all subgroups.26 Among patients who had measurable disease at baseline, objective response rates were 23 or 12% in patients receiving olaparib or placebo, respectively; complete responses were achieved in 2 patients who received olaparib and in none of those receiving placebo.1, 26 The median duration of response was 24.9 months in patients receiving olaparib and 3.7 months in patients receiving placebo.26
Overall survival in a planned interim analysis (46% data maturity) was 18.9 months in patients receiving olaparib and 18.1 months in patients receiving placebo (hazard ratio, 0.91; 95% confidence interval, 0.56-1.46).26 The final overall survival analysis occurred when data were 70.1% mature (median follow-up of 31.3 or 23.9 months for olaparib or placebo, respectively); reported overall survival was a median of 19 or 19.2 months with olaparib or placebo, respectively.1, 44 Overall survival results were consistent across subgroups.44
In the POLO study, statistically significant progression-free survival benefit has been demonstrated in patients receiving olaparib compared with those receiving placebo; however, no difference in overall survival between the treatment groups has been observed to date.33, 44 Although olaparib-treated patients were more likely to experience serious adverse events and/or withdraw from the study because of adverse events compared with placebo, the magnitude of progression-free survival benefit outweighs the risks; ASCO states that olaparib is recommended as an option for maintenance therapy for patients with metastatic pancreatic cancer harboring an identified germline BRCA mutation.33
ASCO also states that the decision to continue chemotherapy or switch to maintenance therapy with olaparib should be based on patient preference and consideration of whether a maximum response and plateau in response to chemotherapy have been achieved, level of cumulative toxicities associated with chemotherapy treatment, convenience, toxicity, goals of care, cost, and clinical evidence (e.g., lack of overall survival benefit).33
Similar recommendations are made in a more recent guideline from international experts; these experts state that BRCA testing should be offered to all patients with metastatic pancreatic cancer, and that olaparib maintenance treatment is an option for patients with germline BRCA1 or BRCA2 mutations and disease that is stable or responsive to platinum-based chemotherapy.45
HRR Gene-mutated Metastatic Castration-resistant Prostate Cancer
Olaparib is used for the treatment of adults with deleterious or suspected deleterious germline or somatic homologous recombination repair ( HRR ) gene-mutated metastatic castration-resistant prostate cancer who have progressed following prior treatment with enzalutamide or abiraterone.1 An FDA-approved companion diagnostic test is required to confirm the presence of specific biomarkers prior to initiation of olaparib therapy for this indication.1
Efficacy and safety of olaparib for this indication are based principally on the results of a randomized, open-label trial (PROfound).1, 27, 28 The PROfound trial enrolled a total of 387 adult men with metastatic castration-resistant prostate cancer who had evidence of disease progression while receiving enzalutamide or abiraterone for metastatic prostate cancer and/or castration-resistant prostate cancer.1, 27 Patients were required to continue receiving a gonadotropin-releasing hormone (GnRH) analog if they had not undergone bilateral orchiectomy.1, 27 Patients also had to have a mutation in 1 of 15 genes involved in the HHR pathway to be eligible; the presence of a mutation in BRCA1 , BRCA2 , ATM , BRIP1 , BARD1 , CDK12 , CHEK1 , CHEK2 , FANCL , PALB2 , PPP2R2A , RAD51B , RAD51C , RAD51D , or RAD54L was confirmed by central testing using the FoundationOne® CDx assay.27 Patients were included in 1 of 2 cohorts, depending on their HRR gene mutation status.1, 27 Cohort A included 245 patients with mutations in BRCA1 , BRCA2 , or ATM , while cohort B included 142 patients with mutations in BARD1 , BRIP1 , CDK12 , CHEK1 , CHEK2 , FANCL , PALB2 , PPP2R2A , RAD51B , RAD51C , RAD51D , or RAD54L .1, 27 In cohort A, BRCA2 , ATM , and BRCA1 mutations were present in 52, 34, and 5% of patients, respectively.1 In cohort B, the most common mutation was CDK12 (63%); no patients had mutations in FANCL or RAD51C .1 Patients were randomized (stratified by prior receipt of taxane chemotherapy and presence of measurable disease) in a 2:1 ratio within each cohort to receive olaparib 300 mg tablets orally twice daily or investigator's choice of enzalutamide (160 mg orally once daily) or combination therapy with abiraterone acetate (1 g orally once daily) and prednisone 5 mg orally twice daily until disease progression or unacceptable toxicity occurred.1, 27 The primary measure of efficacy was radiological progression-free survival, assessed by blinded independent central review (BICR), in cohort A.1, 27 In the overall study population (cohorts A and B), the median age was 69 years (range: 47-91 years); 69% were white, 95% had an ECOG performance status of 0 or 1, 66% had received prior taxane chemotherapy, 40% had received enzalutamide, 38% had received abiraterone acetate, and 20% had received both enzalutamide and abiraterone acetate.1
In cohort A, median BICR-assessed radiological progression-free survival (at a median follow-up of 7.5 months in the olaparib group and 5.4 months in the standard therapy group) was 7.4 months in patients receiving olaparib and 3.6 months in patients receiving standard therapy.1, 27 The results of a radiological progression-free survival analysis based on investigator assessment were consistent with the results from the independent blinded review.27 Results of an exploratory subgroup analysis suggested that the effect of olaparib on radiological progression-free survival was consistent regardless of prior taxane therapy and BRCA mutation assay (i.e., Myriad BRACAnalysis CDx assay, Foundation Medicine F1CDx assay).1 Among patients who had measurable disease at baseline in cohort A, objective response rates were 33 or 2% in patients receiving olaparib or standard therapy, respectively.1, 27 In this cohort, median overall survival at the time of final analysis (at a median follow-up of 21.9 months in patients receiving olaparib and 21.0 months in patients receiving standard therapy) was 19.1 months in patients receiving olaparib and 14.7 months in patients receiving standard therapy.1, 28
In cohort A and B combined, median BICR-assessed radiological progression-free survival (at a median follow-up of 7.4 months in patients receiving olaparib and 5.5 months in patients receiving standard therapy) was 5.8 months in patients receiving olaparib and 3.5 months in patients receiving standard therapy.1, 27 The results of a radiological progression-free survival analysis based on investigator assessment were consistent with the results from the independent blinded review.27 Results of an exploratory subgroup analysis based on relevant patient characteristics suggested that the effect of olaparib on radiological progression-free survival was consistent across all subgroups in patients in both cohorts.27 Among patients who had measurable disease at baseline in both cohorts, objective response rates were 22 or 4% in patients receiving olaparib or standard therapy, respectively.27 Median overall survival at the time of final analysis (at a median follow-up of 20.7 months in patients receiving olaparib and 20.5 months in patients receiving standard therapy) was 17.3 months in patients receiving olaparib and 14 months in patients receiving standard therapy.28
In an exploratory analysis of cohort B, median BICR-assessed radiological progression-free survival was 4.8 months in the olaparib group and 3.3 months in the standard therapy group).1 Among patients who had measurable disease at baseline in cohort B, objective response rates were 3.7 or 8.3% in patients receiving olaparib or standard therapy, respectively.1 In this cohort, median overall survival at the time of final analysis (at a median follow-up of 18.7 months in the olaparib group and 18.3 months in the standard therapy group) was 14.1 months in patients receiving olaparib and 11.5 months in patients receiving standard therapy.28
The objective response rate in patients with tumors harboring single BRCA2 , ATM , or CDK12 was 56, 10, or 6%, respectively.1 In olaparib-treated patients with a single BRCA2 mutation, the median duration of response was 5.6 months.1
BRCA-mutated Metastatic Castration-resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone
Olaparib is used in combination with abiraterone and prednisone or prednisolone for the treatment of adults with deleterious or suspected deleterious BRCA -mutated metastatic castration-resistant prostate cancer.1 An FDA-approved companion diagnostic test is required to confirm the presence of specific biomarkers prior to initiation of olaparib therapy for this indication.1
Efficacy and safety of olaparib for this indication are based principally on the results of a randomized, double-blind, placebo-controlled trial (PROpel).1, 46 The PROpel trial enrolled 796 adult patients with metastatic castration-resistant prostate cancer.1 Patients were randomized (in a 1:1 ratio) to treatment with olaparib 300 mg twice daily plus abiraterone 1000 mg daily or placebo plus abiraterone 1000 mg daily.1 All patients received either prednisone or prednisolone 5 mg twice daily.1 Patients also received a GnRH analog unless they had previously undergone a bilateral orchiectomy.1 The primary outcome was investigator-assessed radiographic progression-free survival; overall survival was also assessed.1, 46
Of the 796 patients enrolled in the trial, 85 patients (11%) tested positive for BRCA mutation.1 These patients were a median 68 years of age (range: 43-85 years); 72% were white, 22% were Asian, and 66% had an ECOG performance status of 0.1 Metastases were limited to the bone in 53% of patients; 15% had visceral metastases, and 32% had other metastases.1 In the overall trial population, a significant improvement in radiologic progression-free survival was seen with olaparib compared to placebo.1 However, an exploratory subgroup analysis determined that the improvement observed in the overall trial population was primarily attributable to results seen in the subgroup of patients with BRCA mutations.1 Among patients with BRCA -mutated disease, olaparib was associated with longer radiologic progression-free survival compared to placebo; the median radiologic progression-free survival was 8 months in the placebo group and not reached in the olaparib group.1 Overall survival was also greater with olaparib versus placebo; median overall survival was 23 months in the placebo group and not reached in the olaparib group.1
Available guidelines from the American Urological Association (AUA) recommend offering a PARP inhibitor to patients with confirmed or suspected deleterious germline or somatic HRR gene-mutated (including BRCA -mutated) metastatic castration-resistant prostate cancer following prior treatment with enzalutamide or abiraterone acetate, and/or a taxane-based chemotherapy.47 For patients unable to take PARP inhibitors, platinum-based chemotherapy is an alternative.47 Use of PARP inhibitors in combination with abiraterone is not discussed in this guideline.47
Indication | Biomarker | Sample Type |
|---|---|---|
First-line maintenance treatment of germline or somatic BRCA -mutated advanced ovarian cancer | BRCA1 m, BRCA2 m | Tumor, blood |
First-line maintenance treatment of HRD-positive advanced ovarian cancer in combination with bevacizumab | BRCA1 m, BRCA2 m and/or genomic instability | Tumor |
Maintenance treatment of germline or somatic BRCA -mutated recurrent ovarian cancer | BRCA1 m, BRCA2 m | Tumor, blood |
Adjuvant treatment of germline BRCA -mutated, HER2-negative high risk early breast cancer | Germline BRCA1 m, germline BRCA2 m | Blood |
Germline BRCA -mutated, HER2-negative metastatic breast cancer | Germline BRCA1 m, germline BRCA2 m | Blood |
First-line maintenance treatment of germline BRCA -mutated metastatic pancreatic adenocarcinoma | Germline BRCA1 m, germline BRCA2 m | Blood |
Germline or somatic HRR gene-mutated metastatic castration-resistant prostate cancer | ATM m, BRCA1 m, BRCA2 m, BARD1 m, BRIP1 m, CDK12 m, CHEK1 m, CHEK2 m, FANCL m, PALB2 m, RAD51B m, RAD51C m, RAD51D m, RAD54L m | Tumor |
Germline BRCA1 m, germline BRCA2 m | Blood | |
ATM m, BRCA1 m, BRCA2 m | Plasma (circulating tumor DNA) | |
BRCA -mutated metastatic castration-resistant prostate cancer in combination with abiraterone and prednisone or prednisolone | BRCA1 m, BRCA2 m | Tumor, blood, plasma (circulating tumor DNA) |
aIf testing fails or tissue sample is unavailable/insufficient, or when germline testing is negative, consider using an alternative test, if available
Olaparib is administered orally twice daily with or without food.1 The tablets should be swallowed whole and should not be chewed, dissolved, crushed, or divided.1 If a dose of olaparib is missed, the next dose should be taken at the regularly scheduled time.1
Olaparib tablets should be stored at 20-25°C but may be exposed to temperatures ranging from 15-30°C.1 Tablets should be stored in the original container to protect from moisture.1
First-line Maintenance Treatment of BRCA -mutated Advanced Ovarian Cancer
The recommended adult dosage of olaparib for the maintenance treatment of deleterious or suspected deleterious germline or somatic BRCA -mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to first-line platinum-based chemotherapy is 300 mg twice daily.1 Therapy should be continued until disease progression, unacceptable toxicity, or completion of 2 years of treatment.1 In patients with a complete response (no radiological evidence of disease) at 2 years, treatment should be stopped.1 In patients with evidence of disease at 2 years, treatment may be continued beyond 2 years if the patient might derive clinical benefit from an extended duration of olaparib therapy.1
First-line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab
The recommended adult dosage of olaparib in combination with bevacizumab for the maintenance treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer associated with HRD-positive status (defined by a deleterious or suspected deleterious BRCA mutation and/or genomic instability) in complete or partial response to first-line platinum-based chemotherapy is 300 mg twice daily.1 Therapy should be continued until disease progression, unacceptable toxicity, or completion of 2 years of treatment.1 In patients with a complete response (no radiological evidence of disease) at 2 years, treatment should be stopped.1 In patients with evidence of disease at 2 years, treatment may be continued beyond 2 years if the patient might derive clinical benefit from an extended duration of olaparib therapy.1 The recommended dosage of bevacizumab is 15 mg/kg IV every 3 weeks for a total of 15 months (including use during primary chemotherapy and maintenance therapy).1
Maintenance Treatment of BRCA -mutated Recurrent Ovarian Cancer
The recommended adult dosage of olaparib for the maintenance treatment of deleterious or suspected deleterious germline or somatic BCRA -mutated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy is 300 mg twice daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Adjuvant Treatment of BRCA -mutated HER2-negative High-Risk Early Breast Cancer
The recommended adult dosage of olaparib for the adjuvant treatment of deleterious or suspected deleterious germline BRCA -mutated, HER2-negative high-risk early breast cancer previously treated with neoadjuvant or adjuvant chemotherapy is 300 mg twice daily.1 Therapy should be continued for 1 year, or until disease progression or unacceptable toxicity occurs.1
Patients with hormone receptor-positive disease should continue concurrent endocrine therapy as recommended in clinical guidelines.1
Treatment of BRCA -mutated, HER2-negative Metastatic Breast Cancer
The recommended adult dosage of olaparib for deleterious or suspected deleterious germline BRCA -mutated, HER2-negative metastatic breast cancer previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting is 300 mg twice daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
The recommended adult dosage of olaparib for first-line maintenance treatment of deleterious or suspected deleterious germline BRCA -mutated metastatic pancreatic adenocarcinoma that has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen is 300 mg twice daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Treatment of Homologous Recombination Repair (HRR) Gene-mutated Metastatic Castration-resistant Prostate Cancer
The recommended adult dosage of olaparib for the treatment of deleterious or suspected deleterious germline or somatic HRR gene-mutated metastatic castration-resistant prostate cancer that has progressed following prior treatment with enzalutamide or abiraterone is 300 mg twice daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Patients should receive concomitant therapy with a gonadotropin-releasing hormone (GnRH) analog unless they have had a bilateral orchiectomy.1
Treatment of BRCA -mutated Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone
The recommended adult dosage of olaparib in combination with abiraterone and prednisone or prednisolone for the treatment of deleterious or suspected deleterious BRCA -mutated metastatic castration-resistant prostate cancer is 300 mg twice daily.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1 The recommended dosage of abiraterone is 1000 mg orally once daily in combination with prednisone or prednisolone 5 mg orally twice daily.1
Patients should receive concomitant therapy with a GnRH analog unless they have had a bilateral orchiectomy.1
Dosage Modifications for Toxicity
If adverse reactions occur, interruption of therapy or dosage reduction of olaparib should be considered.1 The recommended initial dosage reduction is 250 mg twice daily.1 If further dosage reduction is necessary, the dosage should be reduced to 200 mg twice daily.1
Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of olaparib with drugs that are moderate or strong inhibitors of cytochrome P-450 (CYP) isoenzyme 3A should be avoided.1 If concomitant use of a strong CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the dosage of olaparib to 100 mg twice daily.1 If concomitant use of a moderate CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the dosage of olaparib to 150 mg twice daily.1 If concomitant use of the CYP3A inhibitor is discontinued, the olaparib dosage should be returned (after 3-5 terminal half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the CYP3A inhibitor.1
The manufacturer states that no adjustment to the initial dosage of olaparib is necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 Olaparib has not been studied in patients with severe hepatic impairment (Child-Pugh class C), and the manufacturer makes no specific dosage recommendations for such patients.1
The manufacturer states that no adjustment to the initial dosage of olaparib is necessary in patients with mild renal impairment (creatinine clearance 51-80 mL/minute).1 For patients with moderate renal impairment (creatinine clearance 31-50 mL/minute), the manufacturer recommends an olaparib dosage of 200 mg twice daily.1 Olaparib has not been studied in patients with severe renal impairment or end-stage renal disease (creatinine clearance 30 mL/minute or less), and the manufacturer provides no specific dosage recommendations for such patients.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Myelodysplastic Syndrome/Acute Myeloid Leukemia
In clinical studies enrolling 2219 patients with various BRCA -mutated, germline BRCA -mutated, homologous combination repair (HRR) gene-mutated, or homologous recombination deficiency (HRD)-positive cancers who received olaparib as monotherapy or as part of a combination regimen, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) were reported in approximately 1.2% of patients; of the reported MDS/AML cases, 54% had a fatal outcome.1 All of these patients had received previous chemotherapy with platinum-containing agents and/or other DNA-damaging antineoplastic agents, including radiation therapy.1 The median duration of olaparib therapy in patients who developed MDS/AML was approximately 2 years, but duration of therapy varied from less than 6 months to over 4 years.1
In the SOLO-1 study in patients with newly diagnosed advanced BRCA -mutated ovarian cancer, cases of MDS/AML were reported in 1.9% of patients receiving olaparib and 0.8% of patients receiving placebo.1 In the PAOLA-1 study in HRD-positive patients with newly diagnosed advanced ovarian cancer, cases of MDS/AML were reported in 1.6% of patients who received olaparib and 2.3% of patients who received control.1
In the SOLO-2 study in patients with BRCA -mutated platinum-sensitive relapsed ovarian cancer, cases of MDS/AML were reported in 8% of patients who received olaparib and 4% of patients who received placebo.1 The duration of olaparib therapy in patients who developed MDS/AML ranged from 0.6 years to 4.5 years.1
Monitor CBC at baseline and then monthly in patients receiving olaparib.1 Olaparib therapy should not be initiated until patients have recovered from hematologic toxicity caused by previous chemotherapy (to grade 1 or less).1 If prolonged hematologic toxicity occurs during therapy, olaparib should be withheld and CBC should be monitored weekly until recovery to grade 1 or less.1 If hematologic toxicity persists for more than 4 weeks following interruption of therapy, patients should be referred to a hematologist for further evaluation, including bone marrow analysis and cytogenetic testing of a blood sample.1 If MDS/AML is confirmed, olaparib should be discontinued.1
Pneumonitis, including severe and fatal cases, has been reported with therapy.1 In clinical studies, involving olaparib administration as monotherapy or in combination with other agents, the incidence of pneumonitis was 1%.1
Olaparib therapy should be interrupted and prompt diagnostic evaluation should occur in patients who have new or worsening pulmonary symptoms or if a radiologic abnormality occurs.1 If pneumonitis is confirmed, olaparib should be discontinued and the patient treated appropriately.1
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action and animal findings, olaparib may cause fetal harm; the drug has been shown to be teratogenic, embryotoxic, and fetotoxic in animals at exposures below the recommended human dosage.1
Pregnancy should be avoided during olaparib therapy.1 Pregnancy testing is recommended for females of reproductive potential prior to initiation of olaparib therapy.1 Females of reproductive potential should be advised to use effective contraception while receiving olaparib and for at least 6 months after discontinuance of therapy.1 Males with female partners of reproductive potential or partners who are pregnant should be advised to use effective contraception while receiving olaparib and for 3 months after discontinuance of therapy.1 Male patients should not donate sperm while receiving olaparib and for 3 months after discontinuance of therapy.1 If olaparib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential risk to the fetus and the potential risk for loss of the pregnancy.1
Cases of venous thromboembolism, including severe or fatal pulmonary embolism, have occurred in patients receiving olaparib.1
Combined data from the PROfound and PROpel studies indicate that venous thromboembolic events occurred in 8% of patients with metastatic castration-resistant prostate cancer who received olaparib compared with 2.5% of patients who received control.1 Pulmonary embolism occurred in 6% of patients who received olaparib and 1.5% of patients who received control.1
Patients should be monitored for signs and symptoms of venous thrombosis and pulmonary embolism.1 If venous thrombosis or pulmonary embolism occurs, patients should be treated as medically appropriate (e.g., long-term anticoagulation).1
Hepatotoxicity, including Drug-Induced Liver Injury
Hepatotoxicity, including severe and potentially fatal cases of drug-induced liver injury, reported during therapy.1 Clinicians should assess bilirubin and transaminases at baseline and throughout treatment.1 If abnormal liver tests develop after olaparib therapy, clinicians should monitor for liver test abnormalities and clinical signs and symptoms of hepatic toxicity more frequently.1 If drug-induced liver injury is suspected, olaparib should be withheld.1 If drug-induced livery injury is confirmed, discontinue olaparib.1
Olaparib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 In animal reproduction studies, olaparib given to pregnant rats during organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below the recommended human dose.1
Pregnancy testing is recommended for females of reproductive potential prior to initiation of olaparib therapy.1
It is not known whether olaparib is distributed into human milk.1 Because of the potential for serious adverse reactions to olaparib in breast-fed infants, women should be advised not to breast-feed while receiving the drug and for 1 month after the last dose.1
Females and Males of Reproductive Potential
Olaparib may cause fetal harm if administered during pregnancy.1 Verify pregnancy status prior to initiating olaparib.1
Advise females of reproductive potential to use effective contraceptive methods while receiving olaparib and for at least 6 months after the drug is discontinued.1 Advise males who have female partners of reproductive potential or partners who are pregnant to use effective contraceptive methods while receiving olaparib and for 3 months after the drug is discontinued.1 Advise males to refrain from donating sperm while receiving olaparib and for 3 months after the drug is discontinued.1
Safety and efficacy of olaparib have not been established in pediatric patients.1
Of the 2901 patients with advanced solid tumors who received olaparib monotherapy in clinical trials, 23% were 65 years of age or older, 7% were 75 years of age or older, and 0.4% were 85 years of age or older.1 Of the 535 patients with advanced solid tumors who received olaparib in combination with bevacizumab, 38% were 65 years of age or older, and 6% were 75 years of age or older.1 Of the 398 patients with advanced solid tumors who received olaparib in combination with abiraterone and prednisone or prednisolone, 67% were 65 years of age or older, and 24% were 75 years of age or older.1 No differences in overall safety or effectiveness were observed in these geriatric patients compared to younger patients.1
In patients with mild hepatic impairment (Child-Pugh class A), mean AUC and peak plasma concentration of olaparib increased by 15 and 13%, respectively, compared with individuals with normal hepatic function.1
In moderate hepatic impairment (Child-Pugh class B), mean AUC increased by 8% and peak plasma concentration decreased by 13% compared to individuals with normal hepatic function.1 Hepatic impairment did not affect protein binding of olaparib.1
No adjustment to the initial dosage of olaparib is necessary in patients with mild or moderate hepatic impairment.1
The pharmacokinetic profile of olaparib has not been established in patients with severe hepatic impairment (Child-Pugh class C).1
In patients with mild renal impairment (creatinine clearance 51-80 mL/minute), mean AUC and peak plasma concentration of olaparib increased by 24 and 15%, respectively, compared with individuals with normal renal function; no adjustment to the initial dosage of olaparib is necessary in patients with mild renal impairment.1
Moderate renal impairment (creatinine clearance 31-50 mL/minute) increased the mean AUC and peak plasma concentration of olaparib by 44 and 26%, respectively, compared with individuals with normal renal function.1 The manufacturer recommends an olaparib dosage of 200 mg twice daily in patients with moderate renal impairment.1
The pharmacokinetic profile of olaparib has not been established in patients with severe renal impairment or end-stage renal disease (creatinine clearance 30 mL/minute or less).1
The most common adverse effects of olaparib (as monotherapy) reported in ≥10% of patients in clinical studies include nausea, fatigue (including asthenia), anemia, vomiting, diarrhea, decreased appetite, headache, dysgeusia, cough, neutropenia, dyspnea, dizziness, dyspepsia, leukopenia, and thrombocytopenia.1
The most common adverse effects of olaparib in combination with bevacizumab reported in ≥10% of patients in clinical studies include nausea, fatigue (including asthenia), anemia, lymphopenia, vomiting, diarrhea, neutropenia, leukopenia, urinary tract infection, and headache.1
The most common adverse effects of olaparib in combination with abiraterone and prednisone or prednisolone reported in ≥10% of patients in clinical studies include anemia, fatigue, nausea, diarrhea, decreased appetite, lymphopenia, dizziness, and abdominal pain.1
Olaparib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A.1 In vitro, olaparib is a substrate and inhibitor of P-glycoprotein (P-gp).1 In vitro studies also indicate that olaparib induces CYP2B6 and both inhibits and induces CYP3A.1 Olaparib is predicted to be a weak CYP3A inhibitor.1 In vitro studies indicate that olaparib is an inhibitor of uridine diphosphate-glucuronosyltransferase (UGT) 1A1.1, 1
In vitro, olaparib is an inhibitor of breast cancer resistance protein (BCRP), organic anion transport protein (OATP) 1B1, organic cation transporter (OCT) 1 and OCT2, organic anion transporter (OAT) 3, and multidrug and toxic compound extrusion (MATE) 1 and MATE2K.1
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of olaparib with moderate or strong inhibitors of CYP3A may result in increased plasma concentrations of olaparib.1 When the strong CYP3A inhibitor itraconazole was administered concomitantly with olaparib, peak plasma concentrations and systemic exposure of olaparib were increased by 42 and 170%, respectively.1 Concomitant administration of fluconazole, a moderate CYP3A inhibitor, and olaparib is predicted to increase peak plasma concentrations and AUC of olaparib by 14 and 121%, respectively.1
Concomitant use of olaparib with moderate or strong inhibitors of CYP3A should be avoided, and selection of an alternative drug with less CYP3A inhibition potential should be considered.1 If concomitant use of the moderate or strong CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the dosage of olaparib to 100 mg twice daily during concomitant administration of a strong CYP3A inhibitor and to 150 mg twice daily during concomitant administration of a moderate CYP3A inhibitor.1 If concomitant use of the CYP3A inhibitor is discontinued, the olaparib dosage should be returned (after 3-5 terminal half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the CYP3A inhibitor.1
Concomitant use of olaparib with moderate or strong inducers of CYP3A may result in decreased plasma concentrations of olaparib.1 When the strong CYP3A inducer rifampin was administered concomitantly with olaparib, peak plasma concentrations and AUC of olaparib were decreased by 71 and 87%, respectively.1 Concomitant administration of efavirenz, a moderate CYP3A inducer, and olaparib is predicted to decrease peak plasma concentrations and AUC of olaparib by 31 and 60%, respectively.1
Concomitant use of olaparib with moderate or strong inducers of CYP3A should be avoided.1
Grapefruit and Seville Oranges
Grapefruit products and Seville oranges are known to inhibit CYP3A and should be avoided.1
Olaparib, an inhibitor of mammalian poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) enzymes, including PARP-1, PARP-2, and PARP-3, is an antineoplastic agent.1 PARP enzymes are involved in normal cellular homeostasis, including DNA transcription and DNA repair.1 In vitro studies have demonstrated that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, which result in DNA damage and cancer cell death.1 Additionally, the PARP-1 enzyme has been shown to help regulate androgen receptor activity in prostate cancer models.1 PARP inhibitors such as olaparib appear to be selective for tumor cells that harbor certain homologous recombination deficiencies, including those harboring BRCA1 and BRCA2 mutations.2, 10 In vitro, olaparib inhibited growth of select tumor cell lines.1 In addition, olaparib reduced tumor growth of xenograft models of human cancer in mice both as a single agent or following platinum-based chemotherapy.1 Increased cytotoxicity and anti-tumor activity were observed following olaparib treatment in cell lines and mouse tumor models with deficiencies in BRCA1/2 , ATM , and other genes involved in homologous recombination repair, and correlated with platinum response.1 Olaparib treatment in combination with androgen receptor inhibition resulted in cytotoxicity in vitro and anti-tumor activity in mouse xenograft models.1
Following oral administration, peak plasma concentrations of the drug are attained in a median of 1.5 hours.1 Following repeated doses of olaparib, an AUC mean accumulation ratio of 1.8 is observed.1 Administration of olaparib with a high-fat, high-calorie meal delayed the rate of absorption (time to peak concentrations delayed by 2.5 hours), but did not substantially affect the extent of absorption (mean AUC increased by approximately 8%).1 Data suggest that systemic exposure of olaparib increases approximately proportionally over the dose range of 25-450 mg, and peak plasma concentrations increase slightly less than proportionally over the same dose range.1 Olaparib is primarily metabolized by CYP3A.1 Following oral administration of a single radiolabeled dose of olaparib, 44% of the radioactivity was recovered in urine and 42% was recovered in feces; the majority of the dose was excreted as metabolites.1 Olaparib is approximately 82% bound to plasma proteins when given at the recommended dosage.1 The mean terminal plasma half-life of the drug is 14.9 hours.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Olaparib is obtained through designated specialty pharmacies and specialty distributors. 13 Contact manufacturer or consult the manufacturer website for specific availability information.13
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 100 mg | ||
150 mg | Lynparza® | AstraZeneca |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions May 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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34. Banerjee S, Moore K, Colomba N, et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol . 2021;22:1721-1731.
35. DiSilvestro P, Banerjee S, Colombo N, et al. Overall survival with maintenance olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: the SOLO1/GOG 3004 trial. J Clin Oncol . 2022;41:609-617.
36. Ray-Coquard I, Leary A, Pignata S, et al. Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial. Ann Oncol . 2023 Aug;34(8):681-692.
37. Tew W, Lacchetti C, Kohn E; PARP Inhibitors in the Management of Ovarian Cancer Guideline Expert Panel. Poly(ADP-Ribose) polymerase inhibitors in the management of ovarian cancer: ASCO guideline rapid recommendation update. J Clin Oncol . 2022;40(33):3878-3883.
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39. Robson M, Im S, Senkus E, et al. 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. Eur J Cancer . 2023;184:39-47.
40. Burstein HJ, Somerfield MR, Barton DL, et al. Endocrine treatment and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO guideline update. J Clin Oncol . 2021;39(35):3959-3977. doi:10.1200/JCO.21.01392
41. Moy B, Rumble RB, Come SE, et al. Chemotherapy and targeted therapy for patients with human epidermal growth factor receptor 2-negative metastatic breast cancer that is either endocrine-pretreated or hormone receptor-negative: ASCO guideline update. J Clin Oncol . 2021;39(35):3938-3958. doi:10.1200/JCO.21.01374
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44. Kindler H, Hammel P, Reni M, et al. Overall survival results from the POLO trial: a phase III study of active maintenance olaparib versus placebo for germline BRCA-mutated metastatic pancreatic cancer. J Clin Oncol . 2022;40:3929-3939.
45. Conroy T, Pfeiffer P, Vilgrain V, et al. Pancreatic cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol . 2023;34:987-1002. .
46. Saad F, Clarke N, Oya M, et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol . 24:1094-1108.
47. Lowrance W, Breau R, Chou R, et al. Updates to advanced prostate cancer: AUA/SUO guideline (2023). J Urol . 2023;209:1082-1090.
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