Reimbursement Review

Olaparib

Requester: Public drug programs

Therapeutic area: Pancreatic cancer

What Is Pancreatic Cancer?

• Pancreatic ductal adenocarcinoma (PDAC) is an aggressive exocrine malignancy arising from the ductal cells of the pancreas and accounts for more than 90% of all pancreatic cancers. It is characterized by late presentation, rapid disease progression, and poor prognosis.

• In Canada, pancreatic cancer is the third leading cause of cancer-related death, responsible for approximately 7% of all cancer deaths. In 2024, an estimated 7,100 people in Canada were diagnosed with pancreatic cancer and 6,100 died from it, with a 5-year net survival of about 10%. Approximately 5% of patients with PDAC carry a gBRCA1 or BRCA2 mutation.

What Are the Treatment Goals and Current Treatment Options for Pancreatic Cancer?

• The treatment goals for patients with advanced or metastatic PDAC are to prolong survival, delay disease progression, control symptoms, and maintain or improve health-related quality of life (HRQoL). Because progression is almost inevitable, the overall intent of treatment in this setting is palliative.

• In Canada, the current first-line systemic treatment options are FOLFIRINOX (leucovorin [folinic acid], fluorouracil, irinotecan, and oxaliplatin) or gemcitabine in combination with nab-paclitaxel, both of which are administered intravenously and have demonstrated survival benefits compared to single-drug gemcitabine. For patients with a known gBRCA1 or gBRCA2 mutation, a platinum-containing regimen such as FOLFIRINOX is generally preferred because of improved sensitivity to DNA-damaging agents. However, access to timely germline testing varies across provinces, which may limit the ability to personalize treatment based on mutation status.

What Is Olaparib and Why Did Canada’s Drug Agency Conduct This Review?

• Olaparib is a targeted poly-(ADP-ribose) polymerase (PARP) inhibitor that is administered orally at a dose of 300 mg (two 150 mg tablets) taken twice daily, for a total daily dose of 600 mg, until disease progression or unacceptable toxicity. Health Canada has approved olaparib as monotherapy for the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCA-mutated metastatic PDAC whose disease has not progressed on a minimum of 16 weeks of first-line platinum-based chemotherapy, with confirmed gBRCA mutation before treatment initiation.

• At the request of the participating public drug programs, Canada’s Drug Agency (CDA-AMC) reviewed olaparib to inform a recommendation on whether it should be reimbursed for the maintenance treatment of adults with deleterious or suspected deleterious gBRCA-mutated locally advanced unresectable or metastatic PDAC whose disease has not progressed on prior systemic therapy. This is the first CDA-AMC review of olaparib for this indication.

How Did CDA-AMC Evaluate Olaparib?

• CDA-AMC reviewed the clinical evidence on the beneficial and harmful effects, and compared the costs of olaparib versus other treatments used in Canada for maintenance treatment of adults with deleterious or suspected deleterious gBRCA-mutated locally advanced unresectable or metastatic PDAC whose disease has not progressed on prior systemic therapy. Placebo (with or without standard of care) and continued prior systemic therapy as maintenance therapy were considered relevant treatments to compare with olaparib.

• The clinical evidence was identified through systematic searches for available studies.

• The review was also informed by 1 clinician group submission in response to our call for input and by input from the participating public drug programs around issues that may impact their ability to implement a recommendation.

• Two clinical experts with representation from the Prairies and British Columbia were consulted as part of the review process.

What Were the Findings?

Clinical Evidence

• CDA-AMC reviewed evidence from 1 phase III, double-blind, randomized controlled trial (the POLO trial) comparing olaparib with placebo as maintenance treatment in 154 adult patients with deleterious or suspected deleterious gBRCA-mutated metastatic PDAC whose disease had not progressed after at least 16 weeks of first-line platinum-based chemotherapy.

• The POLO trial was inadequate to demonstrate a benefit of olaparib compared with placebo in overall survival (OS). The probability of OS at 3 years was numerically higher with olaparib; however, these data are uncertain due to the few patients at risk at this time point and measures of precision not being reported. The impact of olaparib compared with placebo on OS may have been attenuated due to higher postprogression PARP inhibitor use in the placebo group. The presence and magnitude of any underestimation are uncertain and were not substantiated in sensitivity analyses.

• Progression-free survival (PFS) was significantly longer with olaparib compared with placebo, which the clinical experts considered clinically meaningful given the aggressive nature of metastatic PDAC and the limited maintenance options.

• The POLO trial was inadequate to demonstrate a benefit of olaparib compared with placebo in second PFS. Although the probability of second PFS was higher in the olaparib group than the placebo group at 3 years, these data are uncertain due to the few patients at risk at this time point and measures of precision not being reported. Similarly to OS, the interpretation of this end point is affected by a higher use of postprogression PARP inhibitors in the placebo group.

• Evidence from the POLO trial suggests little to no difference in HRQoL over the first 6 months of treatment. The interpretation of HRQoL results was limited by the reduced numbers of patients available to complete the questionnaires at clinically relevant follow-up times and the uncertainty in the between-group minimal important difference for patients with pancreatic cancer. Further, aspects of HRQoL specific to pancreatic cancer were measured but not reported. The experts noted that the results are reassuring given the ongoing disease burden and side-effect profile of active therapy.

• Adverse events (AEs) (including severe AEs and grade 3+ AEs) were more frequent with olaparib, consistent with the expected safety profile of PARP inhibitors. The clinical experts described the overall safety profile as manageable and predictable. No new or unexpected safety signals were observed.

• Evidence comparing olaparib with active maintenance chemotherapy (e.g., continued prior systemic therapy) was unavailable.

Economic Evidence

• Reimbursing olaparib for maintenance treatment of adults with deleterious or suspected deleterious gBRCA-mutated locally advanced unresectable or metastatic PDAC whose disease has not progressed on prior systemic therapy is expected to increase costs to the public drug programs.

Background

Introduction

The objective of the clinical review is to review and critically appraise the evidence on the beneficial and harmful effects of olaparib 150 mg oral tablets in the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCA-mutated locally advanced unresectable or metastatic adenocarcinoma of the pancreas whose disease has not progressed on prior systemic therapy. The focus will be placed on comparing olaparib to relevant comparators in clinical practice in Canada and identifying gaps in the current evidence. The economic review consists of a cost comparison of olaparib compared with relevant comparators for the same population. The comparators considered relevant to the reviews were placebo with or without standard of care, and continued prior systemic therapy as maintenance therapy. The information on the drug under review is presented in Table 1.

Table 1: Information on the Drug Under Review and on the Canada’s Drug Agency Review

CDA-AMC = Canada’s Drug Agency; PARP = poly-(ADP-ribose) polymerase.

Context for the Review

The public drug programs, via the Oncology Working Group, have requested a review of olaparib for the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCA-mutated locally advanced unresectable or metastatic adenocarcinoma of the pancreas whose disease has not progressed on prior systemic therapy. This is the first Canada’s Drug Agency (CDA-AMC) review of olaparib for this indication. The requested indication is broader than the Health Canada–approved indication, which limits use to patients whose disease has not progressed on a minimum of 16 weeks of first-line platinum-based chemotherapy.

Submission History for the Drug Under Review

• CDA-AMC has previously reviewed olaparib through the reimbursement review process for several indications, other than the 1 requested, including for ovarian, prostate, and breast cancers.

  • For ovarian cancer, olaparib was first reviewed in September 2016 for the maintenance treatment of adults with platinum-sensitive relapsed BRCA-mutated epithelial ovarian, fallopian tube, or primary peritoneal cancer following response to platinum-based chemotherapy, for which a “do not reimburse” recommendation was issued. A subsequent review in September 2017 recommended reimbursement for maintenance monotherapy in adults with platinum-sensitive relapsed BRCA-mutated high-grade serous ovarian, fallopian tube, or primary peritoneal cancer who had completed at least 2 prior lines of platinum-based chemotherapy and achieved a radiologic response to their most recent regimen. In December 2019, the pan-Canadian Oncology Drug Review Expert Review Committee issued a reimbursement recommendation for olaparib monotherapy as first-line maintenance treatment of newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer.

  • For prostate cancer, olaparib monotherapy was reviewed for the treatment of adults with metastatic castration-resistant prostate cancer and homologous recombination repair gene mutations whose disease progressed following prior treatment with a new hormonal agent, resulting in a “reimburse with conditions” recommendation in April 2021. In January 2024, CDA-AMC issued a “reimburse with conditions” recommendation for olaparib in combination with abiraterone and prednisone (or prednisolone) for first-line treatment of adults with deleterious or suspected deleterious germline and/or somatic BRCA-mutated metastatic castration-resistant prostate cancer in whom chemotherapy is not clinically indicated.

  • For breast cancer, olaparib received a “reimburse with clinical criteria and/or conditions” recommendation in March 2023 for the adjuvant treatment of adults with deleterious or suspected deleterious gBRCA-mutated, HER2-negative, high-risk early breast cancer previously treated with neoadjuvant or adjuvant chemotherapy.

Sources of Information

The contents of the clinical review are informed by studies identified through systematic literature searches, input received from interested parties (clinician group and drug programs), and input from clinical experts consulted for this review.

Calls for patient group, clinician group, and industry input are issued for each Non-Sponsored Reimbursement Review. One clinician group submission was received from Ontario Health (Cancer Care Ontario) Gastrointestinal Cancer Drug Advisory Committee. Information for this submission was gathered by email. No submissions were received from patient groups or industry. The full submissions received are available on the project landing page in the consolidated input document.

Input from clinician groups was considered throughout the review, including in the selection of outcomes to include in the clinical review and in the interpretation of the clinical evidence. Relevant clinician group input is summarized in the Disease Background, Current Management, and Unmet Needs and Existing Challenges sections.

The drug programs provide input on each drug being reviewed through the reimbursement review process by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted for this review are summarized and provided to the expert committee in a separate document.

Each review team includes at least 1 clinical expert with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process. Two specialists with expertise in the diagnosis and management of gastrointestinal malignancies participated as part of the review team, with representation from the Prairies and British Columbia.

Disease Background

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive exocrine malignancy arising from the ductal epithelium of the pancreas. It represents more than 90% of all pancreatic cancers.^1-3 In Canada, pancreatic cancer is ranked as the third leading cause of cancer-related death, accounting for approximately 7% of all cancer deaths.⁴ In 2024, an estimated 7,100 people in Canada were diagnosed with pancreatic cancer and 6,100 died from it; the 5-year net survival remains approximately 10%.⁴ In US data, the 5-year survival for metastatic pancreatic cancer is approximately 2% to 3%.^5-7 The prevalence of BRCA1 or BRCA2 mutations in PDAC is estimated to be approximately 5%, with higher rates observed in patients who are of Ashkenazi Jewish ancestry.⁸

It is typically at an advanced stage that PDAC presents nonspecific symptoms such as fatigue, weight loss, abdominal or back pain, and painless jaundice, contributing to delayed diagnosis and poor overall prognosis.⁹ International guidelines, including those from the American Society of Clinical Oncology (ASCO)¹⁰ and the European Society for Medical Oncology,¹¹ endorse germline genetic testing for BRCA mutations in patients with PDAC, with ASCO recommending universal germline (and relevant somatic) testing for all treatment-eligible patients. These recommendations aim to guide therapy selection and enable cascade testing in families.

However, in Canada, the implementation of germline genetic testing for PDAC is not standardized nationally and varies by province. Some provinces, such as British Columbia,¹² have adopted oncology-initiated germline testing programs for all patients with pancreatic cancer as part of provincially funded initiatives. In Ontario,¹³ current testing criteria also include all individuals with a personal history of PDAC, irrespective of age or family history. However, testing access and funding remain inconsistent across provinces, with differences in referral pathways, laboratory capacity, and availability at cancer centres. According to clinical experts consulted for this review, gBRCA testing turnaround times vary across provinces, and results may not be available before the initiation of chemotherapy, thereby limiting their ability to inform initial treatment decisions.

Current Management

Treatment Goals

Clinician groups agreed with the clinical experts consulted for this review that the treatment goals for patients with advanced or metastatic PDAC are to prolong survival, delay disease progression, improve symptoms, and maintain or improve health-related quality of life (HRQoL). The clinical experts further noted that the overall intent of treatment in this setting is palliative, as disease progression is inevitable.

Current Treatment Options

The clinical experts and clinician group mentioned that in Canada, the standard first-line systemic therapies for advanced or metastatic pancreatic cancer are FOLFIRINOX (a four-drug chemotherapy combination that includes leucovorin [folinic acid], fluorouracil, irinotecan, and oxaliplatin) or gemcitabine in combination with nab-paclitaxel. The clinical experts added that these regimens have been shown to prolong survival when compared to single-drug gemcitabine. For patients known to have BRCA-mutated disease, first-line chemotherapy would generally incorporate a platinum drug, most commonly through FOLFIRINOX, given the greater benefit observed in this subgroup.^14,15 However, timely access to BRCA testing results before initiating chemotherapy is inconsistent across Canada, with experts noting that in Alberta, results are typically not available before treatment is started, while in British Columbia, testing is offered to all patients with PDAC, but results may still not be ready before chemotherapy begins. This variability limits the ability to tailor treatment based on mutation status. All currently used systemic therapies are given intravenously in hospital or clinic settings.

Unmet Needs and Existing Challenges

The clinical experts and clinician group noted that current treatments for advanced or metastatic pancreatic cancer have limited efficacy, with most patients’ disease eventually progressing and long-term survival remaining poor. They also agreed that current chemotherapy regimens are associated with substantial toxicity, leading to poor tolerability.

The clinical experts emphasized the impact of cumulative chronic peripheral neuropathy as a key treatment-limiting toxicity, and they highlighted the need for oral treatment options to improve convenience and reduce the burden of frequent IV administration. Clinician groups further identified gaps such as the lack of targeted maintenance options for patients with gBRCA mutations after initial disease control and the absence of well-tolerated oral maintenance treatments that can reduce treatment burden while sustaining disease control.

Considerations for Using the Drug Under Review

Place in Therapy

The clinical experts and clinician group indicated that olaparib would be used as a maintenance therapy for patients with metastatic pancreatic cancer who have a gBRCA1 or gBRCA2 mutation and whose disease remains stable or responding after systemic chemotherapy. It would be taken orally as a single drug, providing an alternative to continued IV chemotherapy.

One clinical expert suggested that, given the rarity of gBRCA1 or gBRCA2 mutations and delays in receiving genetic test results in Canada, olaparib could reasonably be considered for patients who did not receive platinum-based therapy initially, as well as those whose disease remains stable or is responding after second or later lines of treatment, if otherwise eligible.¹⁶ In addition, there are disparities in the criteria for genetic testing for patients with pancreatic cancer in Canada.

Patient Population

The clinical experts and clinician group agreed that the patients most likely to benefit from olaparib are those with gBRCA1 or gBRCA2-mutated metastatic pancreatic cancer whose disease remains stable or responding after platinum-based chemotherapy. Patients with BRCA-negative tumours or progressive disease were considered least suitable.

One clinical expert emphasized that timely access to BRCA testing is a major barrier across Canada, given that delays may prevent patients from receiving therapy within their limited survival time frame; faster turnaround was identified as critical. Genetic testing is recommended for all patients with pancreatic cancer as per ASCO or the European Society for Medical Oncology guidelines; however, this is only available in British Columbia and Ontario. Other provinces have more stringent criteria for genetic testing.

The clinician group highlighted additional eligibility considerations, including the Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 and adequate organ function. They also stressed the importance of validated genetic assays, supported by access to genetic counselling and laboratory diagnostics. In addition, the clinician group expressed support for extending olaparib maintenance to patients with somatic BRCA mutations,¹⁶ which extends beyond the trial evidence and Health Canada’s approved indication. Poor performance status was also cited as a reason patients may be unsuitable for treatment.

Assessing the Response to Treatment

The clinical experts and clinician group indicated that CT scans are the most common modality to assess treatment response, typically performed every 3 months in line with routine practice.

The clinical experts emphasized that a clinically meaningful response would be reflected in improvements in overall survival (OS) and quality of life, and they noted that durable improvements in progression-free survival (PFS), particularly with a long-term plateau in the PFS curve, would also be considered clinically meaningful.

The clinician group highlighted additional measures used in practice, including monitoring CA19-9 trends when elevated at baseline, and incorporating clinical assessments of symptoms and performance status.

Discontinuing Treatment

The clinical experts and clinician group agreed that olaparib should be discontinued in cases of disease progression or intolerable adverse events (AEs), or based on patient preference.

The clinician group further noted that deterioration in performance status should also be considered when deciding to discontinue treatment.

Prescribing Considerations

The clinical experts and clinician group agreed that olaparib should be prescribed by a medical oncologist with expertise in pancreatic cancer to ensure appropriate diagnosis, prescribing, and monitoring, with continued access to a medical oncologist during treatment.

One clinical expert emphasized the importance of specialist involvement, whereas clinician groups highlighted that olaparib is a take-home cancer drug that can be given in the community cancer centre.

Additional Considerations

The clinical experts and clinician group highlighted that delays and inconsistencies in BRCA testing are major barriers to accessing olaparib. The clinical expert stressed the need for faster turnaround if the drug is funded, whereas clinician groups noted that underdiagnosis is likely due to inconsistent testing and emphasized the system-wide need to ensure routine gBRCA testing for patients with metastatic pancreatic cancer.

The clinical experts also pointed out that the requested indication is different than Health Canada’s approval, suggesting that access should extend to patients with gBRCA1 or gBRCA2 mutations who remain stable on later lines of therapy, considering the limited time for access for those who did not receive first-line platinum-based chemotherapy, particularly given the rarity of BRCA-mutated pancreatic cancer, rather than being restricted to those treated in the first-line setting. In addition, the experts highlighted that olaparib’s oral administration and lack of peripheral neuropathy make it especially suitable for patients in rural areas who face challenges with frequent IV chemotherapy.

Clinical Review

Methods

The review team conducted a systematic review to identify evidence for olaparib for the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCA-mutated locally advanced unresectable or metastatic adenocarcinoma of the pancreas whose disease has not progressed on prior systemic therapy. Studies were selected according to the eligibility criteria in Table 2. Long-term extension studies of included randomized controlled trials, indirect treatment comparisons that adhered to the eligibility criteria (except for the study design criteria), and studies addressing gaps that did not meet the eligibility criteria but were considered to address important gaps in the systematic review evidence were included.

Relevant comparators included treatments used in clinical practice in Canada for the patient population under review. Clinical expert input and patient and clinician group input were considered when selecting outcomes (and follow-up times) for review. Selected outcomes are those considered relevant to expert committee deliberations. Detailed methods for the literature search(es), study selection, and data extraction are in Appendix 1 of the Supplemental Material (available on the project landing page).

Table 2: Systematic Review Eligibility Criteria

AE = adverse event; AESI = adverse event of special interest; AML = acute myeloid leukemia; HRQoL = health-related quality of life; MDS = myelodysplastic syndrome; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PFS2 = second progression-free survival; RCT = randomized controlled trial; SAE = serious adverse event.

^aPlacebo was included as a comparator because RCTs with active comparators may not exist, based on prior scoping.

^bIn clinical practice in Canada, choice of continuous maintenance therapy is based on clinical judgment and may consist of modified-dose regimens such as FOLFIRINOX (a combination of leucovorin [folinic acid], fluorouracil, irinotecan, and oxaliplatin), FOLFIRI (a combination of leucovorin [folinic acid], fluorouracil, and irinotecan), or fluorouracil and leucovorin (a combination of fluorouracil and folinic acid used as maintenance or modified therapy); approaches like PANOPTIMOX (a modified FOLFIRINOX-based approach alternating induction and maintenance therapy, evaluated in the PANOPTIMOX-PRODIGE 35 trial); or gemcitabine plus nab-paclitaxel.

Clinical Evidence

An information specialist conducted a literature search of key bibliographic databases, trial registries, and grey literature sources, using a peer-reviewed search strategy. The initial search was completed on August 28, 2025, with alerts maintained until the Formulary Management Expert Committee meeting on January 22, 2026. Refer to Appendix 1 in the Supplemental Material for detailed search strategies.

From the search for primary studies, the review team identified 373 unique records via the searches of databases and registers, of which 368 were excluded by title and abstract. The review team screened 5 records by full text and included 3 reports of 1 study (the POLO trial).^17-19 No potentially relevant records were identified from other sources. No reports of long-term extensions of the included study or studies addressing gaps were identified.

From the search for indirect treatment comparisons, the review team identified 159 unique records via the searches of databases and registers, of which none met the eligibility criteria by title and abstract screening.

A list of excluded studies, including reasons for exclusion, is in the Supplemental Material in Appendix 1.

Systematic Review

Description of Studies

Study Characteristics

The POLO trial^17-19 is a randomized, multicentre, double-blind, placebo-controlled, phase III trial sponsored by AstraZeneca and conducted across 119 sites in 12 countries: Australia, Belgium, Canada (n = 3 patients), France, Germany, Israel, Italy, Korea, the Netherlands, Spain, the UK, and the US.²⁰ The study aimed to evaluate the efficacy and safety of maintenance therapy with olaparib monotherapy versus placebo in adult patients with gBRCA-mutated metastatic PDAC whose disease had not progressed following first-line platinum-based chemotherapy.

The POLO trial enrolled patients aged 18 years and older with histologically or cytologically confirmed metastatic PDAC, a documented deleterious or suspected deleterious gBRCA1 or BRCA2 mutation (identified by central BRACAnalysis CDx, or local testing with subsequent confirmation), and an ECOG performance status of 0 to 1. Patients must have received 16 weeks or more of continuous first-line platinum chemotherapy without disease progression; platinum could have been stopped due to toxicity after the 16-week minimum. Adequate organ and marrow function was required. Patients with measurable or nonmeasurable disease were eligible, and prior platinum therapy for another cancer was permitted if at least 12 months had elapsed.

A total of 154 patients were randomized 3:2 to receive olaparib tablets (300 mg twice daily) or matching placebo between January 2015 and January 2019. Randomization used a central interactive web/interactive voice response system with blocked allocation, no stratification factors, and unique enrolment codes. Randomization occurred 4 to 8 weeks after completion of chemotherapy, with treatment beginning promptly thereafter. Blinding applied to patients and investigators; placebo and olaparib tablets were identical in appearance, and unblinding was permitted only in medical emergencies or for regulatory reporting of unexpected serious AEs (SAEs). Patients continued treatment until radiologic progression, unacceptable toxicity, withdrawal of consent, or death. Crossover to olaparib was not permitted during this trial. After discontinuation of the study drug due to disease progression or unacceptable toxicity, subsequent therapies were given at the investigators’ discretion.

Tumour imaging with CT or MRI was performed at baseline, every 8 weeks for the first 40 weeks, and every 12 weeks thereafter until disease progression, with blinded independent central review (BICR) per modified Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1. HRQoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life. Questionnaire Core-30 item (EORTC QLQ-C30) at baseline, every 4 weeks until progression, at discontinuation, and 30 days posttreatment; EORTC QLQ Pancreatic Cancer Module (EORTC QLQ-PAN26) was administered weekly during cycle 1 and every 4 weeks thereafter.

After treatment discontinuation, patients were followed for efficacy and safety. Patients with progression per RECIST were taken off the study drug but continued in follow-up for second PFS (PFS2) and OS, with survival assessed every 8 weeks by clinic visits, phone calls, physician records, or public registries until the final OS analysis. Patients who discontinued treatment for other reasons but without documented progression remained under scheduled imaging until progression occurred. In select cases, patients may remain on olaparib after RECIST-defined progression if both the investigator and the sponsor's physician agree that there is clinical benefit and no major toxicity. All patients underwent a safety follow-up visit 30 days after the last dose, during which SAEs were collected for 30 days posttreatment. PFS2 was assessed every 8 weeks after the first progression (as determined by investigator judgment of radiologic and/or symptomatic progression or death), and details of subsequent therapies were recorded. Final analysis was planned after approximately 89 PFS events and 106 deaths. Patients deriving benefit could remain on olaparib until local approval or program discontinuation.

The primary end point was PFS, defined as the time from randomization to centrally confirmed radiologic progression or death. Relevant secondary end points included OS, PFS2, objective response rate (ORR) by BICR, safety (AEs, laboratory measures, vital signs), and HRQoL assessed by the EORTC QLQ-C30. A 10-point or greater within-group change in the global health status scale was considered clinically meaningful by the study authors. Relevant exploratory end points included analyses of EORTC QLQ-C30 functioning domains and QLQ-PAN26 symptom scales.

Details regarding detailed inclusion criteria and relevant outcome measures are in Appendix 2 of the Supplemental Material.

Statistical Testing and Analysis Populations

A total sample size of 145 patients was planned. The design assumed a true hazard ratio of 0.54, corresponding to a 3.4-month improvement in median PFS over an assumed 4-month median PFS on placebo, with 80% power and a 1-sided significance level of 2.26%.^17,21

Three preplanned, event-driven analyses were specified in the statistical analysis plan, each associated with specific end points:

• Interim PFS analysis: Conducted after approximately 44 PFS events (about 50% of the planned total) to assess futility. This analysis occurred before the primary database lock and it was not formally reported.

• Final PFS analysis (data cut-off [DCO]1): Conducted after approximately 87 PFS events, corresponding to the January 15, 2019, DCO. This analysis represented the primary hypothesis testing for PFS, with secondary end points, including OS, ORR, PFS2, and HRQoL, also assessed at this cut-off.

• Final OS analysis (DCO2): Conducted after approximately 106 OS events, corresponding to the July 21, 2020, DCO. This analysis included the final OS assessment and updated analyses of secondary and exploratory outcomes (PFS [investigator assessment], PFS2, HRQoL, and safety).

Statistical testing followed a prespecified hierarchical procedure to control the overall type I error rate for OS and PFS. PFS was tested first, and only if significant would OS be formally tested via an alpha-recycling procedure. Other secondary and exploratory end points were not multiplicity-adjusted and were considered supportive. Statistical significance at the interim PFS analysis would have been declared if the 1-sided P value was < 0.005; the final PFS analysis used an adjusted alpha of approximately 2.26% to maintain an overall 1-sided type I error rate of 2.5%. At the final OS analysis (DCO2), statistical significance was prespecified at a 2-sided P < 0.046, reflecting alpha allocation across the interim and final analyses.

Efficacy analyses were conducted in the intention-to-treat population, defined as all randomized patients. The safety population comprised all patients who received at least 1 dose of study treatment.

Patient Disposition

Between January 2015 and January 2019, a total of 3,315 patients with metastatic PDAC were screened for eligibility in the POLO trial. Of these, 247 patients (7.5%) were identified as having a gBRCA mutation. A total of 167 patients provided consent for randomization, and 154 underwent random assignment in a 3:2 ratio to olaparib (n = 92) or placebo (n = 62). After randomization, 1 patient in each arm was found not to meet eligibility criteria; both were included in the intention-to-treat efficacy population but not in the safety analysis set, as neither received study treatment. Thus, 90 of 92 patients in the olaparib arm (97.8%) and 61 of 62 patients in the placebo arm (98.4%) received 1 dose or more and were included in the safety population.

At the primary DCO (January 15, 2019), 30 (32.6%) patients in the olaparib arm and 8 (12.9%) patients in the placebo arm remained on treatment. At the final OS analysis (DCO 2, July 21, 2020), 13 patients (14.1%) in the olaparib group (treatment duration 20.0 to 57.5 months) and 2 patients (3.2%) in the placebo group (treatment duration 45.8 to 48.2 months) were still receiving study drug. At the time of the January 2019 DCO, 60 (65%) patients in the olaparib group and 53 (85%) patients in the placebo group had discontinued the study drug. Most discontinuations in both groups were attributed to disease progression (55 patients [60%] in the olaparib group and 49 patients [79%] in the placebo group). At the time of the July 2020 DCO, 77 patients (83.7%) in the olaparib arm and 59 patients (95.2%) in the placebo arm had discontinued the study. The majority of discontinuations were due to disease progression, reported in 66 patients (71.7%) in the olaparib arm and 55 patients (88.7%) in the placebo arm.

Baseline Characteristics

Baseline demographics and disease characteristics of patients enrolled in the POLO trial are presented in Table 3.

Table 3: Summary of Baseline Characteristics in the Included Study

ECOG = Eastern Cooperative Oncology Group; FOLFIRINOX = leucovorin (folinic acid), fluorouracil, irinotecan, and oxaliplatin.

^aFour patients who underwent randomization on the basis of results of local germline BRCA mutation test did not undergo confirmatory BRACAnalysis CDx testing as part of the trial.

^bPatients may be counted in more than 1 category.

^cOne patient in the olaparib arm received 70 days (10 weeks) of first-line XELOX (oxaliplatin and capecitabine) chemotherapy; this was listed as an important protocol deviation.

^dOne patient in the placebo arm received 56 days (8 weeks) of first-line XELOX chemotherapy, but received 127 days (18.1 weeks) of the complete regimen.

Source: Golan et al. (2019),¹⁷ Kindler et al. (2022).¹⁸

Treatment Exposure and Concomitant Medications

At the time of the primary PFS analysis (January 15, 2019; DCO1), the corresponding median durations were 6.0 months in the olaparib arm and 3.7 months in the placebo arm.¹⁷ Relative dose intensity was high in both groups, with a median of 99.3% (range, 45 to 100) in the olaparib arm and 100% (range, 35 to 100) in the placebo arm.¹⁷

At the time of the final analysis (July 21, 2020; DCO2), the median duration of treatment was 7.5 months (range, 0.8 to 57.5) in the olaparib arm and 3.7 months (range, 0.1 to 48.2) in the placebo arm.¹⁸ Relative dose intensity was not reported at the final analysis.

At the time of the primary PFS analysis (January 15, 2019; DCO1), subsequent anticancer therapy was common after study treatment discontinuation and was received by 62% of patients in the olaparib group and 87% of patients in the placebo group. The most frequent second-line therapies were platinum-based regimens, most often FOLFIRINOX. Use of subsequent poly-(ADP-ribose) polymerase (PARP) inhibitors was reported in 7.8% of patients in the olaparib group and 27.1% of patients in the placebo group. Information about concomitant medications was not reported. Subsequent therapy was not reported at the final analysis.

Critical Appraisal

Internal Validity

The use of centralized randomization minimizes the risk of bias in the randomization process. However, owing to the small sample size, there is a higher risk that prognostic balance was not fully achieved, as evidenced by imbalances in multiple demographic and disease characteristics at baseline (e.g., age, sex, ECOG status, BRCA mutation type, site of metastases, location of primary tumour, type of previous chemotherapy). Although the clinical experts consulted for this review asserted that imbalances in these characteristics may not affect the outcomes, there remains the potential that the estimated effects could be influenced in part by differences in prognosis rather than solely by true treatment effects. A multivariate Cox regression for PFS, adjusted for factors that were imbalanced at baseline, resulted in a similar hazard ratio as the primary analysis. However, the variables included in the model were selected post hoc, it is unclear whether these are all strong prognostic factors, and the number of variables included in the model was large relative to the sample size. Therefore, the results are at risk of bias and should not be interpreted to be confirmation that there is no impact of potential prognostic imbalances on the study results.²²

The study was adequately powered to detect a statistically significant treatment effect for PFS; however, like many RCTs, it was likely powered to detect only the most common harms. Both OS and PFS were controlled for multiple testing to minimize the risk of type I errors. Other relevant end points, including PFS2, ORR, and HRQoL were not adjusted for multiple testing, which increases the risk of type I errors; however, the results for none of these end points were statistically significant. Efficacy analyses were undertaken on the intention-to-treat population, which is appropriate for estimating the effect of assignment to the interventions. However, the analysis of ORR was undertaken only among patients with measurable disease at baseline, and randomization was not stratified for this factor. Further, the analysis of the duration of response was undertaken only among patients with a response. There is a risk that prognostic balance was not maintained in either of these subpopulations, resulting in risk of bias for these end points.

A double-blind design with matching placebo tablets was used to minimize the risk of bias in the measurement of the outcomes. However, due to between-group imbalances in AEs distinctive to olaparib (e.g., anemia, nausea, fatigue) and the use of a placebo comparator, there is a risk that patients, investigators, and treating clinicians could have inferred the treatment group assignments. If this were to have occurred, there would be a risk of bias in the measurement of subjective end points, including subjective harms, HRQoL, PFS2 (investigator-assessed), and the final evaluation of PFS (investigator-assessed). The bias would likely favour the olaparib group. The measurement of objective end points (OS) and those measured by BICR (primary analysis of PFS, ORR) would be unaffected. A thorough investigation of the risk of bias due to deviations from the intended protocol was limited due to substandard reporting (i.e., protocol deviations not being reported). From the reported data (i.e., reasons for treatment discontinuation), no obvious issues were identified; however, a conclusive risk of bias judgment cannot be made.

There was a notable imbalance between groups in the proportion of patients who received a PARP inhibitor as a subsequent anticancer therapy. In the olaparib group, 6 patients (7.8%) received a PARP inhibitor after discontinuation, compared with 16 patients (27.1%) in the placebo group. The imbalance in postprogression PARP use would be expected to attenuate the observed OS difference and is not reflective of current practice in Canada, where olaparib would be used as maintenance rather than in later treatment lines. Sensitivity analyses using a rank-preserving structural failure time model to adjust for subsequent PARP use produced results consistent with the primary OS analysis, suggesting that the estimated effect of olaparib was not attenuated. However, the rank-preserving structural failure time mode relies on the unverifiable assumption that the treatment effect of olaparib is constant regardless of the line of therapy in which it is used,²³ which is unlikely to be clinically plausible. Other subsequent anticancer therapies, mainly platinum-based chemotherapy, were common in both groups, though they appeared relatively balanced across arms. The clinical experts considered these regimens to be consistent with current practice in Canada; therefore, they are unlikely to have meaningfully influenced the observed OS results.

For time-to-event end points, stratified log-rank tests and Cox proportional hazards models were used. The validity of the proportional hazards assumption was not explicitly tested or reported. Visual inspection of the Kaplan-Meier (KM) plots for OS, PFS, and PFS2 at the final analysis by the CDA-AMC review team suggested violations of the proportional hazards assumption. This was evidenced by a delayed separation of the KM curves for PFS (around 4 months) and PFS2 (around 8 months). The KM curves for OS crossed multiple times before separating around 24 months, at which time the estimates are unstable due to the low number of patients at risk. Therefore, the ratio of the hazards is not constant over time, and reliance on the hazard ratio when interpreting the effect of olaparib relative to placebo for these end points will be misleading. The KM-estimated probabilities of remaining event-free at clinically relevant follow-up times are not affected by this limitation. However, the reporting of these probabilities was limited in the trial publications; the 95% confidence intervals (CIs) for within-group probabilities and between-group differences in probabilities with 95% CIs were not reported. Therefore, the CDA-AMC review team was unable to complete a comprehensive appraisal of the precision of the absolute between-group effects. Further, for OS and PFS2, the KM-estimated probabilities of remaining event-free were only reported for a later follow-up time (36 months) despite plans to report results at other time points (6, 12, 18, 24, and 48 months). The estimates at 36 months are subject to higher uncertainty because there were few patients at risk at this time. The decision by the study authors not to report data at the other preplanned time points may have been influenced by the magnitude and/or direction of effects at these times. Used alone, the 36-month time point does not provide a comprehensive picture of the effects of olaparib compared with placebo for either end point.

The interpretation of results for other end points was also affected by substandard reporting. For example, no absolute between-group differences with 95% CIs were reported for ORR and duration of response, precluding any judgments regarding the precision of these estimates.

Assessments of the risk of bias due to informative censoring and missing outcome data were also limited due to substandard reporting for most relevant end points. The proportion of patients in each group who discontinued early from the trial was not reported. For the survival end points (OS, PFS, PFS2), at both DCOs, the proportion of patients censored and reasons for censoring in both groups were not explicitly reported. Therefore, the risk of bias due to informative censoring for these end points at both DCOs is uncertain. For ORR, the proportion of patients who were not evaluable was not reported. Consequently, it is unclear how many patients in each group contributed to the analyses, and the risk of bias due to missing outcome data is uncertain. For HRQoL as assessed via the EORTC QLQ-C30 global health status and quality of life scale (change from baseline and time to deterioration), 97% and 94% of patients in the olaparib and placebo groups, respectively, completed the questionnaire at baseline. Thereafter, the proportion of evaluable patients decreased over time in both groups (73% versus 58% at week 12, 47% versus 21% at week 24, and 25% versus 10% at week 48). Missing data were imputed under a missing at random assumption (i.e., that the missing data can be predicted based on observed values), which is not plausible. Therefore, there is a high risk of bias due to missing outcome data for all postbaseline time points assessed. Censoring rules and the proportions of patients censored in each group for time to deterioration were not reported; however, given the high rates of attrition in both groups, there is a high risk of bias due to information censoring.

HRQoL was assessed with validated EORTC instruments (QLQ-C30 and PAN26). The CDA-AMC review team identified no evidence in the literature for an estimated minimal important difference (MID) among patients with pancreatic cancer. The authors of the POLO trial prespecified a 10-point within-group change as clinically meaningful based on a study by Osaba et al. (1998).²⁴ However, this study suggests a within-group MID of 5 to 10 points and was conducted in a sample of patients with breast cancer and non–small cell lung cancer. A more recent systematic review by Musoro et al. (2023)²⁵ summarized estimated between-group MIDs across 9 cancer types. These mostly ranged between 5 and 10 points across EORTC QLQ-C30 scales. Although the observed between-group differences in the POLO trial (e.g., −2.5 for the global health status and quality of life scale; −4.5 for physical functioning) remain less than 5 and therefore may not be clinically important, this could not be determined with certainty, given the lack of a literature-based between-group MID specific to patients with pancreatic cancer. The reporting of HRQoL results was limited to the EORTC QLQ-C30; although pancreatic cancer–specific symptoms were to be assessed using the EORTC QLQ-PAN26, no results have been published. Further, analyses of HRQoL were planned for DCO2, although the results of these analyses were not reported. This raises the possibility of selective nonreporting, given that the decision whether to publish these data may have been made based on the magnitude and/or direction of the results.

External Validity

• The POLO trial population was generally aligned with the Health Canada indication for olaparib maintenance therapy (adult patients with metastatic PDAC and a deleterious or suspected deleterious gBRCA1 or gBRCA2 mutation who had not progressed on platinum-based chemotherapy). However, the trial exclusively studied patients in the first-line maintenance setting, and therefore does not provide evidence for patients who remain stable after later lines of therapy. According to the clinical experts consulted, such patients may be considered for olaparib in practice in Canada; however, this would represent extrapolation beyond the trial evidence, and the efficacy and safety of olaparib in this context remain unknown.

• Patients enrolled in the POLO trial were required to have an ECOG performance status of 0 or 1, excluding those with poorer performance status (2 or greater), which may limit applicability to patients with poorer performance status. However, the clinical experts consulted for this review noted that most patients eligible to receive first-line platinum-based chemotherapy, required for entry into the POLO trial, would already need to have good performance status (ECOG 0 to 1). Consequently, they indicated that the study population is broadly representative of those who would be considered for maintenance olaparib in Canada. The experts added that in real-world practice, not all patients have an ECOG performance status of 0 to 1 at the time of maintenance consideration, but those with poorer status are rally not candidates for further active therapy.

• Although the POLO trial included 3 sites in Canada, only 3 patients were enrolled from Canada. As a result, most of the evidence reflects patients treated in other health systems, which may limit the ability to fully assess whether supportive care practices, treatment pathways, and patient characteristics align with those in practice in Canada. However, the clinical experts consulted for this review considered the findings generalizable to patients in Canada who have pancreatic cancer with a gBRCA mutation and who are eligible for first-line platinum-based chemotherapy.

• The POLO trial population was aligned with the scope of this review and with the Health Canada indication (adult patients with metastatic PDAC and a gBRCA1 or gBRCA2 mutation who had not progressed on platinum-based chemotherapy). However, the trial exclusively studied patients in the first-line maintenance setting, and therefore does not provide evidence for patients who remain stable after later lines of therapy. The clinical expert noted that, in practice, such patients may also be considered for PARP inhibitor therapy, though this would be extrapolation beyond the trial evidence. The reimbursement request also included patients with locally advanced, unresectable pancreatic cancer; although these patients were not enrolled in the POLO trial, the clinical expert indicated that they are typically managed using the same systemic treatment approaches as those with metastatic disease.

• Although the POLO trial enrolled patients across 12 countries, the study population was predominantly white (92%). Limited racial and ethnic diversity may restrict generalizability to more diverse populations in Canada. However, the clinical experts consulted for this review noted that this distribution reflects the populations in which gBRCA1 and gBRCA2 mutations are more common and, therefore, is not expected to meaningfully limit the applicability of the findings to the setting in Canada.

• Olaparib was administered at the Health Canada–approved dose (300 mg twice daily).

• The POLO trial required patients to have received at least 16 weeks (approximately 4 months) of first-line platinum-based chemotherapy without disease progression before randomization. The clinical experts consulted for this review noted that while 4 months may appear short, extending the minimum requirement to 6 months would have excluded many patients due to disease progression. They considered the eligibility threshold used in the POLO trial to be reasonable and consistent with real-world practice because it captures patients who are stable on platinum therapy and suitable for maintenance treatment.

• Placebo was used as the comparator in the POLO trial, which does not reflect practice in Canada. The study authors state that in some clinical practices, treatment with platinum chemotherapy for more than 6 months may be limited by chronic peripheral neuropathy and other cumulative treatment-related AEs, making placebo a relevant comparator. However, in Canada, patients whose disease remains stable after first-line platinum-based chemotherapy often continue to receive some form of modified maintenance, such as reduced-dose FOLFIRINOX, FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan), or fluorouracil and leucovorin by infusion, rather than being taken off treatment entirely. Although some patients may request a complete break from chemotherapy, according to the clinical experts, in practice, these breaks are short (1 to 2 cycles) due to the poor outcomes of the disease. Therefore, the relative benefits and harms of olaparib compared with active chemotherapy maintenance remain unknown.

• The trial authors assessed outcomes relevant to practice in Canada (PFS, OS, PFS2, ORR, HRQoL, and safety), and the follow-up duration was adequate to capture these outcomes.

Results

Efficacy

Results for outcomes important to this review are presented in Table 4.

Key results include the following:

• At DCO2, the median duration of follow-up for OS in censored patients was longer with olaparib (31.3 months) compared to placebo (23.9 months). Median OS was similar between groups (19.0 versus 19.2 months). The 3-year probabilities of OS were 33.9% and 17.8%, respectively. Probabilities of OS at other prespecified time points were not reported.

• The median follow-up among censored patients at the time of the primary PFS analysis (DCO1) was longer in the olaparib group compared to the placebo group. The median PFS, 12-month, and 24-month probabilities of PFS for each group were reported, but between-group differences were not reported. The hazard ratio favoured olaparib over placebo. Analyses at longer follow-up (DCO2) were aligned overall with the primary analysis.

• At DCO2, the median time to PFS2 was longer with olaparib compared to placebo. The 3-year probabilities of PFS2 were reported for each study group, but the between-group difference was not reported. Probabilities of PFS2 at other prespecified time points were also not reported.

• At DCO1, among patients with measurable disease, the evidence was insufficient to suggest a difference in ORR between olaparib and placebo. The median duration of response was numerically higher with olaparib compared to placebo.

• The evidence was insufficient to suggest a difference in HRQoL outcomes measured by the EORTC QLQ-C30 and EORTC QLQ-C30 symptom subscales.

• Although the EORTC QLQ-PAN26 questionnaire was prespecified, results were not reported in the available publications.

Table 4: Summary of Key Efficacy Results From the Included Study

BICR = blinded independent central review; CI = confidence interval; CR = complete response; DCO = data cut-off; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; HR = hazard ratio; HRQoL = health-related quality of life; NE = not evaluated; NR = not reported; OR = odds ratio; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PFS2 = second progression-free survival; SD = standard deviation; TSCMD = time to sustained clinically meaningful deterioration.

^aEstimated using the Kaplan-Meier method.

^bEstimated using stratified Cox proportional hazards models. Multiplicity was not controlled for this analysis.

^cAnalyzed using the log-rank test. The final analysis of OS and the primary analysis of PFS were adjusted for multiple comparisons.

^dAnalyzed using the log-rank test; the P value was nominal and not adjusted for multiplicity.

^eEstimated using the Clopper–Pearson method for 95% CIs; duration of response was estimated using the Kaplan-Meier method.

^fBetween-group comparison was based on the Cochran-Mantel-Haenszel test, stratified by randomization factors. Multiplicity was not controlled.

^gA change from baseline of 10 points or greater was predefined as clinically meaningful.

^hEstimated using a mixed model for repeated measures across all time points.

ⁱBetween-group differences were considered statistically significant if P < 0.05.

^jMultiplicity was not controlled for HRQoL analyses.

Source: Golan et al. (2019),¹⁷ Hammel et al. (2019),¹⁹ Kindler et al. (2022).¹⁸

Harms

AEs of any grade, grade 3 or higher AEs, serious AEs, AEs leading to treatment discontinuation, deaths, and AEs of special interest are summarized in Table 6 in the Supplemental Material document in Appendix 3.

Key results include the following:

• At DCO2, compared with placebo, a larger proportion of patients in the olaparib arm experienced 1 or more AEs of any grade (98.9% versus 91.8%), grade 3 or greater AEs (48.9% versus 24.6%), and serious AEs (31.1% versus 16.4%). Treatment discontinuation due to AEs occurred in 8 patients (8.9%) in the olaparib group and 1 patient (1.6%) in the placebo group.

• At DCO2, the most common AEs of any grade that occurred more frequently with olaparib compared with placebo were nausea (49% versus 25%), fatigue (47% versus 26%), diarrhea (38% versus 16%), abdominal pain (32% versus 26%), anemia (32% versus 16%), constipation (28% versus 12%), decreased appetite (28% versus 7%), and vomiting (26% versus 16%). The nature of the SAEs was not elaborated on within the publications.

• At DCO2, grade 3 or greater AEs were more frequent with olaparib and were mainly anemia (12% versus 3%) and fatigue (6% versus 0%). Other grade 3 or greater events occurred in 3% or fewer patients in either group.

• One patient (1.1%) in the olaparib arm died of a stent-related duodenal perforation during follow-up; this was not considered related to study treatment according to the investigators. No deaths due to AEs occurred in the placebo group.

• For AEs of special interest, at DCO2, 1 case of grade 1 pneumonitis was reported in the olaparib arm. No cases of myelodysplastic syndrome or acute myeloid leukemia were observed in either treatment arm. Hematologic toxicity (grade 3 or greater anemia) occurred in 12.2% of patients receiving olaparib and 3.3% receiving placebo.

Discussion

Efficacy

The POLO trial was insufficient to demonstrate a statistically significant OS benefit for olaparib compared with placebo as maintenance therapy for patients with gBRCA-mutated metastatic PDAC whose disease had not progressed following first-line platinum-based chemotherapy. Median OS was similar between groups. Although the point estimate for the probability of OS at 3 years was numerically higher with olaparib, the precision of the between-group difference is unknown (not reported). Further, few patients were at risk at this time point so there is uncertainty in the true magnitude of the between-group difference. The authors provided no rationale for not reporting survival probabilities at earlier time points, when larger numbers of patients were at risk, as planned in the protocol. It is possible that the 3-year time point was selected for presentation (and results for other time points not presented) based on the magnitude and direction of the observed effects. The KM curves did not separate until approximately 24 months, and there is higher uncertainty in estimates at later time points. There is the potential that the effect of olaparib compared with placebo on OS was attenuated due to higher subsequent PARP inhibitor use in the comparator group; however, the presence and magnitude of any bias is uncertain. A sensitivity analysis leveraging the rank-preserving structural failure time model to attempt to adjust for postprogression PARP inhibitor use yielded nearly identical results to the main analysis; however, it should be noted that the rank-preserving structural failure time model is subject to an unverifiable assumption (i.e., that olaparib has an equal treatment effect no matter when the treatment is received), which may not be clinically plausible.

Despite these limitations, the experts acknowledged that a subset of patients may achieve prolonged disease control; however, they emphasized that the overall absolute gain in OS survival appears to be small and not clearly clinically meaningful. According to the clinical experts, the principal advantage of olaparib may lie in its oral administration and avoidance of cumulative toxicities associated with continued IV chemotherapy, including chronic peripheral neuropathy, which can preclude or impact subsequent chemotherapy tolerance, thereby improving patient acceptability and treatment convenience. Further, the POLO trial provides no evidence of the benefits and harms of olaparib versus a relevant chemotherapy comparator.

Olaparib extended the median PFS by approximately 3 to 4 months compared with placebo, with consistently higher probabilities of patients remaining progression-free at 6, 12, and 24 months. However, the precision of the between-group differences is unknown (not reported). According to the clinical experts consulted, a gain of this magnitude is clinically meaningful in metastatic pancreatic cancer. They explained that maintaining disease control for an additional 3 to 4 months is valuable because patients have already received months of intensive chemotherapy, and a comparable magnitude of PFS benefit has defined prior practice-changing regimens. This period of stability may delay the need for further IV chemotherapy, even in the absence of a demonstrated OS advantage. The clinical experts noted that RECIST-defined progression in trials may differ from clinical judgment in practice, but the direction and magnitude of effect align with what would be considered important in routine care. However, it should be noted again that the comparator is placebo, which is not relevant in practice. Therefore, the effect of maintenance olaparib on PFS compared with the current standard of care is unknown.

At the primary analysis, the proportion of patients with an objective response was numerically higher with olaparib (23%) than with placebo (12%), but this difference was not statistically significant. Further, the results are at risk of bias, given that this end point could only be measured among patients with measurable disease at baseline. Because randomization was not stratified by this characteristic, it is uncertain whether there was prognostic balance across the treatment group in this subpopulation of patients. The clinical experts noted that eliciting tumour shrinkage is not the primary therapeutic goal of maintenance therapy; rather, the intent is to prolong PFS and maintain quality of life following an initial response or stable disease on chemotherapy. They described the overall response rate as somewhat lower than expected for a targeted drug; however, they highlighted the durability of responses, with a median duration of approximately 25 months compared with 4 months for placebo. The clinical experts added that responses in the placebo arm were considered unlikely to represent true spontaneous tumour regression and were instead attributed to delayed effects of prior platinum-based chemotherapy or variability in imaging assessment, which the experts indicated would be expected in this population. They considered this prolonged response clinically meaningful for the small subset of patients who benefit, even though the overall response rate is limited. However, because the comparator is placebo, an option not routinely used as maintenance therapy in practice in Canada, the clinical relevance of the between-group difference in ORR is uncertain.

The POLO trial was insufficient to demonstrate a statistically significant improvement in PFS2 with olaparib compared with placebo. At the final analysis, median PFS2 was 16.9 months with olaparib and 9.3 months with placebo. The clinical experts viewed the PFS2 findings as generally supportive of the direction of benefit observed for PFS. Similarly to OS, the authors only reported the probabilities of PFS2 at 36 months, at which point the results are very uncertain due to the low number of patients at risk. No rationale was provided for not reporting the probabilities at other planned time points, and it is possible that the decision to report only the 36-month probabilities was informed by the magnitude and direction of effects at this and other time points. The precision of the between-group probability of PFS2 at 36 months is unknown (not reported). Similarly to OS, the results for PFS2 are reflective of the effects of olaparib relative to placebo plus any subsequent treatments used in both treatment groups. The authors did not report any sensitivity analyses to account for the higher use of subsequent PARP inhibitors in the placebo group.

In the POLO trial, differences between olaparib and placebo arms for global health status or physical functioning appeared small over the first 6 months of treatment. Between-group differences (−2.5 and −4.5 points, respectively) were below the 10-point threshold defined by the authors for clinical importance and literature-based MIDs; however, it should be noted that there is uncertainty in this threshold, given that no MID has been estimated in the literature specifically for patients with pancreatic cancer. Therefore, the precision of the between-group effects is also uncertain. These results are at risk of bias due to missing outcome data given that the number of patients available to complete the questionnaires declined over time and the missing data were imputed under a missing at random assumption, which is unlikely to be reasonable. Mean changes in symptoms from baseline were small, and no statistically or clinically meaningful between-group differences were observed for pain, nausea and vomiting, dyspnea, insomnia, constipation, or diarrhea. The estimates for fatigue and appetite loss were near the 10-point threshold, which may represent clinically important differences; often considered clinically meaningful, however, interpretation is limited by uncertainty in the minimal important differences for PDAC. According to the clinical experts consulted, these findings suggest that quality of life may be maintained during olaparib treatment compared with placebo. They noted that patients receiving active therapy often experience some decline due to treatment-related adverse effects, so the absence of deterioration relative to placebo is reassuring. The experts emphasized that olaparib did not appear to worsen patients’ quality of life, which they viewed as meaningful in the context of advanced pancreatic cancer and ongoing disease burden. Of note, patients also completed the EORTC QLQ-PAN26 during the trial, although the results have not been reported. This questionnaire is used as a supplement to the EORTC QLQ-C30 and focuses on specific symptoms related to pancreatic cancer. It should be considered that the decision not to report these results could have been made based on the magnitude and/or direction of the findings.

Harms

In the POLO trial, AEs were more frequent with olaparib than with placebo, consistent with the expected safety profile of PARP inhibitors. Nearly all patients experienced at least 1 AE (compared with 92% in the placebo group), and approximately half experienced a grade 3 or greater event (compared with 25% in the placebo group). The most common toxicities were nausea, fatigue, diarrhea, abdominal pain, and anemia. The clinical experts consulted by CDA-AMC described the overall safety profile as very manageable, noting that most observed AEs were low grade, were generally consistent with expected PARP inhibitor toxicity, and could be effectively managed with supportive care or temporary dose interruption.

Anemia was the most clinically relevant toxicity, reported in about 1 in 8 patients at grade 3 or higher severity. The clinical experts explained that management would typically involve transfusion when hemoglobin decreases to less than 70 g/L, or at higher levels if the patient is symptomatic, and dose reduction would be reserved for persistent or severe cases. These management strategies align with standard oncology practice and the product monograph recommendations.

The experts further noted that, in their experience, olaparib is generally easier for patients to tolerate than continued IV chemotherapy, given its oral administration and avoidance of cumulative toxicities such as chronic peripheral neuropathy. This was viewed as an advantage for patient convenience and treatment acceptability, provided that regular monitoring for anemia is maintained. However, there are no studies evaluating the benefits and harms of olaparib compared with standard chemotherapy as maintenance therapy among patients with gBRCA-mutated metastatic PDAC whose disease had not progressed following first-line platinum-based chemotherapy.

No new or unexpected safety signals were identified. One patient in the olaparib group died due to a stent-related duodenal perforation, which the authors considered to be unrelated to the study treatment. There were no reports of myelodysplastic syndrome, acute myeloid leukemia, or other treatment-related deaths; however, this trial was powered only to detect the most common harms. The absence of long-term follow-up data limits conclusions about delayed toxicities, and the use of a placebo comparator precludes direct comparison with active maintenance chemotherapy.

Conclusion

In the POLO trial, maintenance therapy with olaparib did not demonstrate a statistically significant improvement in OS compared with placebo. Although the probability of OS was higher among patients treated with olaparib compared with placebo at later follow-up, there is uncertainty in the reported effects at this time point because measures of precision were not reported and few patients were at risk. Interpretation of OS and PFS2 is limited by higher postprogression PARP inhibitor use in the placebo arm and limited relevance of the comparator, which is not representative of usual care in Canada.

Olaparib prolonged median PFS by approximately 3 to 4 months compared with placebo, representing a delay in disease progression that the clinical experts considered clinically meaningful in the context of metastatic pancreatic cancer, a disease characterized by rapid progression and limited therapeutic options. However, because the comparator was placebo rather than continued chemotherapy, the effect of maintenance olaparib on PFS relative to current standard practice is unknown. PFS2 results were not statistically significant, but they were directionally consistent with the pattern observed for PFS; however, PFS2 incorporates the effects of subsequent therapies and does not provide clear evidence of a sustained treatment effect, particularly in the absence of an OS benefit. Objective responses were infrequent; however, tumour shrinkage is not the primary therapeutic goal of maintenance therapy. Among the small subset of patients whose disease responded, responses were notably durable, but the clinical relevance of this finding is uncertain given the low overall response rate and the use of placebo as a comparator, which does not reflect usual maintenance strategies in practice in Canada.

Results of the POLO trial suggested that there may be little to no difference compared with placebo in HRQoL; however, these results are uncertain due to a lack of literature-based MID and a risk of bias due to missing outcome data. Further, aspects of HRQoL specific to patients with pancreatic cancer were measured but not reported. The safety profile was consistent with experience in other tumour types, with predictable and manageable toxicities. Anemia was the most common grade 3 or greater event and was described by the clinical experts consulted for this review as manageable in practice with transfusion or dose adjustment when needed.

Overall, olaparib maintenance provides a clinically meaningful delay in disease progression compared with placebo and has a tolerable safety profile. For patients with gBRCA1 or gBRCA2–mutated metastatic pancreatic cancer who remain stable on platinum-based chemotherapy, olaparib offers an oral, less intensive treatment alternative that may help reduce treatment burden while maintaining disease control. However, the benefits and harms of olaparib maintenance therapy compared with the current standard of care have not been studied.

Economic Review

Methods

The economic review consisted of a cost comparison of olaparib compared with fluorouracil plus leucovorin, FOLFIRI, and gemcitabine plus nab-paclitaxel for the maintenance treatment of adults with deleterious or suspected deleterious gBRCA-mutated locally advanced unresectable or metastatic PDAC whose disease has not progressed on prior systemic therapy.

Based on public list prices, olaparib is expected to have a per-patient cost of $7,834 per 28 days (refer to Appendix 4 of the Supplemental Material). Fluorouracil plus leucovorin, gemcitabine plus nab-paclitaxel, and FOLFIRI are expected to have per-patient costs of $2,373, $5,724, and $5,915 per 28 days, respectively. The incremental costs of olaparib compared with fluorouracil plus leucovorin, gemcitabine plus nab-paclitaxel, and FOLFIRI are $5,461, $2,110, and $1,919 per patient per 28 days, respectively. Therefore, the reimbursement of olaparib for the maintenance treatment of adults with deleterious or suspected deleterious gBRCA-mutated locally advanced unresectable or metastatic PDAC whose disease has not progressed on prior systemic therapy is expected to increase overall drug acquisition costs. Additional items for consideration are provided in the following bullets:

• According to the clinical review, evidence from the POLO trial suggests that, compared to placebo, olaparib improved PFS, with little to no difference in HRQoL over the first 6 months of treatment. Results of OS and PFS2 were uncertain due to the low number of patients at risk at 3 years and measures of precision not being reported. AEs were more frequent with olaparib and consistent with the expected safety profile of PARP inhibitors. No evidence was identified regarding the comparative efficacy and safety of olaparib versus active comparators.

• As of November, 2025, olaparib is only available as a brand name product in Canada (Lynparza). There are 3 generic submissions currently under review by Health Canada. Therefore, 1 or more generic versions of olaparib may become available. According to the pan-Canadian Pharmaceutical Alliance Tiered Pricing Framework, after 3 months of funding, the price of a single-source generic decreases to 55% of the brand reference price.²⁶ Assuming a price consistent with 55% of the price of the reference brand, the cost of generic olaparib would be $4,309 per 28 days. If more than 1 generic product becomes available, the cost of olaparib would be further reduced.

• No health care resource use outcomes were reported in the clinical trial. Clinical experts consulted for this review provided the following considerations regarding the possible impacts of the reimbursement of olaparib on the use of health care resources: olaparib requires germline genetic testing for BRCA mutations and, therefore, it is expected that olaparib would be associated with higher costs relative to all other comparators. On the other hand, treatment administration costs of olaparib would be lower because it is an oral tablet and all other comparators require IV infusion; costs related to laboratory tests and unplanned outpatient visits or inpatient admissions would also likely be lower with olaparib given that its comparators require more frequent laboratory tests to monitor for toxicities, and the AEs from chemotherapy could lead to unplanned visits.

• Olaparib was not previously reviewed by CDA-AMC for locally advanced unresectable or metastatic PDAC. As of November 2025, there are no drugs under review for adenocarcinoma of the pancreas. CDA-AMC previously reviewed irinotecan in combination with fluorouracil and leucovorin (2014) and nab-paclitaxel in combination with gemcitabine (2014) for adult patients with metastatic PDAC, issuing positive recommendations for reimbursement.

• No cost-effectiveness studies conducted in Canada that assessed the cost-effectiveness of olaparib against active comparators for the population of this review were identified based on a literature search conducted on August 28, 2025, with alerts maintained until the Formulary Management Expert Committee meeting on January 22, 2026. One cost-utility analysis conducted in Canada was published in 2023 based on the POLO trial.²⁷ The cost-utility analysis only included placebo as a comparator, which is not reflective of the current standard of care for the population of this review. Therefore, results from the cost-utility analysis cannot provide any information on the cost-effectiveness of olaparib relevant to its comparators.

Conclusion

The reimbursement of olaparib for the maintenance treatment of deleterious or suspected deleterious gBRCA-mutated locally advanced unresectable or metastatic PDAC in adults whose disease has not progressed on prior systemic therapy is expected to increase overall drug acquisition costs. Based on the clinical review conclusions, compared to placebo, olaparib may extend PFS, with uncertain impact on OS and little to no impact on HRQoL. There were no direct or indirect comparisons of olaparib with active regimens used for the maintenance treatment of adults with deleterious or suspected deleterious gBRCA-mutated locally advanced unresectable or metastatic PDAC; therefore, the comparative efficacy of olaparib versus identified comparators is unknown.

Given that olaparib is associated with higher drug acquisition costs and unknown clinical benefit, reimbursement of olaparib will add costs to the public health care system with unknown benefit.

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