Patient-Reported Outcomes in OlympiA: A Phase III, Randomized, Placebo-Controlled Trial of Adjuvant Olaparib in gBRCA1/2 Mutations and High-Risk Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer.

PURPOSE: The OlympiA randomized phase III trial compared 1 year of olaparib (OL) or placebo (PL) as adjuvant therapy in patients with germline BRCA1/2, high-risk human epidermal growth factor receptor 2-negative early breast cancer after completing (neo)adjuvant chemotherapy ([N]ACT), surgery, and radiotherapy. The patient-reported outcome primary hypothesis was that OL-treated patients may experience greater fatigue during treatment. METHODS: Data were collected before random assignment, and at 6, 12, 18, and 24 months. The primary end point was fatigue, measured with the Functional Assessment of Chronic Illness Therapy-Fatigue scale. Secondary end points, assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 item, included nausea and vomiting (NV), diarrhea, and multiple functional domains. Scores were compared between treatment groups using mixed model for repeated measures. Two-sided P values <.05 were statistically significant for the primary end point. All secondary end points were descriptive. RESULTS: One thousand five hundred and thirty-eight patients (NACT: 746, ACT: 792) contributed to the analysis. Fatigue severity was statistically significantly greater for OL versus PL, but not clinically meaningfully different by prespecified criteria (≥3 points) at 6 months (diff OL v PL: NACT: -1.3 [95% CI, -2.4 to -0.2]; P = .022; ACT: -1.3 [95% CI, -2.3 to -0.2]; P = .017) and 12 months (NACT: -1.6 [95% CI, -2.8 to -0.3]; P = .017; ACT: -1.3 [95% CI, -2.4 to -0.2]; P = .025). There were no significant differences in fatigue severity between treatment groups at 18 and 24 months. NV severity was worse in patients treated with OL compared with PL at 6 months (NACT: 6.0 [95% CI, 4.1 to 8.0]; ACT: 5.3 [95% CI, 3.4 to 7.2]) and 12 months (NACT: 6.4 [95% CI, 4.4 to 8.3]; ACT: 4.5 [95% CI, 2.8 to 6.1]). During treatment, there were some clinically meaningful differences between groups for other symptoms but not for function subscales or global health status. CONCLUSION: Treatment-emergent symptoms from OL were limited, generally resolving after treatment ended. OL- and PL-treated patients had similar functional scores, slowly improving during the 24 months after (N)ACT and there was no clinically meaningful persistence of fatigue severity in OL-treated patients.

Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial.

PURPOSE: Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)-directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non-small-cell lung cancer. Treatments are limited for other HER2-expressing solid tumors. METHODS: This open-label phase II study evaluated T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment or without alternative treatments. The primary end point was investigator-assessed confirmed objective response rate (ORR). Secondary end points included safety, duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS: At primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. The median follow-up was 12.75 months. In all patients, the ORR was 37.1% (n = 99; [95% CI, 31.3 to 43.2]), with responses in all cohorts; the median DOR was 11.3 months (95% CI, 9.6 to 17.8); the median PFS was 6.9 months (95% CI, 5.6 to 8.0); and the median OS was 13.4 months (95% CI, 11.9 to 15.5). In patients with central HER2 IHC 3+ expression (n = 75), the ORR was 61.3% (95% CI, 49.4 to 72.4), the median DOR was 22.1 months (95% CI, 9.6 to not reached), the median PFS was 11.9 months (95% CI, 8.2 to 13.0), and the median OS was 21.1 months (95% CI, 15.3 to 29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths. CONCLUSION: Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pretreated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.

Olaparib efficacy in patients with germline BRCA-mutated, HER2-negative metastatic breast cancer: Subgroup analyses from the phase III OlympiAD trial.

In the primary analysis of the phase III OlympiAD trial, olaparib significantly prolonged progression-free survival (PFS) vs chemotherapy treatment of physician's choice (TPC) in patients with germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer (mBC). We report subgroup analyses for the final analysis at a median OS follow-up of 18.9 months (olaparib) and 15.5 months (TPC). Patients (N = 302) with gBRCAm, HER2-negative mBC and ≤2 previous lines of chemotherapy for mBC were randomized 2:1 to open-label olaparib (300 mg twice daily) or TPC. All subgroup analyses were prespecified except site of metastases. Investigator-assessed median PFS was 8.0 months (95% confidence interval [CI] 5.8-8.4; 176/205 events) for olaparib and 3.8 months (95% CI 2.8-4.2; 83/97 events) for TPC (hazard ratio 0.51, 95% CI 0.39-0.66). In subgroup analyses, median PFS hazard ratios (95% CI) favored olaparib: hormone receptor status (triple-negative: 0.47, 0.32-0.69; hormone receptor-positive: 0.52, 0.36-0.75); gBRCAm (BRCA1: 0.49, 0.35-0.71; BRCA2: 0.49, 0.33-0.74); site of metastases (visceral/CNS: 0.53, 0.40-0.71; non-visceral: 0.45, 0.23-0.98); prior chemotherapy for mBC (yes: 0.51, 0.38-0.70; no: 0.49, 0.30-0.82); prior platinum-based chemotherapy for BC (yes: 0.49, 0.30-0.83; no: 0.50, 0.37-0.69); progressive disease at randomization (yes: 0.48, 0.35-0.65; no: 0.61, 0.36-1.07). Investigator-assessed objective response rates were higher across all subgroups with olaparib (35-68%) vs TPC (5-40%). Global health status/health-related quality of life increased in all subgroups with olaparib vs decreased/no change with TPC. These data confirm the consistency of olaparib benefit across patient subgroups in OlympiAD.

OlympiAD extended follow-up for overall survival and safety: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.

BACKGROUND: In the Phase III OlympiAD study, olaparib significantly prolonged progression-free survival versus chemotherapy treatment of physician's choice (TPC) in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2-negative metastatic breast cancer (mBC). In the final pre-specified analysis (64% maturity), median overall survival (OS) was 19.3 months for olaparib and 17.1 months for TPC (P = 0.513). Post-hoc extended follow-up, 25.7 months longer than previously reported for OS, is reported. PATIENTS AND METHODS: Patients with gBRCAm, human epidermal growth factor receptor 2-negative mBC, who had received ≤2 lines of chemotherapy for metastatic disease, were randomised 2:1 to olaparib (300 mg bid) or TPC. During extended follow-up, OS was analysed every 6 months using the stratified log-rank test (overall population) and Cox proportional hazards model (pre-specified subgroups). RESULTS: In the overall population (302 patients; 76.8% maturity), median OS was 19.3 months for olaparib and 17.1 months for TPC (hazard ratio 0.89, 95% confidence interval 0.67-1.18); median follow-up was 18.9 and 15.5 months, respectively. Three-year survival was 27.9% for olaparib versus 21.2% for TPC. With olaparib, 8.8% of patients received study treatment for ≥3 years versus none with TPC. In first-line mBC, median OS was longer for olaparib than TPC (22.6 versus 14.7 months; hazard ratio 0.55, 95% confidence interval 0.33-0.95) and 3-year survival was 40.8% for olaparib versus 12.8% for TPC. No new serious adverse events related to olaparib were observed. CONCLUSIONS: OS was consistent with previous analyses from OlympiAD. These findings support the possibility of meaningful long-term survival benefit with olaparib, particularly in first-line mBC.

Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer.

BACKGROUND: Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation-associated early breast cancer. METHODS: We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival. RESULTS: A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P = 0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest. CONCLUSIONS: Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.).

Modernizing Clinical Trial Eligibility Criteria: Recommendations of the ASCO-Friends of Cancer Research Laboratory Reference Ranges and Testing Intervals Work Group.

PURPOSE: In clinical research, eligibility criteria promote patient safety and optimize the evidence generated from clinical trials. However, overly stringent eligibility criteria, including laboratory requirements, may limit enrollment, resulting in delayed trial completion and potentially limiting applicability of trial results to a general practice population. EXPERIMENTAL DESIGN: Starting in 2018, a working group consisting of experts in direct patient care, the FDA, industry, and patient advocacy developed recommendations to guide the optimal use of laboratory reference ranges and testing intervals in clinical trial eligibility criteria and study procedures. The working group evaluated current eligibility criteria across different clinical trial phases and performed a literature review to evaluate the impact of and justification for laboratory test eligibility requirements and testing intervals in clinical trials. Recommendations were developed on the basis of the goals of promoting safety and optimizing the evidence generated, while also expanding eligibility and applicability, and minimizing excess burden of trial participation. RESULTS: In general, we found little variation over time and trial phase in laboratory test requirements, suggesting that these eligibility criteria are not refined according to ongoing clinical experience. We propose recommendations to optimize the use of laboratory tests when considering eligibility criteria. CONCLUSIONS: Tailoring the use of laboratory test requirements and testing intervals may increase the number and diversity of patients in clinical trials and provide clinical data that more closely represent the general practice populations.See related commentary by Giantonio, p. 2369.

Pharmacokinetics and Safety of Olaparib in Patients with Advanced Solid Tumours and Renal Impairment.

BACKGROUND: Olaparib, a potent oral poly(ADP-ribose) polymerase inhibitor, is partially renally cleared. We investigated the pharmacokinetics and safety of olaparib in patients with mild or moderate renal impairment to provide dosing recommendations. METHODS: This phase I open-label study assessed the pharmacokinetics, safety and tolerability of single-dose, oral 300-mg olaparib tablets in adults (aged 18-75 years) with solid tumours. Patients had normal renal function, or mild or moderate renal impairment (estimated creatinine clearance ≥ 81, 51-80 or 31-50 mL/min, respectively). Blood was collected for 96 h, and urine samples collected for 24 h post-dose. Patients could continue taking olaparib 300 mg twice daily for a long-term safety assessment. RESULTS: Overall, 44 patients received one or more doses of olaparib and 38 were included in the pharmacokinetic assessment. Patients with mild renal impairment had an area under the curve geometric least-squares mean ratio of 1.24 (90% confidence interval 1.06-1.47) and a geometric least-squares mean maximum plasma concentration ratio of 1.15 (90% confidence interval 1.04-1.27) vs. those with normal renal function. In patients with moderate renal impairment, the geometric least-squares mean ratio for the area under the curve was 1.44 (90% confidence interval 1.10-1.89) and for the maximum plasma concentration was 1.26 (90% confidence interval 1.06-1.48) vs. those with normal renal function. No new safety signals were detected in patients with mild or moderate renal impairment. CONCLUSIONS: In patients with mild renal impairment, the small increase in exposure to olaparib was not considered clinically relevant. In patients with moderate renal impairment, exposure to olaparib increased by 44%; thus, these patients should be carefully monitored and the tablet dose should be adjusted to 200 mg twice daily. CLINICAL TRIALS REGISTRATION: NCT01894256.

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes.

BACKGROUND: Olaparib (Lynparza™) is a PARP inhibitor approved for advanced BRCA-mutated (BRCAm) ovarian cancer. PARP inhibitors may benefit patients whose tumours are dysfunctional in DNA repair mechanisms unrelated to BRCA1/2. We report exploratory analyses, including the long-term outcome of candidate biomarkers of sensitivity to olaparib in BRCA wild-type (BRCAwt) tumours. METHODS: Tumour samples from an olaparib maintenance monotherapy trial (Study 19, D0810C00019; NCT00753545) were analysed. Analyses included classification of mutations in genes involved in homologous recombination repair (HRR), BRCA1 promoter methylation status, measurement of BRCA1 protein and Myriad HRD score. RESULTS: Patients with BRCAm tumours gained most benefit from olaparib; a similar treatment benefit was also observed in 21/95 patients whose tumours were BRCAwt but had loss-of-function HRR mutations compared to patients with no detectable HRR mutations (58/95). A higher median Myriad MyChoice® HRD score was observed in BRCAm and BRCAwt tumours with BRCA1 methylation. Patients without BRCAm tumours derived benefit from olaparib treatment vs placebo although to a lesser extent than BRCAm patients. CONCLUSIONS: Ovarian cancer patients with tumours harbouring loss-of-function mutations in HRR genes other than BRCA1/2 may constitute a small, molecularly identifiable and clinically relevant population who derive treatment benefit from olaparib similar to patients with BRCAm.

Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy.

BACKGROUND: In Study 19, maintenance monotherapy with olaparib significantly prolonged progression-free survival vs placebo in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer. METHODS: Study 19 was a randomised, placebo-controlled, Phase II trial enrolling 265 patients who had received at least two platinum-based chemotherapy regimens and were in complete or partial response to their most recent regimen. Patients were randomised to olaparib (capsules; 400 mg bid) or placebo. We present long-term safety and final mature overall survival (OS; 79% maturity) data, from the last data cut-off (9 May 2016). RESULTS: Thirty-two patients (24%) received maintenance olaparib for over 2 years; 15 (11%) did so for over 6 years. No new tolerability signals were identified with long-term treatment and adverse events were generally low grade. The incidence of discontinuations due to adverse events was low (6%). An apparent OS advantage was observed with olaparib vs placebo (hazard ratio 0.73, 95% confidence interval 0.55‒0.95, P = 0.02138) irrespective of BRCA1/2 mutation status, although the predefined threshold for statistical significance was not met. CONCLUSIONS: Study 19 showed a favourable final OS result irrespective of BRCA1/2 mutation status and unprecedented long-term benefit with maintenance olaparib for a subset of platinum-sensitive, recurrent ovarian cancer patients.

Biological and clinical evidence for somatic mutations in BRCA1 and BRCA2 as predictive markers for olaparib response in high-grade serous ovarian cancers in the maintenance setting.

To gain a better understanding of the role of somatic mutations in olaparib response, next-generation sequencing (NGS) of BRCA1 and BRCA2 was performed as part of a planned retrospective analysis of tumors from a randomized, double-blind, Phase II trial (Study 19; D0810C00019; NCT00753545) in 265 patients with platinum-sensitive high-grade serous ovarian cancer. BRCA1/2 loss-of-function mutations were found in 55% (114/209) of tumors, were mutually exclusive, and demonstrated high concordance with Sanger-sequenced germline mutations in matched blood samples, confirming the accuracy (97%) of tumor BRCA1/2 NGS testing. Additionally, NGS identified somatic mutations absent from germline testing in 10% (20/209) of the patients. Somatic mutations had >80% biallelic inactivation frequency and were predominantly clonal, suggesting that BRCA1/2 loss occurs early in the development of these cancers. Clinical outcomes between placebo- and olaparib-treated patients with somatic BRCA1/2 mutations were similar to those with germline BRCA1/2 mutations, indicating that patients with somatic BRCA1/2 mutations benefit from treatment with olaparib.

Quality of life during olaparib maintenance therapy in platinum-sensitive relapsed serous ovarian cancer.

BACKGROUND: Maintenance monotherapy with the poly(ADP-ribose) polymerase inhibitor olaparib significantly prolongs progression-free survival over placebo in patients with platinum-sensitive relapsed serous ovarian cancer, with greatest benefit seen in patients with a BRCA1/2 mutation (BRCAm). Preservation of health-related quality of life (HRQoL) is important during maintenance therapy; we evaluated the effect of olaparib on HRQoL in this Phase II trial (NCT00753545, Study 19). METHODS: Patients received olaparib 400 mg b.i.d. (capsules) or placebo until progression. Patient-reported HRQoL and disease-related symptoms were evaluated using the FACT-Ovarian (FACT-O) questionnaire (completed at baseline and every 28 days until progression), the FACT/NCCN Ovarian Symptom Index (FOSI) and the Trial Outcome Index (TOI). TOI of the FACT-O was the primary measure. RESULTS: Overall, 265 women were randomised to maintenance olaparib (n=136) or placebo (n=129). Compliance for HRQoL assessment was high (∼80% over time). Most patients in both arms reported a best response of 'no change' on TOI (81%) and other HRQoL measures. There were no statistically significant differences in time to worsening or improvement rates of TOI, FOSI and FACT-O scores in the overall, BRCAm and germline BRCAm populations. CONCLUSIONS: Maintenance treatment with olaparib was well tolerated and had no adverse impact on HRQoL in this study of patients with platinum-sensitive relapsed serous ovarian cancer who had responded to their most recent platinum-based therapy (partial or complete response). Interpretation of the HRQoL results in this population may differ from patients who have not responded to their most recent platinum-based therapy.

Effect of Itraconazole and Rifampin on the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors: Results of Two Phase I Open-label Studies.

PURPOSE: The metabolism of olaparib, a potent inhibitor of poly(ADP-ribose) polymerase (PARP) with demonstrated efficacy in patients with BRCA-mutated ovarian cancer, is mediated by cytochrome P450 (CYP) enzymes (predominantly CYP3A4/5). We assessed the potential of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) to alter the pharmacokinetic (PK) profile of olaparib following single oral tablet doses. METHODS: Two Phase I, open-label, non-randomized trials were conducted in patients with advanced solid tumors. In Study 7, patients received olaparib alone and co-administered with itraconazole; in Study 8, a separate group of patients received olaparib alone and co-administered with rifampin. No interaction between itraconazole and olaparib was concluded if two-sided 90% CIs for the treatment ratios of AUC and/or AUC0-t and Cmax fell within the bioequivalence range of 0.80-1.25. An interaction between rifampin and olaparib was concluded if the lower limit of the 90% CI for the treatment ratios was <0.5 (ie, >50% decrease in olaparib AUC or Cmax in the presence of rifampin compared with olaparib alone). FINDINGS: In Study 7 (N = 59; 17 male, 42 female), 56 and 53 patients were evaluable for PK analysis following treatment with olaparib alone and olaparib plus itraconazole, respectively; in Study 8 (N = 22; 4 male, 18 female), all patients were evaluable. Co-administration of olaparib with itraconazole resulted in a statistically significant increase in the relative bioavailability of olaparib: Cmax treatment ratio, 1.42 (90% CI, 1.33-1.52); mean AUC treatment ratio, 2.70 (90% CI, 2.44-2.97). Mean CL/F and Vz/F were reduced (8.16 vs 3.05 L/h and 192 vs 75.1 L), although mean t½ was unchanged (15.0 vs 15.6 hours). Co-administration of olaparib with rifampin resulted in a statistically significant decrease in the relative bioavailability of olaparib: Cmax treatment ratio, 0.29 (90% CI, 0.24-0.33); mean AUC treatment ratio, 0.13 (90% CI, 0.11-0.16). CL/F and Vz/F were increased when olaparib and rifampin were co-administered (6.36 vs 48.3 L/h and 112 vs 1076 L); however, mean t½ was unchanged (13.0 vs 15.8 hours). Safety data for olaparib following tablet dosing were consistent with the known safety profile. IMPLICATIONS: Exposure to olaparib was significantly increased when co-administered with the potent CYP3A4 inhibitor itraconazole, and significantly decreased when co-administered with the potent CYP3A4 inducer rifampin, compared with olaparib alone. Potent CYP3A4 enzyme inhibitors and inducers should be avoided during olaparib treatment. ClinicalTrials.gov identifiers: NCT01900028 (Study 7) and NCT01929603 (Study 8).

Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial.

BACKGROUND: In patients with platinum-sensitive recurrent serous ovarian cancer, maintenance monotherapy with the PARP inhibitor olaparib significantly improves progression-free survival versus placebo. We assessed the effect of maintenance olaparib on overall survival in patients with platinum-sensitive recurrent serous ovarian cancer, including those with BRCA1 and BRCA2 mutations (BRCAm). METHODS: In this randomised, placebo-controlled, double-blind, phase 2 trial involving 82 sites across 16 countries, patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more courses of platinum-based chemotherapy and had responded to their latest regimen were randomly assigned (1:1) using a computer-generated sequence to receive oral maintenance olaparib (as capsules; 400 mg twice a day) or a matching placebo by an interactive voice response system. Patients were stratified by ancestry, time to progression on penultimate platinum, and response to most recent platinum. Patients and investigators were masked to treatment assignment by the use of unique identifiers generated during randomisation. The primary endpoint of the trial was progression-free survival. In this updated analysis, we present data for overall survival, a secondary endpoint, from the third data analysis after more than 5 years' follow-up (intention-to-treat population). We did the updated overall survival analysis, described in this Article at 77% data maturity, using a two-sided α of 0·95%. As the study was not powered to assess overall survival, this analysis should be regarded as descriptive and the p values are nominal. We analysed randomly assigned patients for overall survival and all patients who received at least one dose of treatment for safety. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT00753545. FINDINGS: Between Aug 28, 2008, and Feb 9, 2010, 265 patients were randomly assigned to olaparib (n=136) or placebo (n=129). 136 patients had deleterious BRCAm. The data cutoff for this analysis was Sept 30, 2015. An overall survival advantage was seen with maintenance olaparib versus placebo in all patients (hazard ratio [HR] 0·73 [95% CI 0·55-0·96]; nominal p=0·025, which did not meet the required threshold for statistical significance [p<0·0095]; median overall survival was 29·8 months [95% CI 26·9-35·7] for those treated with olaparib vs 27·8 months [24·9-33·7] for those treated with placebo), and in patients with BRCAm (HR 0·62 [95% CI 0·41-0·94] nominal p=0·025; 34·9 months [95% CI 29·2-54·6] vs 30·2 months [23·1-40·7]). The overall survival data in patients with BRCA wild-type were HR 0·83 (95% CI 0·55-1·24, nominal p=0·37; 24·5 months [19·8-35·0] for those treated with olaparib vs 26·6 months [23·1-32·5] for those treated with placebo). 11 (15%) of 74 patients with BRCAm received maintenance olaparib for 5 years or more. Overall, common grade 3 or worse adverse events in the olaparib and placebo groups were fatigue (11 [8%] of 136 patients vs four [3%] of 128) and anaemia (eight [6%] vs one [1%]). 30 (22%) of 136 patients in the olaparib group and 11 (9%) of 128 patients in the placebo group reported serious adverse events. In patients treated for 2 years or more, adverse events in the olaparib and placebo groups included low-grade nausea (24 [75%] of 32 patients vs two [40%] of five), fatigue (18 [56%] of 32 vs two [40%] of five), vomiting (12 [38%] of 32 vs zero), and anaemia (eight [25%] of 32 vs one [20%] of five); generally, events were initially reported during the first 2 years of treatment. INTERPRETATION: Despite not reaching statistical significance, patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy after platinum-based chemotherapy appeared to have longer overall survival, supporting the reported progression-free survival benefit. Clinically useful long-term exposure to olaparib was seen with no new safety signals. Taken together, these data support both the long-term clinical benefit and tolerability of maintenance olaparib in patients with BRCA-mutated platinum-sensitive recurrent serous ovarian cancer. FUNDING: AstraZeneca.

Olaparib does not cause clinically relevant QT/QTc interval prolongation in patients with advanced solid tumours: results from two phase I studies.

BACKGROUND: Some therapeutic agents in oncology can be causally associated with specific cardiovascular events including QT/QTc interval prolongation. We investigated the effect of multiple dosing of the oral poly (ADP-ribose)-polymerase (PARP) inhibitor, olaparib (tablet formulation) on QT/QTc interval. METHODS: Two phase I, open-label, three-part studies (NCT01921140 [study 4] and NCT01900028 [study 7]) were conducted in adults with refractory/resistant advanced solid tumours. In both studies, parts A and B assessed the QT/QTc interval effects of single-dose oral olaparib 100 (study 4) or 300 (study 7) mg and multiple-dose olaparib 300 mg bid for 5 days, respectively, while part C evaluated continued access to olaparib for additional safety analyses. An ANCOVA model tested the primary objective of multiple-dose effects of olaparib on QT interval corrected using Fridericia's formula (QTcF). RESULTS: Data from 119 and 109 patients were pooled from parts A and B, respectively, for QT/QTc analysis. At pre-dose and up to 12 h post-dose, the upper limits of the 90 % confidence intervals (CIs) for the difference in QTcF least squares means after olaparib multiple dosing versus control (day -1) were <10 ms, suggesting a lack of clinically relevant effect on cardiac repolarization. A slight shortening of QTcF was observed at most time points versus control. QTcF results for the individual studies and single-dose olaparib paralleled the primary multiple-dose pooled analysis, with upper limits of the 90 % CIs < 10 ms. CONCLUSION: Olaparib tablets administered as multiple or single doses had no clinically significant effect on QT/QTc interval.

Olaparib maintenance therapy in patients with platinum-sensitive, relapsed serous ovarian cancer and a BRCA mutation: Overall survival adjusted for postprogression poly(adenosine diphosphate ribose) polymerase inhibitor therapy.

BACKGROUND: Maintenance treatment with the oral poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor olaparib (Lynparza) in Study 19 (study number, D0810C00019; ClinicalTrials.gov identifier, NCT00753545) significantly improved progression-free survival in comparison with a placebo for patients with platinum-sensitive, relapsed serous ovarian cancer with a BRCA1/2 mutation (BRCAm), but an interim analysis revealed no statistically significant overall survival (OS) benefit. However, 23% of the patients receiving the placebo switched to a PARP inhibitor after progression. To investigate whether this had a confounding effect on OS, this article reports an exploratory post hoc analysis that excluded all patients from sites where 1 or more placebo patients received postprogression PARP inhibitor treatment. METHODS: In Study 19, 136 of the 265 patients receiving olaparib or a placebo had a BRCAm. Sixteen patients treated at 11 of the 82 investigational sites received a PARP inhibitor after progression; these sites were excluded from this analysis, and 97 BRCAm patients at 50 sites were included. OS was assessed with a Cox proportional hazards model analogous to the primary study analysis. A supporting rank-preserving structural failure time (RPSFT) model analysis was undertaken for all 136 BRCAm patients. RESULTS: The OS hazard ratio (HR) was 0.52 (95% confidence interval [CI], 0.28-0.97) for the 97 BRCAm patients, whereas for the interim OS analysis with all 136 BRCAm patients, it was 0.73 (95% CI, 0.45-1.17). The supportive RPSFT analysis HR was approximately 0.66. CONCLUSIONS: The numerical improvement in the OS HR suggests that in Study 19, postprogression PARP inhibitor treatment had a confounding influence on the interim OS analysis for BRCAm patients. There is a degree of uncertainty due to the small sample size and the lack of data maturity. Cancer 2016;122:1844-52. © 2016 American Cancer Society.

Phase II Study of Olaparib (AZD-2281) After Standard Systemic Therapies for Disseminated Colorectal Cancer.

BACKGROUND: Effective new agents for patients with colorectal cancer (CRC) with disease progression during standard therapy regimens are needed. We hypothesized that poly ADP ribose polymerase (PARP) inhibitor therapy in patients with CRC and inefficient tumor DNA repair mechanisms, such as those with high-level microsatellite instability (MSI-H), would result in synthetic lethality. METHODS: This was an open-label phase II trial testing olaparib 400 mg p.o. b.i.d. for patients with disseminated, measurable CRC failing standard therapies with centrally confirmed tumor MSI status. The primary endpoint was the tumor response, assessed by RECIST, version 1.0. The secondary endpoints were safety/toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-three patients (20 microsatellite stable [MSS], 13 MSI-H) were enrolled. The median age for all patients was 57 years and for MSS and MSI-H patients was 51 and 61 years, respectively. All patients received at least one 28-day cycle of olaparib. No patient had a complete or partial response. Nausea (48%), fatigue (36%), and vomiting (33%) were the most commonly reported treatment-related adverse events. The median PFS for all patients was 1.84 months. No statistically significant differences were found in the median PFS or OS for the MSS group compared with the MSI-H group. CONCLUSION: Single-agent olaparib delivered after failure of standard systemic therapy did not demonstrate activity for CRC patients, regardless of microsatellite status. Future trials, testing PARP inhibitors in patients with CRC should focus on the use of DNA-damaging chemotherapy and/or radiation therapy, combined with PARP inhibitors, remembering the toxicity reported in the present study. IMPLICATIONS FOR PRACTICE: Microsatellite instability (MSI-H) colorectal tumors exhibit hypermethylation in tumor mismatch repair genes, or have mutations in one or more of these genes resulting from a germ-line defect (Lynch syndrome). PARP inhibitors such as olaparib are most effective in tumors associated with inability to repair DNA damage. However, in this trial, single agent olaparib failed to elicit responses in patients with MSI-H colorectal tumors, and in those with microsatellite-stable tumors. It is possible that by adding olaparib to radiation therapy, or to a systemic DNA damaging agent, tumor lethality could be obtained. However, the price would be increased toxicity.

Olaparib tablet formulation: effect of food on the pharmacokinetics after oral dosing in patients with advanced solid tumours.

BACKGROUND: The oral PARP inhibitor olaparib has shown efficacy in patients with BRCA-mutated cancer. This Phase I, open-label, three-part study (Parts A-C) in patients with advanced solid tumours evaluated the effect of food on the pharmacokinetics (PK) of olaparib when administered in tablet formulation. METHODS: PK data were obtained in Part A using a two-treatment period crossover design; single-dose olaparib 300 mg (two 150 mg tablets) was administered in two prandial states: fasted and fed. In Part B, patients received olaparib tablets (300 mg bid) for 5 days under fasting conditions; in Part C, patients were allowed continued access to olaparib. Safety was assessed throughout, with data reported for Parts A and B. RESULTS: A total of 60 and 56 patients were evaluable for safety and PK analyses, respectively; 57 patients entered Part B. Rate of olaparib absorption was slower in the presence of food (t max delayed by 2.5 h), resulting in a statistically significant ~21 % decrease in peak plasma exposure (C max) [ratio of geometric means (90 % CI), 0.79 (0.72, 0.86)] but only a marginal increase in olaparib absorption (AUC0-∞) [ratio of geometric means (90 % CI), 1.08 (1.01, 1.16)]. The point estimate and 90 % CI for the AUC0-∞ treatment ratio were within pre-defined bioequivalence limits (0.80-1.25). Adverse event data were consistent with the known safety profile of olaparib. CONCLUSIONS: Results of this study showed that a high-fat meal decreases the rate of absorption and peak exposure to olaparib 300 mg tablets, although in the absence of an effect on the extent of olaparib absorption.

Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer.

PURPOSE: Gastric cancer cell lines, particularly those with low levels of ataxia telangiectasia mutated (ATM), a key activator of DNA damage response, are sensitive to the poly (ADP-ribose) polymerase inhibitor olaparib. We compared the efficacy of olaparib plus paclitaxel (olaparib/paclitaxel) with paclitaxel alone in patients with recurrent or metastatic gastric cancer and assessed whether low ATM expression is predictive of improved clinical outcome for olaparib/paclitaxel. PATIENTS AND METHODS: In this phase II, double-blind study (Study 39; NCT01063517), patients were randomly assigned to oral olaparib 100 mg twice per day (tablets) plus paclitaxel (80 mg/m(2) per day intravenously on days 1, 8, and 15 of every 28-day cycle) or placebo plus paclitaxel (placebo/paclitaxel), followed by maintenance monotherapy with olaparib (200 mg twice per day) or placebo. The study population was enriched to 50% for patients with low or undetectable ATM levels (ATMlow). Primary end point was progression-free survival (PFS). RESULTS: One hundred twenty-three of 124 randomly assigned patients received treatment (olaparib/paclitaxel, n = 61; placebo/paclitaxel, n = 62). The screening prevalence of ATMlow patients was 14%. Olaparib/paclitaxel did not lead to a significant improvement in PFS versus placebo/paclitaxel (overall population: hazard ratio [HR], 0.80; median PFS, 3.91 v 3.55 months, respectively; ATMlow population: HR, 0.74; median PFS, 5.29 v 3.68 months, respectively). However, olaparib/paclitaxel significantly improved overall survival (OS) versus placebo/paclitaxel in both the overall population (HR, 0.56; 80% CI, 0.41 to 0.75; P = .005; median OS, 13.1 v 8.3 months, respectively) and the ATMlow population (HR, 0.35; 80% CI, 0.22 to 0.56; P = .002; median OS, not reached v 8.2 months, respectively). Olaparib/paclitaxel was generally well tolerated, with no unexpected safety findings. CONCLUSION: Olaparib/paclitaxel is active in the treatment of patients with metastatic gastric cancer, with a greater OS benefit in ATMlow patients. A phase III trial in this setting is under way.

Effect of Food on the Pharmacokinetics of Olaparib after Oral Dosing of the Capsule Formulation in Patients with Advanced Solid Tumors.

BACKGROUND: The oral, potent poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, is well tolerated at doses of ≤400 mg twice daily (BID) (administered as capsules), and has shown efficacy in patients with advanced BRCA-mutated ovarian and breast cancer. METHODS: This Phase I, open-label, randomized trial investigates the effect of food on the pharmacokinetics of olaparib in patients with refractory/resistant advanced solid tumors. In Part A, a three-period crossover study, patients received a single oral dose of olaparib 400 mg (8 × 50 mg capsules) in three prandial states: fasted, a high-fat meal or a standard meal (with a 5-14 day washout). Blood samples for pharmacokinetic (PK) assessments were taken pre-dose and up to 72 h post-dose. After completing Part A, patients could enter Part B, where they would receive olaparib 400 mg BID. RESULTS: 32 patients were randomized; 31 contributed to the PK statistical analysis and entered Part B. The presence of food slowed the rate of absorption (time to maximal plasma concentration [t max] was delayed by ~2 h). Maximum plasma concentration (C max) was increased by 10% following a standard meal and was unchanged with a high-fat meal (ratio of geometric means [90% confidence interval (CI)]: 1.10 [1.02-1.20] for standard and 1.00 [0.92-1.09] for high-fat meal). The extent of olaparib absorption (AUC) was increased by ~20% in the fed state (ratio of geometric means: 1.21 [1.10-1.33] for standard and 1.19 [1.08-1.31] for high-fat meal). CONCLUSIONS: The presence of food decreased the rate and increased the extent of absorption of olaparib following oral dosing of the capsule formulation. However, the effects of food on olaparib PK were not deemed clinically important, according to predefined criteria. Safety data were consistent with the known safety profile of olaparib. FUNDING: AstraZeneca.

Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.

PURPOSE: Olaparib is an oral poly (ADP-ribose) polymerase inhibitor with activity in germline BRCA1 and BRCA2 (BRCA1/2) -associated breast and ovarian cancers. We evaluated the efficacy and safety of olaparib in a spectrum of BRCA1/2-associated cancers. PATIENTS AND METHODS: This multicenter phase II study enrolled individuals with a germline BRCA1/2 mutation and recurrent cancer. Eligibility included ovarian cancer resistant to prior platinum; breast cancer with ≥ three chemotherapy regimens for metastatic disease; pancreatic cancer with prior gemcitabine treatment; or prostate cancer with progression on hormonal and one systemic therapy. Olaparib was administered at 400 mg twice per day. The primary efficacy end point was tumor response rate. RESULTS: A total of 298 patients received treatment and were evaluable. The tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and 31.1% (60 of 193; 95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to 23.9), 21.7% (five of 23; 95% CI, 7.5 to 43.7), and 50.0% (four of eight; 95% CI, 15.7 to 84.3) in ovarian, breast, pancreatic, and prostate cancers, respectively. Stable disease ≥ 8 weeks was observed in 42% of patients (95% CI, 36.0 to 47.4), including 40% (95% CI, 33.4 to 47.7), 47% (95% CI, 34.0 to 59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with ovarian, breast, pancreatic, or prostate cancer, respectively. The most common adverse events (AEs) were fatigue, nausea, and vomiting. Grade ≥ 3 AEs were reported for 54% of patients; anemia was the most common (17%). CONCLUSION: Responses to olaparib were observed across different tumor types associated with germline BRCA1/2 mutations. Olaparib warrants further investigation in confirmatory studies.