Methods for Treating Breast Cancer

Abstract

The present disclosure relates to methods for the adjuvant treatment of a subject with germline mutant BRCA1 and / or BRCA2 breast cancer, where the subject has previously undergone local treatment and neoadjuvant or adjuvant chemotherapy for the breast cancer.

Description

[Technical field]

[0001] The present disclosure relates to adjuvant treatment for subjects with HER2-negative, BRCA1 and / or BRCA2 germline mutated breast cancer who have previously received local treatment (e.g., surgery to remove breast tissue) and neoadjuvant or adjuvant chemotherapy. [Background technology]

[0002] Poly(ADP-ribose)-polymerase inhibitors target homologous recombination repair-deficient cancers through synthetic lethality. Novel therapies are needed to reduce recurrence in patients with early-stage breast cancer associated with BRCA1 / 2 germline mutations. Summary of the Invention [Means for solving the problem]

[0003] In one aspect, the document describes a method of preventing, reducing or delaying recurrence of breast cancer in a subject following local treatment and neoadjuvant or adjuvant chemotherapy, the method comprising: administering to a subject a therapeutically effective amount of 4-[(3-{[4-(cyclopropanecarbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]-2H-phthalazin-1-one (olaparib), or a hydrate, solvate, or prodrug thereof; Includes.

[0004] In a further aspect, the specification describes a method of treating a subject having breast cancer following local therapy and neoadjuvant or adjuvant chemotherapy, the method comprising adjuvant treatment of the subject with a therapeutically effective amount of 4-[(3-{[4-(cyclopropane-carbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]-2H-phthalazin-1-one (olaparib), or a hydrate, solvate, or prodrug thereof.

[0005] In a further aspect, the description describes 4-[(3-{[4-(cyclopropanecarbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]-2H-phthalazin-1-one (olaparib) or a hydrate, solvate or prodrug thereof for use in adjuvant treatment (or for use in the manufacture of a medicament for adjuvant treatment), following local treatment and neoadjuvant or adjuvant chemotherapy, of a subject with breast cancer.

[0006] In a further aspect, the specification describes a method of improving invasive disease survival (or overall survival or distant disease-free survival) by providing adjuvant treatment to a subject previously diagnosed with HER2-negative germline mutated BRCA1 and / or BRCA2 breast cancer, which subject has previously received local treatment (e.g., surgery, such as surgery to remove diseased breast tissue) and neoadjuvant or adjuvant chemotherapy, the method comprising administering to such subject a therapeutically effective amount of 4-[(3-{[4-(cyclopropane-carbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]-2H-phthalazin-1-one (olaparib), or a hydrate, solvate or prodrug thereof.

[0007] The accompanying drawings are included to provide a further understanding of the disclosed compositions and methods, and are incorporated in and constitute a part of this specification. The drawings illustrate one or more embodiments of the present disclosure, and together with the description, serve to explain the principles and operation of the present disclosure. [Brief description of the drawings]

[0008] [Figure 1] Figure 1 shows Kaplan-Meier estimates of survival for subjects receiving either adjuvant olaparib therapy or placebo. Panel (A) shows invasive disease-free survival (IDFS). Panel (B) shows distant disease-free survival. Panel (C) shows overall survival (OS). [Diagram 2] FIG. 2 shows subgroup analysis of invasive disease-free survival. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Detailed Description of the Drawings Figure 1. Kaplan-Meier estimates of survival: According to the STEEP system, the primary endpoint of invasive disease-free survival (Panel A) is defined as the time from randomization to the date of one of the following events: ipsilateral invasive breast tumor; locoregional invasive disease; distant recurrence; contralateral invasive breast cancer; second primary invasive cancer; or death from any cause. Patients without a documented invasive disease-free survival event were censored at the date the patient was last notified that they were disease-free.

[0010] Distant disease-free survival (Panel B) is defined as the time from randomization to documented evidence of first distant recurrence of breast cancer or death. Distant recurrence includes the following events: distant recurrence (metastatic disease - breast cancer either biopsy-confirmed or radiologically diagnosed as recurrent invasive breast cancer); death due to any cause including breast cancer, non-breast cancer, or unknown causes; second primary non-breast invasive cancer. Evidence of distant recurrence requires either radiological examination or histopathological confirmation by biopsy.

[0011] Overall survival (Panel C) is defined as the time from the date of randomization to death from any cause. The P value for the border for significance in this pre-specified event-driven interim analysis was <0.01.

[0012] P<0.005 was required to show statistical significance for these endpoints, so 99.5% confidence intervals are presented for hazard ratios for invasive disease-free survival and distant disease-free survival. Similarly, P<0.01 was required to show statistical significance for overall survival, so 99% confidence intervals are presented for hazard ratios for overall survival.

[0013] Based on the pooling strategy for stratification factors, factors listed in Supplementary Appendix section 3.3, both Cox model hazard ratio estimates and log-rank tests were performed with hormone receptor status as the single stratification factor.

[0014] Event-free rates at 12, 24 and 36 months in each group are shown above and below the curve.

[0015] CI indicates confidence interval, DDFS indicates distant disease-free survival, and IDFS indicates invasive disease-free survival.

[0016] Figure 2. Subgroup analysis of invasive disease-free survival: the black vertical line indicates the overall hazard ratio estimate, and the dotted vertical line indicates a hazard ratio of 1.00 as recommended by Cuzick. 23 The size of the blue box corresponds to the number of events contributing to the estimate of treatment effect (i.e., the proportion relative to the square root of (1 / variance of the estimated hazard ratio)). No tests for heterogeneity reached statistical significance, even without correction for multiple comparisons. The CPS&EG score is a staging system for disease-specific survival in breast cancer patients treated with neoadjuvant chemotherapy. 20 It incorporates pretreatment clinical stage, estrogen receptor status, nuclear grade and pathological stage after neoadjuvant chemotherapy. ACT indicates adjuvant chemotherapy; HER2 indicates human epidermal growth factor receptor 2; HR+ indicates hormone receptor positive; NACT indicates neoadjuvant chemotherapy; TNBC indicates triple-negative breast cancer.

[0017] *Prespecified subgroup analysis. All patients who received neoadjuvant chemotherapy were included, regardless of whether they had hormone receptor-positive or triple-negative disease.

[0018] Detailed Description of the Disclosure As used herein, the term "about" when referring to any given numerical value means within ±10%, ±5%, or ±2% of that value.

[0019] The disclosed method also requires administration of olaparib. As used herein, "olaparib" refers to 4-[(3-{[4-(cyclopropane-carbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]-2H-phthalazin-1-one or a hydrate, solvate, or prodrug thereof. 4-[(3-{[4-(cyclopropane-carbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]-2H-phthalazin-1-one having the following structure is disclosed in WO 2004 / 080976 A1, which is incorporated herein by reference. [ka]

[0020] Olaparib is preferably administered in the form of a pharmaceutical composition. The therapeutically effective amount of Olaparib has already been established. As described herein, the therapeutically effective amount of Olaparib is in the range of about 400-800 mg / day. For example, in certain methods described herein, Olaparib is administered in an amount of about 600 mg per day (e.g., about 300 mg taken twice a day). EXAMPLES

[0021] Poly(ADP-ribose)-polymerase inhibitors target cancers with homologous recombination repair deficiencies due to synthetic lethality. Novel therapies are needed to reduce recurrence in patients with early-stage breast cancer associated with BRCA1 / 2 germline mutations.

[0022] We conducted a randomized, double-blind, phase 3 study including patients with HER2-negative early breast cancer with BRCA1 / 2 germline pathogenic / pathogenic-like variants (gBRCA-P / LP variants) and high-risk clinicopathological factors after local treatment and (neo)adjuvant chemotherapy. Patients were randomized (1:1) to receive one year of oral olaparib or placebo. The primary endpoint was invasive disease-free survival.

[0023] 1836 patients were randomized. At the time of a prespecified event-driven interim analysis with a median follow-up of 2.5 years, 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference 8.8%; 95% CI 4.5%, 13.0%; hazard ratio (HR) for invasive disease-free survival 0.58; 99.5% confidence interval (CI), 0.41, 0.82; p<0.0001). 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference 7.1%; 95% CI 3.0%, 11.1%; HR for distant disease-free survival 0.57; 99.5% CI 0.39, 0.83; p<0.0001). Fewer olaparib-related deaths were associated with olaparib compared with placebo (59 vs. 86); the HR for overall survival was 0.68 (99% CI 0.44, 1.05; p=0.024), not statistically significant at the interim analysis boundary of p<0.01. Safety data were consistent with the known toxicities of olaparib, with no excess serious adverse events or adverse events of special interest.

[0024] Among patients with high-risk HER2-negative early breast cancer and gBRCA-P / LP variants, adjuvant olaparib after completion of local treatment and (neo)adjuvant chemotherapy significantly improved both invasive disease-free and distant disease-free survival, with limited impact on overall patient-reported quality of life (OlympiA NCT02032823, BIG 6-13, NSABP B-55).

[0025] In one embodiment, the improvement in invasive disease-free survival in olaparib-treated patients at about 3 years is up to about 10%, such as up to about 9%, such as up to about 8%, such as about 1 to about 9%, such as about 1 to about 8%, such as about 5% to about 10%, such as about 5% to about 9%. In one embodiment, the improvement in invasive disease-free survival in olaparib-treated patients at about 3 years is about 9%. In one embodiment, the improvement in invasive disease-free survival in olaparib-treated patients at 3 years is about 9%.

[0026] In one embodiment, the improvement in distant disease free survival in olaparib treated patients at about 3 years is up to about 8%, such as up to about 7%, such as about 1 to about 8%, such as about 1 to about 7%, such as about 3% to about 8%, such as about 3% to about 7%. In one embodiment, the improvement in distant disease free survival in olaparib treated patients at about 3 years is about 7%. In one embodiment, the improvement in distant disease free survival in olaparib treated patients at 3 years is about 7%.

[0027] In one embodiment, the improvement in overall survival in olaparib-treated patients at about 3 years is about 4%. In one embodiment, the improvement in overall survival in olaparib-treated patients at about 3 years is about 4%.

[0028] Approximately 5% of unselected breast cancer patients harbor germline BRCA1 or BRCA2 pathogenic / pathogenic-like (P / LP) mutations, currently referred to as variants (gBRCA-P / LP variants) 1、2 Such variants are associated with a strong family history of breast cancer, early age, and synchronous or metachronous contralateral breast and ovarian cancer. 3 or is more likely in individuals of known founder variant ethnic origin 1、2 Patients with BRCA1-P / LP variants are particularly predisposed to triple-negative (i.e., type 2 human epidermal growth factor receptor [HER2]-negative, estrogen receptor-negative, and progesterone receptor-negative) breast cancer (TNBC), whereas patients with BRCA2-P / LP variants more frequently develop estrogen receptor-positive tumors. 4~6 Germline testing for such variants is now selectively performed in such breast cancer patients. 7 .

[0029] BRCA1 and BRCA2 encode proteins essential for homologous recombination DNA repair. 8 Breast cancers with gBRCA-P / LP variants and biallelic inactivation show evidence of defective homologous recombination 9、10 Inhibitors of the PARP family of enzymes exploit the principle of synthetic lethality to selectively kill tumor cells that harbor homologous recombination defects.11~14 Proof of concept for clinical activity was demonstrated in advanced gBRCA-P / LP variant-associated breast, ovarian, prostate, and pancreatic cancers, justifying a randomized trial design. 15~17 In the OlympiA study detailed herein, the inventors hypothesized that olaparib would be beneficial as an adjuvant treatment for patients with gBRCA-P / LP variant-associated early breast cancer who are at high risk of recurrence despite standard of care local and systemic treatment. 18、19 .

[0030] method Study Design and Monitoring The study was designed and conducted as a collaborative research partnership between Breast International Group (BIG) and sponsors NRG Oncology in the United States (US) and AstraZeneca (AZ) outside the US. OlympiA was a prospective, randomized, multicenter, multinational, double-blind, placebo-controlled clinical trial that randomly assigned eligible patients to receive olaparib 300 mg twice daily or matching placebo for 1 year after completion of standard (neo)adjuvant chemotherapy and local therapy (Figure S1: Trial schematic in the Supplementary Appendix).

[0031] The trial recruited patients from 420 sites across 23 countries (Table S1 in the Supplementary Appendix).

[0032] Patients and eligibility criteria Eligible patients had gBRCA-P / LP variants and high-risk, HER2-negative primary breast cancer as determined by local or central testing after definitive local treatment and neoadjuvant or adjuvant chemotherapy. If local laboratories reported eligible gBRCA-P / LP variants, this was used to support eligibility. Details of gBRCA-P / LP variant screening, local and central gBRCA-P / LP variant testing and concordance are provided in Figure S2 and Tables S2 / S3 in the Supplementary Appendix. All gBRCA-P / LP variant eligibility decisions were made by the Trial Genetics Advisory Committee. Local estrogen receptor, progesterone receptor, and HER2 test results were used for determination of hormone receptor status for stratification (cut point for positivity was ≥1%), and for hormone receptor positivity-specific stage criteria for eligibility (details on central adjudication of receptor status and concordance for all patients recruited from outside China are provided in the Supplementary Appendix Tables S4 and S5).

[0033] Patients were required to have completed all local treatments, including radiation therapy, that interact with PARP inhibition at least 2 weeks and within 12 weeks prior to study enrollment. Patients had completed at least 6 cycles of neoadjuvant or adjuvant chemotherapy containing anthracycline, taxane, or both. Platinum chemotherapy was permitted. Adjuvant bisphosphonates and adjuvant endocrine therapy in patients with hormone receptor-positive disease were administered according to the study site guidelines. No postoperative chemotherapy was permitted in patients who received neoadjuvant chemotherapy. Patients with triple-negative breast cancer treated with adjuvant chemotherapy were required to have axillary lymph node-positive disease or an invasive primary tumor with lesions ≥ 2 cm in size. Patients treated with neoadjuvant chemotherapy were required to have residual invasive breast cancer in the breast or resected lymph nodes (no pathological complete response from neoadjuvant treatment).

[0034] Patients treated with adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer were required to have ≥4 pathologically confirmed positive lymph nodes. For those treated with neoadjuvant chemotherapy, they were required to have not achieved pCR with a CPS&EG score ≥3 (a combined scoring system to estimate the probability of recurrence based on clinical and pathological stage [CPS] and estrogen receptor status and histologic grade [EG]). <363 20 Full eligibility criteria can be found in Supplementary Appendix Section 3.2.

[0035] Randomization and Treatment Patients were randomized in a 1:1 ratio to receive 52 weeks of treatment with 300 mg olaparib or matching placebo tablets taken orally twice daily.

[0036] Patients were stratified by hormone receptor status (positive vs. negative), NACT vs. ACT, and current use of platinum chemotherapy for breast cancer (yes vs. no).

[0037] evaluation After randomization, medical histories and physical examinations were obtained every 4 weeks for 24 weeks, every 3 months through year 2, every 6 months through years 3-5, and annually thereafter. Imaging to evaluate for the development of metastatic disease was obtained at the physician's discretion when symptoms, examination, or clinical findings suggested possible disease recurrence. Patients underwent annual mammograms and / or breast magnetic resonance imaging.

[0038] After a first event, patients were followed for first distant recurrence (if not a first event), CNS metastases, locoregional recurrence, contralateral breast cancer, second primary malignancies, and survival.

[0039] statistical analysis According to the standardized definition of efficacy endpoints (STEEP) system 21The primary endpoint of invasive disease-free survival was defined as the time from randomization to the date of the first occurrence of one of the following events: ipsilateral invasive breast tumor, locoregional invasive disease, distant recurrence, contralateral invasive breast cancer, second primary invasive cancer, or death from any cause. Patients without a confirmed invasive disease-free survival event were censored at the date the patient was last known to be disease-free.

[0040] Efficacy analyses were based on the intention-to-treat (ITT) population. Survival functions were estimated by the Kaplan-Meier method. A stratified Cox proportional hazards model was used to estimate hazard ratios and confidence intervals, and the comparison of survival between treatment groups was tested by the stratified log-rank test. The Cox assumptions were not confirmed because the hazard ratios were very low early on. According to our statistical analysis plan, bounded mean survival times were calculated, which confirmed the results obtained from the Cox model analysis. Safety was evaluated in the population that received at least one dose of study drug.

[0041] The study was planned with a sample size of 1800 patients such that the primary analysis would be driven by 330 invasive disease-free survival events in the ITT population to achieve 90% power to detect a hazard ratio (HR) of 0.7 assuming a two-sided 5% significance level. One interim analysis of the ITT population was planned when 165 invasive disease-free survival events were observed in the first 900 patients enrolled (mature cohort). At the time of the interim analysis, the analysis of this mature cohort was also prespecified, requiring HRs of similar magnitude to provide confidence in the durability of the ITT results. Secondary analyses included distant disease-free survival, overall survival, and safety. Superiority boundaries based on a hierarchical multiple testing procedure were used to adjust for type I error rates at the time of the interim analysis. 22 was p<0.005 for invasive disease-free survival, followed by p<0.005 for distant disease-free survival and p<0.01 for overall survival; confidence intervals for HRs were selected to match the desired significance levels for each endpoint at the interim analyses (see Figure S3 in the Supplementary Appendix).

[0042] result patient Between June 2014 and May 2019, 1836 patients were randomly assigned to receive olaparib or placebo. 日 At data cutoff, 284 (86%) of 330 primary analysis objective invasive disease-free survival events had been observed, with a median follow-up of 2.5 years (IQR range, 1.5–3.5) in the ITT population and 3.5 years (IQR range, 2.9–4.1) in the mature cohort. After randomization, 10 patients in the olaparib group and 11 patients in the placebo group did not receive the assigned treatment (Figure S4 in the Supplementary Appendix: consort diagram). Patient baseline characteristics were well balanced between the two treatment groups (Tables 1 and S6 in the Supplementary Appendix). 82.2% of patients had triple-negative breast cancer (hormone receptor and HER-2 negative). Half of the patients received adjuvant and semi-neoadjuvant chemotherapy, and most (93.7%) received anthracycline- and taxane-containing regimens. 26.5% had first received a platinum agent in the neoadjuvant setting. gBRCA-P / LP-variants were present in 72.3% of patients in BRCA1 and 27.2% in BRCA2, evenly distributed between treatment arms.

[0043] Effectiveness Early-report efficacy boundaries were crossed at a prespecified interim analysis. Patient survival and invasive disease-free percentage at 3 years was 85.9% in the olaparib group and 77.1% in the placebo group (difference of 8.8%; 95% confidence interval [CI], 4.5%, 13.0%). Invasive disease-free survival was significantly longer in patients assigned to olaparib than to placebo (HR, 0.58; 99.5% confidence interval [CI], 0.41 to 0.82; P < 0.0001) (Figure 1A). Invasive disease-free survival events were reported in 106 and 178 patients in the olaparib and placebo groups, respectively. Event frequencies at all sites were lower with olaparib treatment (Supplementary Appendix Table S7).

[0044] Distant disease-free survival at 3 years was 87.5% in the olaparib group and 80.4% in the placebo group (difference of 7.1%; 95% CI, 3.0%, 11.1%) and was significantly longer in patients who received olaparib (HR, 0.57; 99.5% CI, 0.39 to 0.83; P < 0.0001) ( Fig. 1B ).

[0045] Fewer deaths were reported in the olaparib group (n = 59) compared with placebo (n = 86), with an overall survival HR for death of 0.68; 99% CI, 0.44 to 1.05, p = 0.024 (Figure 1C), which did not cross the prespecified multiple testing procedure significance boundary of p < 0.01 (Figure S3 in the Supplementary Appendix).

[0046] The leading cause of death was breast cancer, occurring in 93.2% of patients in the olaparib group and 95.3% in the placebo group (Table S8 in the Supplementary Appendix ). Deaths without prior invasive disease-free survival events were reported in two patients, both in the olaparib group (one cardiac arrest, one unknown cause; Table S7 in the Supplementary Appendix ).

[0047] Of the prespecified sensitivity analyses described in Section 3.5 Supplementary Appendix, none changed the conclusions reported here (Table S9 Supplementary Appendix).

[0048] Subgroup analyses of invasive disease-free survival revealed point estimates of treatment effect for olaparib over placebo across all stratification groups and prespecified subgroups that were consistent with those in the overall analysis population (Figure 2; Table S10 in the Supplementary Appendix). With confidence intervals intersecting the point estimates of HRs for invasive disease-free survival in the overall population, the benefit of adjuvant olaparib was observed compared with placebo for invasive disease-free survival, regardless of P / LP variants BRCA1 vs. BRCA2, hormone receptor status, or adjuvant vs. neoadjuvant chemotherapy status. 23 There was no evidence to suggest statistical heterogeneity of treatment effects across subgroups.

[0049] safety A total of 1815 patients (911 in the olaparib group and 904 in the placebo group) were included in the safety analysis. The median number of days on the protocol dose of 300 mg twice daily was 338 days in the olaparib group, with a percentage of scheduled dose of 94.8%, and 358 days in the placebo group, with a percentage of scheduled dose of 98.9% (Tables S11–S13 in the Supplementary Appendix). Early treatment discontinuation, including discontinuation due to recurrence, occurred in 236 patients (25.9%) in the olaparib group and 187 patients (20.7%) in the placebo group (Figure S4 in the Supplementary Appendix).

[0050] Table 2 indicates that adverse events occurred in more than 10% of patients, consistent with the product label. Significant adverse events are summarized in Table 3. Grade ≥3 adverse events occurring in more than 1% of patients were anemia (8.7%), neutropenia (4.8%), leukopenia (3.0%), fatigue (1.8%), and lymphopenia (1.2%), all in the olaparib group. Transfusions were rarely required, with 5.8% of patients receiving at least one transfusion in the olaparib group compared with 0.9% in the placebo group, and most receiving only one transfusion (4.1%) (Table S14 in the Supplementary Appendix). Serious adverse events occurred in 79 patients receiving olaparib (8.7%) and 76 patients receiving placebo (8.4%). Adverse events leading to death included cardiac arrest in one patient in the olaparib group and acute myeloid leukemia (AML) and ovarian cancer in one patient each in the placebo group. Adverse events of special interest included interstitial pneumonitis, radiation interstitial pneumonitis, myelodysplastic syndrome (MDS) / AML, and new primary malignancies other than AML / MDS. None were increased with olaparib, but further follow-up is needed for the latter two adverse events of special interest groups, given the short median follow-up of 2.5 years for this report.

[0051] Dose reductions were required in 228 patients (25.0%) in the olaparib group compared with 47 (5.2%) in the placebo group. Adverse events requiring permanent discontinuation of the study drug occurred in 90 patients (9.9%) in the olaparib group and 38 patients (4.2%) in the placebo group. The most common reasons for discontinuation of olaparib were nausea (2.0%), anemia (1.8%), fatigue (1.3%), and neutropenia (1%) (Tables S15 and S16 in the Supplementary Appendix). Results from the EORTC QLQ-C-30 Global Health Status / Quality-of-Life scale indicate that overall quality of health did not decline during 12 months of treatment with either olaparib or placebo. None of the differences between the treatment groups were considered clinically meaningful (Figure S5 in the Supplementary Appendix).

[0052] Consideration Following evidence of progression-free survival benefit, tolerability and improved quality of life compared with standard chemotherapy, olaparib and talazoparib are now approved for the treatment of metastatic gBRCA-P / LP variant-associated breast cancer. 24、25

[0053] OlympiA was designed to test the efficacy of adjuvant PARP inhibitor therapy with olaparib in patients with early stage breast cancer and impaired BRCA1 or BRCA2 homologous recombination function, identified using the presence of BRCA1 or BRCA2 P / LP germline variants as patient selection biomarkers. The trial shows that olaparib given for 52 weeks as adjuvant treatment after (neo)adjuvant chemotherapy and local therapy significantly improves invasive disease-free and distant disease-free survival in such patients. There is no previous evidence to suggest an effect of different PARP inhibitor treatments in relation to BRCA1 vs. BRCA2 status or hormone receptor status. 15、24~26 We found no evidence of heterogeneity, and the confidence intervals for the hazard ratios in these and other subgroups contain point estimates for the treatment effect seen in the overall population.

[0054] The prespecified interim analysis was timed based on having sufficient events in the mature cohort to provide confidence that the treatment effect observed initially at the time of the interim analysis in the ITT population was likely to be sustained. Evidence of olaparib treatment effect in this mature cohort is encouraging (Figure S6 in the Supplementary Appendix).

[0055] Platinum-containing chemotherapy is not considered standard of care for neoadjuvant or adjuvant chemotherapy in HER2-negative early breast cancer. 27、28 Use of platinum-based chemotherapy was included as a stratification factor because platinum-induced DNA adducts are repaired by homologous recombination DNA repair and platinum is known to have specific interactions with gBRCA-P / LP variants in metastatic breast cancer. 29、30 As in other subgroup analyses, testing for heterogeneity did not show evidence of less efficacy of olaparib in patients treated with platinum-based adjuvant or neoadjuvant chemotherapy.

[0056] There were fewer deaths among olaparib-treated patients than among placebo-treated patients, but at this early time point, the difference did not reach the threshold for statistical significance in a prespecified multiple testing procedure. A longer blinded follow-up period is needed to evaluate the effect of olaparib on overall survival.

[0057] The safety profile of olaparib was consistent with that previously reported; adverse events with olaparib treatment were mostly grade 1 or 2. The only grade 3 toxicity, occurring in >5% of patients, was anemia (8.7%), which infrequently required transfusion. Dose interruptions and reductions appear to be effective management strategies. There was no increase in serious adverse events with olaparib. PARP inhibitors are DNA-interacting drugs. 31 , which has the potential to induce mutations in DNA and hematological malignancies 32 These were not increased by olaparib and are ongoing for a further blinded follow-up period.

[0058] The selection of the hormone receptor-positive population at particularly high risk of relapse was driven by regulatory concern that the perceived potential MDS / AML risk exposure for olaparib could not be justified by the low invasive disease-free survival event rate. Patients with gBRCA-P / LP variants constitute a high-risk relapse group that is more likely to require chemotherapy in addition to endocrine therapy. 18、19 , a recent study included 14% of patients with hormone receptor-positive HER2-negative breast cancer treated with neoadjuvant chemotherapy. 33 A high risk of recurrence was observed in OlympiA, with 23% of patients in the hormone receptor-positive population treated with placebo estimated to have an invasive disease-free survival event within 3 years (Figure 2). Olaparib treatment with endocrine therapy (Table S17 in the Supplementary Appendix) was safe and effective in this subgroup, with no difference in treatment efficacy, consistent with the results of other studies in both metastatic and early breast cancer settings. 24~26 .

[0059] Patients with triple-negative breast cancer currently have no approved adjuvant targeted therapy. Based on the results of the CREATE-X trial, patients with triple-negative breast cancer and residual invasive cancer after neoadjuvant chemotherapy are increasingly being treated with neoadjuvant capecitabine chemotherapy. This trial did not examine the effect of neoadjuvant capecitabine in patients with gBRCA-P / LP variants, which are thought to represent less than 15% of those enrolled. 34 Neoadjuvant capecitabine was not permitted in OlympiA because it was not standard treatment when the trial was designed, and therefore the study cannot report on the relative efficacy of olaparib versus capecitabine in this setting. However, in a study in which 45% received capecitabine as a comparator treatment, Robson et al. 24found that olaparib was more effective than chemotherapy in extending progression-free survival in patients with metastatic HER2-negative breast cancer harboring gBRCA-P / LP variants 24、35 .

[0060] OlympiA demonstrates that one year of adjuvant olaparib, with high adherence and a predominantly low-grade toxicity profile, can meaningfully reduce the risk of recurrence and prevent progression to metastatic disease in patients with high-risk early breast cancer and gBRCA-P / LP variants. As a result of greater acceptance of the impact of gBRCA-P / LP variant status on treatment options, patients with gBRCA-P / LP variants are increasingly being identified in oncology practice for early breast cancer. 36 The OlympiA trial provides evidence that germline BRCA1 and BRCA2 sequencing are important biomarkers for the selection of systemic therapy in early stage breast cancer.

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The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 2002; 20:2310-8. 7. NCCN Genetic / Familial High-Risk Assessment: Breast and Ovarian Version 1.2020. National Comprehensive Cancer Network, April 2021.(https: / / www.nccn.org / store / login / login.aspx?ReturnURL=https: / / www.nccn.org / professionals / physician_gls / pdf / genetics_bop.pdf). 8. Tutt A, Ashworth A. The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol Med 2002;8:571-6. 9. Davies H, Glodzik D, Morganella S, et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med 2017; 23:517-525. 10. Staaf J, Glodzik D, Bosch A, et al. Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study. Nat Med 2019; 25:1526-1533. 11. Tutt AN, Lord CJ, McCabe N, et al. Exploiting the DNA repair defect in BRCA mutant cells in the design of new therapeutic strategies for cancer. Cold Spring Harb Symp Quant Biol 2005;70:139-48. 12. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434:917-21. 13. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005; 434:913-7. 14. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361:123-34. 15. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 2010;376:235-44. 16. Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 2010;376:245-51. 17. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1 / 2 mutation. J Clin Oncol 2015; 33:244-50. 18. Shah PD, Patil S, Dickler MN, Offit K, Hudis CA, Robson ME. Twenty-one-gene recurrence score assay in BRCA-associated versus sporadic breast cancers: Differences based on germline mutation status. Cancer 2016;122:1178-84. 19. Tryggvadottir L, Olafsdottir EJ, Olafsdottir GH, et al. Tumour diploidy and survival in breast cancer patients with BRCA2 mutations. Breast Cancer Res Treat 2013;140:375-84. 20. Mittendorf EA, Jeruss JS, Tucker SL, et al. Validation of a novel staging system for disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy. J Clin Oncol 2011; 29:1956-62. 21. Hudis CA, Barlow WE, Costantino JP, et al. Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol 2007; 25:2127-32. 22. Stone A. The application of bespoke spending functions in group-sequential designs and the effect of delayed treatment switching in survival trials. Pharm Stat 2010;9:151-61. 23. Cuzick J. Forest plots and the interpretation of subgroups. Lancet 2005;365:1308. 24. Robson M, Im SA, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 2017; 377:523-533. 25. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med 2018; 379:753-763. 26. Fasching PA, Link T, Hauke J, et al. Neoadjuvant paclitaxel / olaparib in comparison to paclitaxel / carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study). Ann Oncol 2021;32:49-57. 27. Burstein HJ, Curigliano G, Loibl S, et al. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019. Ann Oncol 2019;30:1541-1557. 28. NCCN Clinical Practice Guidelines in Oncology - Breast Cancer Version 5.2020. National Comprehensive Cancer Network, April 2021. (https: / / www2.tri-kobe.org / nccn / guideline / breast / english / breast.pdf). 29. Tutt A, Tovey H, Cheang MCU, et al. Carboplatin in BRCA1 / 2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat Med 2018; 24:628-637. 30. Zhang J, Lin Y, Sun XJ, et al. Biomarker assessment of the CBCSG006 trial: a randomized phase III trial of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer. Ann Oncol 2018;29:1741-1747. 31. Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res 2012; 72:5588-99. 32. Morice PM, Leary A, Dolladille C, et al. Myelodysplastic syndrome and acute myeloid leukaemia in patients treated with PARP inhibitors: a safety meta-analysis of randomised controlled trials and a retrospective study of the WHO pharmacovigilance database. Lancet Haematol 2021;8:e122-e134. 33. Pohl-Rescigno E, Hauke J, Loibl S, et al. Association of Germline Variant Status With Therapy Response in High-risk Early-Stage Breast Cancer: A Secondary Analysis of the GeparOcto Randomized Clinical Trial. JAMA Oncol 2020;6:744-748. 34. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med 2017; 376:2147-2159. 35. Robson ME, Tung N, Conte P, et al. OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol 2019;30:558-566. 36. Tutt A, Ashworth A. Can genetic testing guide treatment in breast cancer? Eur J Cancer 2008; 44:2774-80.

[0062]

Table 1

[0063]

Table 2

[0064]

Table 3

[0065]

Table 4

[0066]

Table 5

[0067] [Table 6]

[0068] Supplementary Appendix This Supplementary Appendix is ​​provided to provide the reader with further information regarding methods of treating the described cancers.

[0069] 3. Supplementary Methods 3.1 Dual platform model used to conduct the OLYMPIA tests The trial was conducted as a partnership between academia, non-profit organisations, government agencies, participating hospitals and industry. Breast International Group (BIG), Frontier Science and Technology Research Foundation (and its member, Frontier Science (Scotland) Ltd), National Cancer Institute, NRG Oncology and AstraZeneca all played key roles. The guiding principles for the conduct of the trial are those of BIG and NRG / NCI. Data will be collected, reviewed and analysed in accordance with the Standard Operating Procedures of Frontier Science (a non-profit organisation) and NRG / NCI. All these organisations are represented on the trial's Steering Committee, along with representatives of the geographical areas involved in the trial and representatives of consumers. A detailed publication policy governs all publications using the trial data and the decision to publish comes from the Steering Committee and not from any individual or separate organisation.

[0070] Two protocols will be used in this study, which differ only in logistical and regulatory content appropriate for the countries they cover (e.g. drug distribution, mechanisms for reporting SAEs during the study, etc.) and are identical in terms of study objectives and scientific content. The protocol under AZ sponsorship covers all patients recruited from non-US clinical trial sites, and the protocol under NRG sponsorship covers patients in the US. These protocols were developed as a collaboration between the above partners.

[0071] This trial used a single randomization system provided by Frontier Science (FS) and is reported as one study. Randomization was performed using a permuted block algorithm with a block size of 4. The randomization system has a built-in random number generator to initiate allocation, and there is no pre-created random list, as blocks are randomly generated when they are needed. Non-US trial sites used the FS front end to enter the randomization system. US trial sites used the NCI OPEN system to retrieve pre-randomized information and then interface with the FS system to complete randomization. All patients, treating physicians, and trial personnel were blinded to treatment allocation, except for the Independent Statistical Center, which was provided with treatment codes by the randomization system administrator to prepare reports for the Independent Data Monitoring Committee (IDMC).

[0072] Patient data collection is performed using two instances of the Rave EDC system, one for US patients maintained by NRG and one for all other patients outside the US maintained by FS. FS and NRG collaborated in the design of the two databases and their respective eCRFs to ensure as much consistency as possible in data collection. Some differences are inevitable due to differences in company and / or regional data collection standards, and all these differences are accounted for in the consistency documentation maintained by AZ. Quality control of the data is performed by Frontier Science and NRG for each Rave instance. Data from both databases are routinely merged into a single integrated database at regular intervals. All statistical analyses and reports for periodic review by the IDMC were performed and reported from the single integrated database built, maintained, and maintained by Frontier Science. The sponsors (NRG / NCI and AstraZeneca) had no access to this database during the conduct of the study. Blinded subsets of data were provided for specific purposes as needed, for example, DSUR reported data to AZ and a subset of PRO data to NRG to enable testing of the analysis program.

[0073] 3.2 Full Eligibility Criteria 1. Provision of informed consent prior to any study-specific procedures.

[0074] 2. Female or male patients must be ≥ 18 years of age.

[0075] 3A. Patients who underwent initial surgery and adjuvant chemotherapy -TNBC patients had to have positive axillary lymph nodes (≥pN1, any tumor size) or negative axillary lymph nodes (pN0) with an invasive primary tumor pathological size >2cm (≥pT2). -ER and / or PgR positive / HER2 negative patients had to have ≥4 pathologically confirmed positive lymph nodes.

[0076] 3B. Patients who received neoadjuvant chemotherapy followed by surgery - TNBC patients must have residual invasive breast cancer in the breast and / or resected lymph nodes (non-pCR). -ER and / or PgR positive / HER2 negative patients must have residual invasive cancer in the breast and / or resected lymph nodes (non-pCR) and a CPS&EG score ≥ 3. An explanation of how to calculate the CPS&EG score (Mittendorf et al 2011; Jeruss et al 2008) is given in Appendix 4.

[0077] 4. Histologically confirmed nonmetastatic primary invasive adenocarcinoma of the breast with one of the two following phenotypes: a) TNBC, defined as: -ER and PgR negative defined as IHC nuclear staining <1%. and - HER2 negative (ineligible for anti-HER2 therapy) defined as: oIHC 0, 1+ no ISH, or o IHC 2+ and ISH non-amplified with a ratio <2.0 and mean HER2 copy number <4 signals / cell if reported, or oISH non-amplified with a ratio <2.0 and mean HER2 copy number <4 signals / cell if reported (no IHC). b) ER and / or PgR positive, HER2 negative breast cancer, defined as: -ER and / or PgR positivity defined as IHC nuclear staining ≥ 1%. and - HER2-negative (ineligible for anti-HER2 therapy), defined as: oIHC 0, 1+ no ISH, or o IHC2+ and ISH non-amplified with a ratio <2.0 and mean HER2 copy number <4 signals / cell if reported, or oISH non-amplified with a ratio <2.0 and mean HER2 copy number <4 signals / cell if reported (no IHC).

[0078] Patients with multifocal or multicentric invasive disease are eligible as long as all lesions for which HER2 characterization is available are HER2 negative.

[0079] Patients with synchronous bilateral invasive disease are eligible as long as both lesions evaluated for HER2 are negative.

[0080] In both above cases, the lesion considered to be at greatest risk for recurrence at the investigator's discretion will be used to determine eligibility.

[0081] 5. A confirmed germline mutation in BRCA1 or BRCA2 that is predicted or suspected to be deleterious (known or predicted to be deleterious / lead to loss of function). Local gBRCA test results, if available, will be used to establish eligibility. If local gBRCA testing results are not available, central testing will be offered to those patients who would otherwise be eligible (see Section 6.2.1).

[0082] 6A. Completion of appropriate breast surgery, defined as: -The inked margins of the breast-conserving surgery or mastectomy must be histologically free of invasive breast cancer and ductal carcinoma in situ, except for the posterior margin if the margin is the pectoralis major fascia or the anterior margin if the margin is the dermis. Patients with positive section margins for lobular carcinoma in situ are eligible. - Breast-conserving patients must receive adjuvant radiotherapy. Patients undergoing mastectomy may receive adjuvant radiotherapy according to local policy and / or international guidelines.

[0083] 6B. Completion of appropriate axillary surgery defined as: Adjuvant chemotherapy patients: - Sentinel lymph node biopsy only if negative or if lymph nodes have only micrometastases (≤2.0 mm); or - Positive sentinel lymph node biopsy followed by axillary lymph node dissection or radiation therapy according to local guidelines, or -Axillary lymph node dissection Neoadjuvant chemotherapy patients: -Sentinel lymph node biopsy performed prior to neoadjuvant chemotherapy: o If negative or if the lymph nodes contain only micrometastases (≦2.0 mm), no further axillary surgery is indicated. o If positive, axillary lymph node dissection or axillary lymph node radiation therapy should follow completion of neoadjuvant chemotherapy. -Sentinel lymph node biopsy performed after neoadjuvant chemotherapy: oIf negative, further axillary surgery is not required. o If positive (micrometastases are considered positive), further axillary surgery is indicated unless the patient is enrolled in a Phase III multicenter clinical trial proposing radiotherapy as an alternative treatment for the axilla. The trial must be pre-approved by the OlympiA Executive Committee. -Axillary lymph node dissection.

[0084] 7. Completion of at least 6 cycles of neoadjuvant or adjuvant chemotherapy containing an anthracycline, taxane, or a combination of both. Prior platinum agents as potentially curative treatment for prior cancer (e.g. ovarian) or as adjuvant or neoadjuvant treatment for breast cancer are permitted. (For neoadjuvant patients, all chemotherapy should be delivered prior to surgery. No additional cycles of chemotherapy after surgery are permitted.)

[0085] 8. Patients must have not received a blood transfusion (packaged red blood cell and / or platelet transfusion) within the past 28 days prior to testing for organ and bone marrow function as defined below, and adequate organ and bone marrow function must be measured within 28 days prior to randomization: Hemoglobin ≥ 10.0 g / dL - Absolute neutrophil count (ANC) ≥ 1.5 x 109 / L -Platelet count ≥100×109 / L - Total bilirubin ≤ ULN (upper limit of normal at the study site), except for elevated total bilirubin < 1.5 x ULN due to Gilbert's disease or similar syndromes involving slow conjugation of bilirubin -AST(SGOT) / ALT(SGPT)≦2.5×ULN -ALP≦2.5×ULN

[0086] To exclude metastatic breast cancer, patients with screening ALT / AST or ALP above the upper limit of normal at the investigational site should undergo a liver ultrasound, CT, or MRI any time between the current breast cancer diagnosis and randomization.

[0087] If ALP and / or corrected calcium levels are above the institute's upper limits, a screening bone scan will be required. (Note: PET CT scan may be used as an alternative imaging technique).

[0088] 9. Serum or plasma creatinine ≤ 1.5 x ULN.

[0089] 10.ECOG performance status 0-1.

[0090] 11A. Women who were not menopausal or had not had a hysterectomy had to demonstrate a negative pregnancy test within 28 days prior to randomization. Menopause is defined as: - Age ≥ 60 years - Age < 60 years and amenorrhea for ≥ 1 year without chemotherapy and / or hormonal therapy - For women under 60 years of age, follicle-stimulating hormone (FSH) and plasma estradiol levels in the menopausal range - Radiation-induced oophorectomy with last menstrual period >1 year ago -Bilateral oophorectomy.

[0091] 11B. Sexually active women of childbearing potential and their partners must agree to use a combination of two highly effective forms of contraception. This begins with the signing of an informed consent and should continue throughout the time they are receiving study treatment and for at least 1 month after the last dose of study drug, or they must completely / truthfully abstain from all forms of sexual activity. Male patients must use condoms during treatment and for 3 months after the last dose of study drug if they have sexual intercourse with a pregnant or fertile woman. Female partners of male patients should also use highly effective forms of contraception if they are fertile (see Appendix E for acceptable methods).

[0092] 12. Patient is willing and able to comply with the protocol for the duration of the study, including treatment and attending scheduled clinic visits and examinations.

[0093] 13. Formalin-fixed, paraffin-embedded (FFPE) tumor sample from primary tumor, required*. *Note: For adjuvant patients, this refers to the surgical specimen; for neoadjuvant patients, both a pretreatment core biopsy and a surgical specimen with residual disease are requested, but only one is required. If the surgical main block is available but cannot be submitted, the investigational site may submit a portion of the invasive tumor from the original block, either by taking at least one core of at least 3 mm in diameter, or by dividing the original block into two parts and re-embedding one into a new block for central submission. If a block containing a pre-neoadjuvant treatment core biopsy is available but cannot be submitted, a section mounted on a glass slide prepared from the block may be submitted. If a tumor sample cannot be provided as requested above or is not available, approval by the investigational team for the patient's enrollment in the trial is required.

[0094] 14. Patients should ideally be randomized into the trial within a maximum of 8 weeks of completion of their last treatment (surgery, chemotherapy or radiotherapy), but in no case longer than 12 weeks.

[0095] 3.3 Calculations for the CPS&EG Staging System The CPS&EG score is a staging system for disease-specific survival in breast cancer patients treated with neoadjuvant chemotherapy. 1 This incorporates pre-treatment clinical stage, estrogen receptor status, nuclear grade and pathological stage after neoadjuvant chemotherapy.

[0096] Calculation explanation: The points for clinical stage + pathological stage + ER status + nuclear grade are added to arrive at a total (CPS&EG score) ranging from 0 to 6.

[0097] [Table 7]

[0098] 3.4 POOLING STRATEGY FOR STRATIFICATION FACTORS The primary stratified log-rank test for IDFS is based on stratification factors determined from the following pooling strategy:

[0099] If there are fewer than 5 IDFS events per treatment group within any individual stratum (starting with 16 strata; 16 including treatment group = 2 × 2 × 2 × 2), remove stratification factors one at a time in the following order until there are at least 5 IDFS events within each individual stratum: 1. Prior use of platinum agents for breast cancer (yes / no) 2. Pre-treatment chemotherapy (neoadjuvant vs. adjuvant) 3. Hormone receptor status (ER and / or PgR positive / HER2 negative vs. TNBC)

[0100] RESULTS: When all three factors were included, there was a stratification with fewer than five IDFS events per treatment group; therefore, prior platinum agent was removed as a stratification factor. When the remaining two factors were included, there was a stratification with fewer than five IDFS events per treatment group; therefore, prior chemotherapy was removed as a stratification factor. Therefore, the primary stratified Cox proportional hazards model and stratified log-rank test for IDFS were based on the stratification factor of hormone receptor status alone.

[0101] 3.5 Sensitivity analysis The protocol specified that seven (7) sensitivity analyses were to be performed if certain criteria were met. In this section, we describe the sensitivity analyses and provide the results in a table in this Supplementary Appendix for those who met the criteria for performing sensitivity analyses.

[0102] 1: Confirmed (Central Myriad study) germline BRCA1 and BRCA2 deleterious / suspected deleterious variants The protocol specified that, where applicable, an analysis for IDFS would be performed based on all randomized patients with a BRCA1 or BRCA2 germline deleterious / suspected deleterious variant (gBRCA-D / SD variant) confirmed by central Myriad testing. This analysis would only be required if the analysis population differed from the primary ITT population (i.e., only if none of the randomized patients were confirmed to have a gBRCA-D / SD variant by central Myriad testing).

[0103] 1539 patients had Myriad-confirmed gBRCA D / SD mutations (see Table S2 in this Supplementary Appendix ).

[0104] Results: The results of this analysis are given in Table S9 of this Supplementary Appendix.

[0105] 2: Incorrect stratification in the randomization system Any patients who were incorrectly stratified in the randomization system (i.e. incorrect details entered at the time of randomization) were included in the primary stratification analysis based on information from the randomization system. Cross-tabulation of stratification factors from the randomization system and accurate baseline data from the eCRF was performed. If >5% of randomized patients were incorrectly stratified (i.e. randomization system data did not match baseline data ascertained in the eCRF), a sensitivity analysis was performed for IDFS using the same model as above but using eCRF information instead of randomization system information. [Note: For all patients, characteristics reported in the eCRF were used to determine subgroups for subgroup analysis, while randomization system information was used to stratify log-rank and Cox model analyses].

[0106] Following a pooling strategy, only hormone receptor status was fitted as a stratification factor. Of 1836 participants in the ITT population, 32 (1.7%) had discordant hormone receptor status between that reported by the randomization system and that reported in the eCRF.

[0107] RESULTS:This sensitivity analysis was not performed as the 5% threshold was not met.

[0108] 3: Central pathology diagnosis The protocol stipulated that if ER and PgR status results from local and central laboratories differed in >5% of randomized patients, a sensitivity analysis would be performed on IDFS using the same model as above, but using the central laboratory results to determine the stratification factor for HR status, and compared with the results from the primary analysis.

[0109] Of the 1452 patients with both central and local hormone receptor status, 147 (10%) had discordant results (Table S5 in this Supplementary Appendix). 247 patients did not have central pathology available due to regulatory requirements by the Chinese authorities. The results of the central receptor status assessment excluding patients from China are shown in Table S4 in this Supplementary Appendix.

[0110] RESULTS: Because a 5% threshold for local-to-central hormone receptor status discordance was met, this sensitivity analysis was performed. The results of this analysis are given in Table S9 in this Supplementary Appendix.

[0111] 4: Important Protocol Deviations (IPDS) Important protocol deviations (IPDs) are a concise list of predefined protocol deviations that are highly likely to affect the primary efficacy and / or secondary safety outcomes. The protocol specified that a "deviation bias" sensitivity analysis could be performed excluding patients with IPDs that could affect the efficacy of the study treatment. This sensitivity analysis would be performed excluding patients with IPDs that could affect the efficacy of the study treatment if >10% of patients in either treatment group did not have the intended disease or indication or did not receive any randomized treatment.

[0112] Of the 1836 patients in the ITT population, 30 (1.6%) did not have the intended disease or indication or did not receive any randomized treatment (see Table S18 in this Supplementary Appendix).

[0113] Results: As the 10% threshold for IPD was not met, this sensitivity analysis was not performed.

[0114] 5. Unadjusted analysis The protocol stipulated that unadjusted (unstratified Cox model) analyses be performed as sensitivity analyses to compare with the initial results.

[0115] RESULTS: A non-stratified Cox model analysis was performed, and the results of this analysis are presented in Table S9 in the Supplementary Appendix.

[0116] 6. Proportional Hazards Assumption This protocol describes the proportional hazards assumption underlying the log-rank test and the Cox model used for the primary analysis. Two approaches are used to assess proportionality, first by examining plots of complementary log-log(time) against log(time), and second by formally testing with the Grambsch-Therneau test (GT) based on scaled Schoenfeld residuals from a Cox model that includes treatment group as a factor. If the GT test is significant (p<0.05) and proportionality is rejected, the marginal mean survival time (RMST) method is used to estimate and test treatment differences while taking into account non-proportional hazards.

[0117] Results: The GT test achieved the p<0.05 threshold, indicating that proportional hazards cannot be assumed. Rejection of the null hypothesis of proportional hazards. The p-value for the GT test with the identity transformation of time was p=0.02, and the p-value for the GT test with the rank transformation of time was p=0.02 (see Table S9 in this Supplementary Appendix).

[0118] Since the null hypothesis of proportionality was rejected, a sensitivity analysis was performed based on the bounded mean survival time (RMST) method, restricting the calculation of RMST within the first 4.1 years (49 months) of follow-up, as specified in the statistical analysis plan. The time limit was defined as the minimum of the maximum of the longest IDFS event times between the two treatment groups. Under non-proportional hazards, the estimated hazard ratio can be interpreted as the average hazard ratio over the observed follow-up period. This hazard ratio may underestimate and overestimate the hazard during different follow-up periods. The results of the RMST analysis lead to the same conclusion as the primary analysis of IDFS, that there is a treatment benefit for the olaparib group. The results of the RMST analysis are given in Table S9 of this supplementary appendix.

[0119] 7. Interval-censored Cox regression The protocol states that interval censoring will be performed as a sensitivity analysis to compare with the initial results. Patients whose visit schedule does not follow the protocol will be fitted to a Cox model using interval censoring. - For patients who had an event and no per-protocol follow-up (defined as >18 months between the event and last visit), the interval from the last date the subject was known to be IDFS-free to the date of recurrence or death will be used. - For patients who were previously censored or had an event and were seen according to the protocol-defined visit schedule, the lower limit of the interval will be set to the date of censoring / event, while the upper limit will be set to missing.

[0120] RESULTS:No patients met the criteria to begin this sensitivity analysis.

[0121] 4. Supplementary Drawings

[0122] [Table 8]

[0123] [Table 9]

[0124] [Table 10]

[0125] [Table 11]

[0126] [Table 12]

[0127] Figure S5: EORTC QLQ-C30 GHQ scores The primary objective of the planned patient-reported outcomes (PRO) substudy is to determine the impact of olaparib on patient-reported fatigue at 6 and 12 months after randomization, as measured by FACIT-Fatigue. Assessment of the impact of olaparib on health-related quality of life over the first 2 years from randomization is one of the secondary objectives of the PRO substudy. This will be assessed by the 2-item General Health Status / Quality of Life (GHQ) scale of the EORTC QLQ-C30 questionnaire. Data for the protocol-planned analysis of PROs in Olympia are immature and data are available for only half of the study sample at the 2-year point, so will not be reported at this time. In addition, the PRO data analysis plan stratifies the study sample and allows for separate analyses for those who received neoadjuvant or adjuvant chemotherapy before study randomization. Here, we present plots of mean EORTC QLQ-C-30 GHQ scores by treatment assignment for patients who received neoadjuvant and adjuvant chemotherapy. These show that the GHQ did not decline during the 12 months of treatment with either olaparib or placebo, and improved slightly in both groups between months 12 and 24. A clinically meaningful difference in the GHQ is greater than 10 points, and the differences between the treatment groups are not clinically important.

[0128] Legend: Mean response of EORTC QLQ-C30 GHQ scores over time by treatment group. Panel A: Patients who completed neoadjuvant chemotherapy. Panel B: Patients who completed adjuvant chemotherapy. GHQ scores range from 0 to 100, with higher scores indicating better quality of life. Adjusted least squares mean responses and 95% CIs for non-baseline time points are obtained from a mixed model for repeated measures analysis of GHQ scores. The model includes treatment, time, and interactions between treatment and time, corresponding baseline scores, and interactions between baseline score and time. Baseline means and 95% CIs are based on raw data.

[0129] Figure S6: KM plot for IDFS in the mature cohort CI refers to confidence interval. *Stratified Cox proportional hazards model. †Kaplan-Meier estimates.

[0130] 5. Supplementary Table

[0131] [Table 13]

[0132] [Table 14]

[0133] [Table 15]

[0134] [Table 16]

[0135] [Table 17]

[0136] [Table 18]

[0137] [Table 19]

[0138] [Table 20]

[0139] [Table 21]

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[0163] 6. References 1. Mittendorf EA, Jeruss JS, Tucker SL, et al. Validation of a novel staging system for disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy. J Clin Oncol 2011; 29:1956-62.

Claims

1. A medicament for preventing, reducing or delaying recurrence of breast cancer in a subject after local treatment and neoadjuvant or adjuvant chemotherapy, 4-[(3-{[4-(Cyclopropanecarbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]-2H-phthalazin-1-one (olaparib) or a hydrate, solvate or prodrug thereof A medicament comprising the same.

2. A medicament for treating a subject with breast cancer after local treatment and neoadjuvant or adjuvant chemotherapy, 4-[(3-{[4-(Cyclopropanecarbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]-2H-phthalazin-1-one (olaparib) or a hydrate, solvate or prodrug thereof, wherein the adjuvant treatment is to administer 4-[(3-{[4-(Cyclopropanecarbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]-2H-phthalazin-1-one (olaparib) or a hydrate, solvate or prodrug thereof to the subject A medicament comprising the same.

3. The medicament according to claim 1 or 2, wherein the subject has one or more germline BRCA1 and / or BRCA2 gene mutations.

4. The medicament according to claim 3, wherein the germline BRCA1 and / or BRCA2 gene mutations are pathogenic or pathogenic-like (gBRCA-P / LP variants).

5. The medicament according to claim 1 or 2, wherein the breast cancer is HER2-negative breast cancer.

6. The medicament according to claim 5, wherein the breast cancer is HER2-negative early-stage (stage II-III) breast cancer.

7. The medicament according to claim 1 or 2, wherein the local treatment includes surgery for removing breast cancer tissue and optionally includes radiotherapy.

8. The medicament according to claim 1 or 2, wherein the subject has completed at least 6 cycles of neoadjuvant or adjuvant chemotherapy.

9. The medicament according to claim 8, wherein the neoadjuvant or adjuvant chemotherapy contains anthracycline, taxane or a combination of both.

10. The medicament according to claim 1 or 2, wherein the therapeutically effective amount of olaparib is administration twice a day at 300 mg.

11. The pharmaceutical according to claim 10, wherein the therapeutically effective amount of olaparib is 300 mg administered twice daily for one year.

12. The pharmaceutical according to claim 1 or 2, wherein non-invasive disease survival is improved as compared to a subject treated with placebo.

13. The pharmaceutical according to claim 12, wherein the probability of non-invasive disease survival is about 86% at about 3 years after the start of olaparib treatment.

14. The pharmaceutical according to claim 12, wherein the probability of non-invasive disease survival improves by about 1 to about 10%, such as by about 1 to about 9% at about 3 years, such as by about 5 to about 9% at about 3 years, after the start of olaparib treatment.

15. A pharmaceutical for use in adjuvant treatment after local treatment and neoadjuvant or adjuvant chemotherapy of a subject with breast cancer, comprising 4-[(3-{[4-(cyclopropanecarbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]-2H-phthalazin-1-one (olaparib) or a hydrate, solvate or prodrug thereof of the pharmaceutical.

16. The pharmaceutical according to claim 15, wherein the subject has one or more germline BRCA1 and / or BRCA2 gene mutations.

17. The pharmaceutical according to claim 16, wherein the germline BRCA1 and / or BRCA2 gene mutations are pathogenic or pathogenic-like (gBRCA-P / LP-mutants).

18. The pharmaceutical according to claim 15, wherein the breast cancer is HER2-negative breast cancer.

19. The pharmaceutical according to claim 18, wherein the breast cancer is HER2-negative early-stage (stage II to III) breast cancer.

20. The pharmaceutical according to claim 15, wherein the local treatment includes surgery for removing breast cancer tissue and optionally includes radiation therapy.

21. The pharmaceutical according to claim 15, wherein the subject has completed at least 6 cycles of neoadjuvant or adjuvant chemotherapy.

22. The pharmaceutical according to claim 21, wherein the neoadjuvant or adjuvant chemotherapy contains anthracycline, taxane or a combination of both.

23. The pharmaceutical according to claim 15, wherein the therapeutically effective amount of olaparib is 300 mg administered twice daily.

24. The pharmaceutical according to claim 23, wherein the therapeutically effective amount of olaparib is 300 mg administered twice daily for one year.

25. The medicament according to claim 15, wherein non-invasive disease survival is improved as compared to subjects treated with placebo.

26. The medicament according to claim 25, wherein the probability of non-invasive disease survival is about 86% at about 3 years after the start of olaparib treatment.

27. The medicament according to claim 25, wherein the probability of non-invasive disease survival improves by about 1 to about 10% at about 3 years after the start of olaparib treatment, such as by about 1 to about 9% at about 3 years, such as by about 5 to about 9% at about 3 years.

28. A medicament for improving invasive disease survival (or overall survival or distant metastasis-free survival) by providing adjuvant treatment to a subject with a previous diagnosis of germline mutant BRCA1 and / or BRCA2 breast cancer, wherein the subject has previously received local treatment and neoadjuvant or adjuvant chemotherapy, and the medicament comprises 4-[(3-{[4-(cyclopropane-carbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]-2H-phthalazin-1-one (olaparib) or a hydrate, solvate or prodrug thereof.

29. The medicament according to claim 28, wherein the breast cancer is HER2-negative breast cancer.

30. The medicament according to claim 29, wherein the breast cancer is HER2-negative early stage (stage II-III) breast cancer.

31. The medicament according to claim 28, wherein the local treatment includes surgery for removing breast cancer tissue and optionally includes radiotherapy.

32. The medicament according to claim 28, wherein the subject has completed at least 6 cycles of neoadjuvant or adjuvant chemotherapy.

33. The medicament according to claim 32, wherein the neoadjuvant or adjuvant chemotherapy contains anthracycline, taxane or a combination of both.

34. The medicament according to claim 28, wherein the therapeutically effective amount of olaparib is administration twice a day at 300 mg.

35. The medicament according to claim 34, wherein the therapeutically effective amount of olaparib is administration twice a day at 300 mg for 1 year.

36. The medicament according to claim 28, wherein non-invasive disease survival is improved as compared to subjects treated with placebo.

37. The medicament according to claim 36, wherein the probability of non-invasive disease survival is about 86% at about 3 years after the start of olaparib treatment.

38. The pharmaceutical according to claim 36, wherein the probability of non-invasive disease survival is improved by about 1% to about 10% at about 3 years after the start of olaparib treatment, for example, by about 1% to about 9% at about 3 years, for example, by about 5% to about 9% at about 3 years.

39. The pharmaceutical according to claim 36, wherein the improvement in non-invasive disease survival at 3 years is about 9%.

40. The pharmaceutical according to claim 28, wherein distant disease-free survival is improved compared to subjects treated with placebo.

41. The pharmaceutical according to claim 40, wherein the improvement in distant disease-free survival at about 3 years is up to about 8%, for example, up to about 7%, for example, about 1% to about 8%, for example, about 1% to about 7%, for example, about 3% to about 8%, for example, about 3% to about 7%.

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