Methods, compositions, and combinations for the treatment of ovarian cancer

Abstract

The disclosure relates to methods, compositions, and combinations for the treatment of ovarian cancer. Specifically, the disclosure relates to methods of treating ovarian cancer in a subject in need thereof, comprising administering to the subject one or more chemotherapy agents, an anti- VEGF antibody or an antigen-binding fragment, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and optionally a PARP inhibitor. The disclosure also relates to combinations for use in the treatment of ovarian cancer comprising one or more chemotherapy agents, an anti- VEGF antibody or an antigen-binding fragment, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and optionally a PARP inhibitor.

Description

AZ Ref.: B7H1-620-WO-PCT   METHODS, COMPOSITIONS, AND COMBINATIONS FOR THE TREATMENT OF OVARIAN CANCER FIELD OF THE DISCLOSURE

[0001] The disclosure relates to methods, compositions, and combinations for the treatment of ovarian cancer. Specifically, the disclosure relates to methods of treating ovarian cancer in a subject in need thereof, comprising administering to the subject one or more chemotherapy agents, an anti-VEGF antibody or an antigen-binding fragment, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and optionally a PARP inhibitor. The disclosure also relates to combinations for use in the treatment of ovarian cancer comprising one or more chemotherapy agents, an anti-VEGF antibody or an antigen-binding fragment, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and optionally a PARP inhibitor. BACKGROUND

[0002] Treatment of cancer commonly entails surgical resection followed by chemotherapy and radiotherapy. The standard treatment regimens show highly variable degrees of long-term success because of the ability of tumor cells to essentially escape by regenerating primary tumor growth and, often more importantly, seeding distant metastasis. Recent advances in the treatment of cancer and cancer-related diseases, disorders, and conditions comprise the use of combination therapy incorporating immunotherapy with more traditional chemotherapy and radiotherapy. Under most scenarios, immunotherapy is associated with less toxicity than traditional chemotherapy because it utilizes the patient's own immune system to identify and eliminate tumor cells.

[0003] Ovarian cancer is among the most lethal gynecologic malignancies in developed countries. Annually in the United States alone, approximately 23,000 women are diagnosed with the disease and almost 14,000 women die from it. Despite progress in cancer therapy, ovarian cancer mortality has remained virtually unchanged over the past two decades.

[0004] Ovarian cancer is the second most common gynecologic cancer in the United States and causes more deaths than any other cancer of the female reproductive system. Unfortunately, as there are no screening options for ovarian cancer, the disease is often detected in later stages of cancer progression and patients are most commonly diagnosed in Stage 3 of ovarian cancer. Stage 3 cancer means that the ovarian cancer cells have spread or grown into nearby organs of 1   AZ Ref.: B7H1-620-WO-PCT   the pelvis, and thus the disease is not contained within the ovaries or fallopian tubes. Because of the late stage of diagnosis, and the aggressiveness of ovarian cancer, the five-year survival rate is only approximately 39%. Current treatment options remain inadequate.   SUMMARY

[0005] The disclosure relates to methods, compositions, and combinations for the treatment of ovarian cancer. Specifically, the disclosure relates to methods of treating ovarian cancer in a subject in need thereof, comprising administering to the subject one or more chemotherapy agents, an anti-VEGF antibody or an antigen-binding fragment, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and optionally a PARP inhibitor. The disclosure also relates to combinations for use in the treatment of ovarian cancer comprising one or more chemotherapy agents, an anti-VEGF antibody or an antigen-binding fragment, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and optionally a PARP inhibitor.

[0006] In one aspect, the disclosure provides a method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject: (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof, and optionally a therapeutically effective amount of a PARP inhibitor

[0007] In another aspect, the disclosure provides a combination for the treatment of ovarian cancer in a subject in need thereof, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof, and optionally a therapeutically effective amount of a PARP inhibitor.

[0008] In a further aspect, the disclosure provides use of a combination in the manufacture of a medicament for the treatment of ovarian cancer in a subject in need thereof, wherein the 2   AZ Ref.: B7H1-620-WO-PCT   combination comprises: (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen- binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof, and optionally a therapeutically effective amount of a PARP inhibitor.

[0009] These and other features and advantages of the present disclosure will be more fully understood from the following detailed description taken together with the accompanying claims. It is noted that the scope of the claims is defined by the recitations therein and not by the specific discussion of features and advantages set forth in the present description. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIGURE 1 illustrates the study design diagram. Dosing and schedule: bevacizumab (15 mg / kg IV q3w); durvalumab (1120 mg IV q3w); olaparib (300 mg po bid); chemotherapy: paclitaxel 175 mg / m2 IV q3w and carboplatin at AUC5 or AUC6 IV q3w. Progression Free Survival (PFS) interim analysis DCO: December 5, 2022. With or without bevacizumab according to local practice; Cycles 2–6; Genomic instability score ≥42 assessed by Myriad MyChoice CDx assay. AUC, area under the curve; bev, bevacizumab; bid, twice daily; CTx, chemotherapy; DCO, data cutoff; durva, durvalumab; FIGO, International Federation of Gynecology and Obstetrics; HRD, homologous recombination deficiency; ITT, intent-to-treat; IV, intravenous; ola, olaparib; OS, overall survival; PC, paclitaxel / carboplatin; po, by mouth; q3w, every 3 weeks; R, randomization; RECIST, Response Evaluation Criteria for Solid Tumors.

[0011] FIGURE 2 illustrates the study design diagram with endpoints. Dosing and schedule: bevacizumab (15 mg / kg IV q3w); durvalumab (1120 mg IV q3w); olaparib (300 mg po bid); chemotherapy: paclitaxel 175 mg / m2 IV q3w and carboplatin at AUC5 or AUC6 IV q3w. PFS interim analysis DCO: December 5, 2022. *With or without bevacizumab according to local practice; †Cycles 2–6; Genomic instability score ≥42 assessed by Myriad MyChoice CDx assay. AUC, area under the curve; bev, bevacizumab; bid, twice daily; CTx, chemotherapy; DCO, data cutoff; durva, durvalumab; FIGO, International Federation of Gynecology and Obstetrics; HRD, homologous recombination deficiency; ITT, intent-to-treat; IV, intravenous; 3   AZ Ref.: B7H1-620-WO-PCT   ola, olaparib; OS, overall survival; PC, paclitaxel / carboplatin; po, by mouth; q3w, every 3 weeks; R, randomization; RECIST, Response Evaluation Criteria for Solid Tumors.

[0012] FIGURE 3 illustrates the multiple testing procedure and PFS interim analysis. For each PFS comparison, the alpha is controlled at the interim and final analysis time-points by using a bespoke spending function separately. FA, final analysis; IA, interim analysis.

[0013] FIGURE 4 illustrates the patients’ characteristics. Percentages may not total 100 because of rounding. *One patient in Arm 2 had unknown FIGO stage. †Includes mixed epithelial, carcinosarcoma and other histology types; Genomic instability assessed using the Myriad MyChoice CDx assay and a cutoff of 42; ECOG, Eastern Cooperative Oncology Group.

[0014] FIGURE 5 illustrates the patient disposition. Patients who discontinued one or more study treatment could continue to receive the remaining study treatments. Percentages may not total 100 because of rounding. *Total period from first dose to earliest date of last non-zero dose +20 days, death or DCO; †Total period from first dose to earliest date of last non-zero dose, death or DCO; Carboplatin or cisplatin substitute; §Paclitaxel or nab-paclitaxel, docetaxel or pegylated liposomal doxorubicin substitute; ‖In patients censored for PFS.

[0015] FIGURE 6 shows Progression Free Survival in the HRD-positive subgroup for Arm 3 vs Arm 1. *In censored patients; †Medians and rates were estimated by KM method; 24- month PFS rates unstable. Median PFS in Arm 3 unstable. §HR and CI were estimated from a stratified. Cox proportional hazards model. P value from a stratified log rank text. Model stratified by timing and outcome of cytoreductive surgery; CI, confidence interval; HR, hazard ratio; KM, Kaplan–Meier.

[0016] FIGURE 7 shows Progression Free Survival in the ITT population Arm 3 vs Arm 1. *In censored patients; †Medians and rates were estimated by KM method; 24-month PFS rates unstable. §HR and CI were estimated from a stratified Cox proportional hazards model. Model stratified by timing and outcome of cytoreductive surgery and geographical region. P value from a stratified log rank text.

[0017] FIGURE 8 shows Progression Free Survival in the ITT population. In censored patients; †Medians and rates were estimated by KM method; 24-month PFS rates unstable. §HR and CI were estimated from a stratified Cox proportional hazards model. Model stratified by timing and outcome of cytoreductive surgery and geographical region. P value from a stratified log rank text. 4   AZ Ref.: B7H1-620-WO-PCT

[0018] FIGURE 9 shows subgroup analysis of PFS by HRD status. Panel A shows the HRD-positive subgroup and Panel B shows the HRD-negative subgroup. *Medians and rates were estimated by KM method. †24-month PFS rates unstable. Median PFS in HRD-positive subgroup Arm 3 and Arm 2 unstable. HR and CI were estimated from an unstratified Cox proportional hazards model.

[0019] FIGURE 10 shows subgroup analyses of PFS Arm 3 vs Arm 1 (ITT population). Consistency of treatment effect between subgroups estimated from an unstratified Cox proportional hazards model. PD-L1 expression was centrally assessed by Ventana SP263 immunohistochemistry assay. Tumor area positivity PD-L1 expression (TAP5): high defined as ≥5%; low defined as <5%; unknown defined as samples where PD-L1 expression was not available. PD-L1, programmed death-ligand 1.

[0020] FIGURE 11 shows the safety summary. Includes AEs with onset or worsening on or after the date of first dose of durvalumab / placebo or olaparib / placebo (overall) or first dose of olaparib / placebo (maintenance phase) until initiation of the first subsequent anticancer therapy following last dose of study treatment or until the end of the safety follow-up period. *Includes events from first dose of durvalumab / olaparib / placebo until end of study. †Investigator- assessed; Based on action taken on AE CRF for at least one treatment. For durvalumab / placebo, dose modification includes skipped or delayed doses, or interruption of the infusion; §Either dose reduction or dose interruption; AE, adverse event; AML, acute myeloid leukemia; CRF, case report form; MDS, myelodysplastic syndrome.

[0021] FIGURE 12 shows any adverse effect with frequency of ≥20%. Includes AEs with onset or worsening on or after the date of first dose of durvalumab / placebo or olaparib / placebo (overall) or first dose of olaparib / placebo (maintenance phase) until initiation of the first subsequent anticancer therapy following last dose of study treatment or until the end the safety follow-up period. *AEs of any grade with overall incidence of ≥20% in any arm and associated incidence in the maintenance phase, excluding alopecia.

[0022] FIGURE 13 shows grade ≥3 adverse effects with frequency of ≥5%. Includes AEs with onset or worsening on or after the date of first dose of durvalumab / placebo or olaparib / placebo (overall) or first dose of olaparib / placebo (maintenance phase) until initiation of the first subsequent anticancer therapy following last dose of study treatment or until the end the 5   AZ Ref.: B7H1-620-WO-PCT   safety follow-up period. *Grade ≥3 AEs with overall incidence of ≥5% in any arm and associated incidence in the maintenance phase.

[0023] FIGURES 14A-14B show the disposition of clinical trial participants at (A) the interim / primary progression-free survival analysis DCO (December 5, 2022) and (B) the final progression-free survival analysis DCO (September 18, 2023). No patients were still receiving paclitaxel or carboplatin at DCO in any treatment arm. DCO, data cutoff; ITT, intention-to-treat.

[0024] FIGURE 15 shows the study design. Patients received a minimum of four and maximum of six cycles of carboplatin / paclitaxel. Patients who had upfront surgery received Cycle 1 of carboplatin / paclitaxel within 8 weeks of surgery. Interval debulking surgery ideally took place within 14 days (and no later than 28 days) after Day 21 of Cycle 3 of carboplatin / paclitaxel; administration of bevacizumab was mandatory in Cycle 2 but was omitted from Cycle 3 immediately prior to interval debulking surgery. If carboplatin / paclitaxel was started within 4 weeks after interval debulking surgery, then bevacizumab was omitted from the first cycle after interval debulking surgery. During Cycle 1 of chemotherapy, patients received carboplatin dosed at an AUC of 5 or 6 intravenously and intravenous paclitaxel 175 mg / m2. Cycle 1 could also include intravenous bevacizumab 15 mg / kg according to local practice. From Cycle 2 onwards, patients received paclitaxel 175 mg / m2 q3w plus carboplatin at an AUC of 5 or 6 q3w (six cycles in total) and bevacizumab 15 mg / kg q3w plus durvalumab placebo followed by maintenance bevacizumab 15 mg / kg q3w (total of 15 months) plus durvalumab placebo plus olaparib placebo (control arm); carboplatin / paclitaxel plus bevacizumab plus intravenous durvalumab 1,120 mg q3w followed by maintenance bevacizumab plus durvalumab 1,120 mg q3w (total of 24 months) plus olaparib placebo (durvalumab arm); or carboplatin / paclitaxel plus bevacizumab plus durvalumab followed by maintenance bevacizumab plus durvalumab plus olaparib tablets 300 mg twice daily (total of 24 months) (durvalumab + olaparib arm). AUC, area under the serum-concentration-time curve; BRCA, BRCA1 and / or BRCA2; FIGO, International Federation of Gynecology and Obstetrics; PARP, poly(ADP-ribose) polymerase; q3w, every 3 weeks; R, randomization; tBRCAm, tumor BRCA mutation.

[0025] FIGURES 16A-16D shows interim PFS analysis (DCO: December 5, 2022) in the (A) non-tBRCAm HRD-positive and (B) intention-to-treat populations, and final PFS analysis (DCO: September 18, 2023) in the (C) non-tBRCAm HRD-positive and (D) intention-to-treat populations. 6   AZ Ref.: B7H1-620-WO-PCT

[0026] FIGURE 17 shows the interim PFS analysis.  BRCA, BRCA1 and / or BRCA2; HRD, homologous recombination deficiency; ITT, intention-to-treat; non-tBRCAm, non-tumor BRCAm; OS, overall survival; PFS, progression-free survival.

[0027] FIGURE 18 shows prespecified subgroup analysis of interim PFS (DCO: December 5, 2022) in the durvalumab+olaparib arm versus the control arm. Consistency of treatment effect between subgroups estimated from an unstratified Cox proportional hazards model. *Macroscopic residual disease after upfront surgery or planned IDS. †tHRRm status was evaluated using a Myriad tumor tissue gene panel. A positive HRRm status was defined as a sample with a pathogenic mutation in any of the following prespecified genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. A negative HRRm status (non-HRRm) was defined as a sample with no pathogenic mutations in any of the prespecified genes. PD-L1 expression was centrally assessed using the Ventana SP263 immunohistochemistry assay (Roche Diagnostics, Rotkreuz, Switzerland). TAP5 high was defined as ≥5%; TAP5 low was defined as <5%; and TAP5 unknown was defined as samples where PD-L1 expression was not available. DCO, data cutoff; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; HRD, homologous recombination deficiency; HRRm, homologous recombination repair mutation; IDS, interval debulking surgery; PFS, progression-free survival; RoW, rest of world; TAP, tumor area positivity PD-L1 expression; tHRRm, tumor homologous recombination repair mutation.

[0028] FIGURES 19A-19C show prespecified subgroup analyses of (A) final progression- free-survival (DCO: September 18, 2023) in the durvalumab plus olaparib arm versus the control arm, (B) interim progression-free survival (DCO: December 5, 2022), and (C) final progression- free-survival (DCO: September 18, 2023) in the durvalumab arm versus the control arm.   Consistency of treatment effect between subgroups estimated from an unstratified Cox proportional hazards model. *Macroscopic residual disease after upfront surgery or planned IDS. †Tumor HRRm status was evaluated using a Myriad tumor tissue gene panel. A positive HRRm status was defined as a sample with a pathogenic mutation in any of the following prespecified genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. A negative HRRm status (non- HRRm) was defined as a sample with no pathogenic mutations in any of the prespecified genes. PD-L1 expression was centrally assessed using the Ventana SP263 immunohistochemistry 7   AZ Ref.: B7H1-620-WO-PCT   assay (Roche Diagnostics, Rotkreuz, Switzerland). TAP5 high was defined as ≥5%; TAP5 low was defined as <5%; and TAP5 unknown was defined as samples where PD-L1 expression was not available. DCO, data cutoff; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; HRD, homologous recombination deficiency; HRRm, homologous recombination repair mutation; IDS, interval debulking surgery; PD-L1, programmed death-ligand 1; RoW, rest of world; TAP, tumor area positivity PD-L1 expression.

[0029] FIGURES 20A-20D show PFS2 analysis (DCO: September 18, 2023) in the (A) intention-to-treat and (B) non-tBRCAm HRD-positive populations, and interim OS analysis (DCO: September 18, 2023) in the (C) intention-to-treat and (D) non-tBRCAm HRD-positive populations. Medians estimated by the Kaplan-Meier method. In A, B, and C, HRs and CIs estimated from an unstratified Cox proportional hazards model. In D, HRs and CIs estimated from a stratified Cox proportional hazards model (stratified by the timing and outcome of cytoreductive surgery). P-value in C from an unstratified log rank text. BRCA, BRCA1 and / or BRCA2; CI, confidence interval; DCO, data cutoff; HR, hazard ratio; HRD, homologous recombination deficiency; NR, not reached; OS, overall survival; PFS2, second disease progression; tBRCAm, tumor BRCAm

[0030] FIGURES 21A-21D show (A) Interim PFS (DCO: December 5, 2022), (B) final PFS (DCO: September 18, 2023), (C) PFS2 (DCO: September 18, 2023), and (D) interim OS (DCO: September 18, 2023) in patients with HRD-negative tumors. Medians estimated by the Kaplan- Meier method; the HRs and CIs were estimated from an unstratified Cox proportional hazards model. DCO, data cutoff; HR, hazard ratio; HRD, homologous recombination deficiency; OS, overall survival; PFS, progression-free survival; PFS2, second disease progression.

[0031] FIGURES 22A-22B show final PFS in (A) Non-tBRCAm HRD positive and (B) Non-tBRCAm ITT groups.

[0032] FIGURES 23A-23B show interim OS in (A) Non-tBRCAm HRD positive and (B) Non-tBRCAm ITT groups.

[0033] FIGURES 24A-24B show unstratified subgroup analysis of HRD-negative population (A) PFS and (B) Interim OS.

[0034] FIGURE 25 shows updated safety information for DCO2.

[0035] FIGURE 26 shows a final PFS and interim OS analysis flow chart. 8   AZ Ref.: B7H1-620-WO-PCT

[0036] FIGURE 27 shows a final PFS analysis for non-tBRCAm HRD-positive population. Medians estimated by the Kaplan-Meier method. HRs and CIs estimated from a stratified Cox proportional hazards model (stratified by the timing and outcome of cytoreductive surgery). P- value from a stratified log rank test. The median (range) duration of follow-up for PFS in censored patients was 28.8 (0.0-40.8), 21.2 (0.0-41.5), and 25.6 (0.0-41.7) months in the control, durvalumab, and durvalumab+olaparib arms at the primary PFS analysis, and 38.4 (0.0-51.6), 33.1 (0.0-50.8), and 34.6 (0.0-51.3) months, respectively, at the final PFS analysis. BRCA, BRCA1 and / or BRCA2; DCO, data cutoff; HR, hazard ratio; HRD, homologous recombination deficiency; non-tBRCAm, non-tumor BRCAm; NR, not reached; OS, overall survival; PFS, progression-free survival.

[0037] FIGURE 28 shows prespecified subgroup analysis for the durvalumab+olaparib arm versus the control arm for final PFS in the non-tBRCAm ITT population. Consistency of treatment effect between subgroups estimated from an unstratified Cox proportional hazards model. *Macroscopic residual disease after upfront surgery or planned IDS. †tHRRm status was evaluated using the MyChoice® CDx assay. A positive HRRm status was defined as a sample with a deleterious or suspected deleterious mutation in any of the following prespecified genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. A negative HRRm status (non-HRRm) was defined as a sample with no deleterious or suspected deleterious mutations in any of the prespecified genes. PD-L1 expression was centrally assessed using the Ventana SP263 immunohistochemistry assay (Roche Diagnostics, Rotkreuz, Switzerland). TAP5 high was defined as ≥5%; TAP5 low was defined as <5%; and TAP5 unknown was defined as samples where PD-L1 expression was not available. DCO, data cutoff; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; HRD, homologous recombination deficiency; HRRm, homologous recombination repair mutation; IDS, interval debulking surgery; ITT, intention-to- treat; PFS, progression-free survival; TAP, tumor area proportion; tHRRm, tumor homologous recombination repair mutation.

[0038] FIGURE 29 shows disposition of clinical trial participants at the final PFS / interim OS analysis DCO (September 18, 2023). *No patients were still receiving paclitaxel or carboplatin at DCO in any treatment arm. DCO, data cutoff; ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival. 9   AZ Ref.: B7H1-620-WO-PCT

[0039] FIGURE 30 shows prespecified subgroup analysis for the durvalumab+olaparib arm versus the control arm for primary PFS in the non-tBRCAm ITT population. Consistency of treatment effect between subgroups estimated from an unstratified Cox proportional hazards model. *Macroscopic residual disease after upfront surgery or planned IDS. †tHRRm status was evaluated using the MyChoice® CDx assay. A positive HRRm status was defined as a sample with a deleterious or suspected deleterious mutation in any of the following prespecified genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. A negative HRRm status (non-HRRm) was defined as a sample with no deleterious or suspected deleterious mutations in any of the prespecified genes. PD-L1 expression was centrally assessed using the Ventana SP263 immunohistochemistry assay (Roche Diagnostics, Rotkreuz, Switzerland). TAP5 high was defined as ≥5%; TAP5 low was defined as <5%; and TAP5 unknown was defined as samples where PD-L1 expression was not available. BRCA, BRCA1 and / or BRCA2; DCO, data cutoff; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; HRD, homologous recombination deficiency; HRRm, homologous recombination repair mutation; IDS, interval debulking surgery; ITT, intention-to-treat; non-tBRCAm, non-tumor BRCAm; PFS, progression- free survival; TAP, tumor area proportion; tHRRm, tumor homologous recombination repair mutation.

[0040] FIGURE 31A-31B shows further results of the PFS2 analysis for (A) non-tBRCAm HRD-positive and (B) non-tBRCAm ITT.

[0041] FIGURE 32A-32B shows further results of the PFS analysis for (A) non-tBRCAm HRD-positive and (B) non-tBRCAm ITT.

[0042] FIGURE 33 shows further results of the unstratified subgroup analysis of HRD- negative population in PFS2.   DETAILED DESCRIPTION

[0043] The disclosure relates to methods, compositions, and combinations for the treatment of ovarian cancer. Specifically, the disclosure relates to methods of treating ovarian cancer in a subject in need thereof, comprising administering to the subject one or more chemotherapy agents, an anti-VEGF antibody or an antigen-binding fragment, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and optionally a PARP inhibitor. The disclosure also relates 10   AZ Ref.: B7H1-620-WO-PCT   to combinations for use in the treatment of ovarian cancer comprising one or more chemotherapy agents, an anti-VEGF antibody or an antigen-binding fragment, an anti-PD-L1 antibody or an antigen-binding fragment thereof, and optionally a PARP inhibitor.

[0044] As utilized in accordance with the present disclosure, unless otherwise indicated or defined, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this disclosure belongs. The following references provide one of skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed.1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.

[0045] In this disclosure, "comprises," "comprising," "containing," and "having," and the like can have the meaning ascribed to them in U.S. patent law and can mean "includes," "including," and the like; "consisting essentially of" or "consists essentially" likewise have the meaning ascribed in U.S. patent law and are open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited are not changed by the presence of more than that which is recited, but excludes prior art aspects.

[0046] Unless specifically stated or obvious from context, the term "or," as used herein, is understood to be inclusive. Unless specifically stated or obvious from context, the terms "a," "an," and "the," as used herein, are understood to be singular or plural. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0047] Unless specifically stated or obvious from context, the term "about," as used herein, is understood as meaning within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. "About" can be understood as meaning within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.

[0048] Any of the methods, compositions, or combinations provided herein can be combined with one or more of any of the other methods, compositions, or combinations provided herein. 11   AZ Ref.: B7H1-620-WO-PCT

[0049] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0050] The term "antibody," as used herein, refers to a protein that is capable of specifically binding to an antigen. Ordinary or conventional mammalian antibodies comprise a tetramer, which is typically composed of two identical pairs of polypeptide chains, each pair consisting of one "light" chain (typically having a molecular weight of about 25 kDa) and one "heavy" chain (typically having a molecular weight of about 50-70 kDa). The terms "heavy chain" and "light chain," as used herein, refer to any immunoglobulin polypeptide having sufficient variable domain sequence to confer specificity for a target antigen. The amino-terminal portion of each light and heavy chain typically includes a variable domain of about 100 to 110 or more amino acids that typically is responsible for antigen recognition. The carboxyl-terminal portion of each chain typically defines a constant domain responsible for effector function. Thus, in a naturally occurring antibody, a full-length heavy chain immunoglobulin polypeptide includes a variable domain (VH) and three constant domains (CH1, CH2, and CH3) and a hinge region between CH1and CH2, wherein the VH domain is at the amino-terminus of the polypeptide and the CH3 domain is at the carboxyl-terminus, and a full-length light chain immunoglobulin polypeptide includes a variable domain (VL) and a constant domain (CL), wherein the VL domain is at the amino- terminus of the polypeptide and the CL domain is at the carboxyl-terminus.

[0051] Within full-length light and heavy chains, the variable and constant domains typically are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D" region of about 10 more amino acids. The variable regions of each light / heavy chain pair typically form an antigen-binding site. The variable domains of naturally occurring antibodies typically exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs. The CDRs from the two chains of each pair typically are aligned by the framework regions, which may enable binding to a specific epitope. From the amino-terminus to the carboxyl-terminus, both light and heavy chain variable domains typically comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. 12   AZ Ref.: B7H1-620-WO-PCT

[0052] The term "antigen-binding fragment" refers to a portion of an intact antibody and / or refers to the antigenic determining variable domains of an intact antibody. It is known that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab′, F(ab′)2, and Fv fragments, linear antibodies, single chain antibodies, diabodies, and multispecific antibodies formed from antibody fragments.

[0053] In one aspect, the disclosure provides a method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject: (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof, and optionally a therapeutically effective amount of a PARP inhibitor.

[0054] In some embodiments of the methods of the disclosure, step (b) occurs after completion of step (a).

[0055] In various embodiments of the first aspect, step (b) can exclude a therapeutically effective amount of a PARP inhibitor. In these embodiments, step (b) includes a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof.

[0056] In some embodiments, the method further comprises administering to the subject prior to step (a): a therapeutically effective amount of one or more chemotherapy agents; or a therapeutically effective amount of one or more chemotherapy agents and an anti-VEGF antibody or antigen-binding fragment thereof. In some embodiments, the method comprises administering to the subject prior to step (a): at least one cycle of the therapeutically effective amount of one or more chemotherapy agents; or a therapeutically effective amount of one or more chemotherapy agents and an anti-VEGF antibody or antigen-binding fragment thereof. The number of treatment doses scheduled within each cycle depends on the chemotherapy agent. In some embodiments, each cycle may contain only 1 dose. In other embodiments, a cycle may contain more than 1 dose. 13   AZ Ref.: B7H1-620-WO-PCT

[0057] In some embodiments, provided herein is a method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject an anti-VEGF antibody or antigen-binding fragment thereof at a dose of from 5 mg / kg to 25 mg / kg. In other embodiments, provided herein is a method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject an anti-VEGF antibody or antigen-binding fragment thereof at a dose of from 5 mg / kg to 20 mg / kg.

[0058] In some embodiments, provided herein is a method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject an anti-VEGF antibody or antigen-binding fragment thereof at a fixed dose of from 800 mg to 1500 mg.

[0059] In one non-limiting embodiment, an anti-VEGF antibody is administered at a fixed dose of 1120 mg (based on an average body weight of 75 kg, this is equivalent to a weight based dose of 15 mg / kg).

[0060] In some embodiments, provided herein is a method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject an anti-VEGF antibody or antigen-binding fragment thereof at a dose of 15 mg / kg.

[0061] In some embodiments, provided herein is a method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject an anti-PD-L1 antibody or antigen-binding fragment thereof at a dose of from 5 mg / kg to 25 mg / kg. In some embodiments, provided herein is a method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject an anti-PD-L1 antibody or antigen-binding fragment thereof at a dose of from 10 mg / kg to 20 mg / kg.

[0062] In some embodiments, provided herein is a method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject an anti-PD-L1 antibody or antigen-binding fragment thereof at a fixed dose of from 800 mg to 1500 mg.

[0063] In some embodiments, provided herein is a method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject an anti-PD-L1 antibody or antigen-binding fragment thereof at a dose of 15 mg / kg or a fixed dose of 1120 mg.

[0064] In one non-limiting embodiment, an anti-PD-L1 antibody is administered using a fixed dose of 1120 mg (based on an average body weight of 75 kg, this is equivalent to a weight based dose of 15 mg / kg). 14   AZ Ref.: B7H1-620-WO-PCT

[0065] In some embodiments, provided herein is a method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject a PARP inhibitor at a fixed dose of from 100 mg to 300 mg.

[0066] In some embodiments, provided herein is a method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject an PARP inhibitor at a fixed dose of 300 mg.

[0067] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is durvalumab. Durvalumab (MEDI4736, Imfinzi®) is a human monoclonal antibody directed against human PD-L1 that is capable of blocking the binding of PD-L1 to both the PD1 and CD80 receptors. Disclosure related to durvalumab can be found in U.S. Patent Nos.8,779,108 and 9,493,565, which are incorporated herein by reference in their entirety.

[0068] Durvalumab and antigen-binding fragments thereof for use in the methods, compositions, and combinations provided herein comprises a heavy chain and a light chain or a heavy chain variable region and a light chain variable region. In some embodiments, durvalumab or antigen-binding fragment thereof for use in the methods, compositions, and combinations provided herein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, durvalumab or antigen-binding fragment thereof for use in the methods, compositions, and combinations provided herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 3-5, and wherein the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 6-8. Those of ordinary skill in the art would easily be able to identify Chothia-defined, Abm-defined, or other CDR definitions known to those of ordinary skill in the art. In some embodiments, durvalumab or antigen-binding fragment thereof for use in the methods, compositions, and combinations provided herein comprises the variable heavy chain and variable light chain CDR sequences of the 2.14H9OPT antibody as disclosed in U.S. Patent Nos.8,779,108 and 9,493,565.

[0069] Durvalumab light chain (LC) variable region: 15   AZ Ref.: B7H1-620-WO-PCT

[0070] EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDAS SRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK (SEQ ID NO: 1)

[0071] Durvalumab heavy chain (HC) variable region:

[0072] EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANI KQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAF DYWGQGTLVTVSS (SEQ ID NO: 2)

[0073] Durvalumab heavy chain CDRs:

[0074] HC-CDR1: GFTFSRYWMS (SEQ ID NO: 3)

[0075] HC-CDR2: NIKQDGSEKYYVDSVKG (SEQ ID NO: 4)

[0076] HC-CDR3: EGGWFGELAFDY SEQ ID NO: 5)

[0077] Durvalumab, light chain CDRs:

[0078] LC-CDR1: RASQRVSSSYLA (SEQ ID NO: 6)

[0079] LC-CDR2: DASSRAT (SEQ ID NO: 7)

[0080] LC-CDR3: QQYGSLPWT (SEQ ID NO: 8)

[0081] As used herein, the term "vascular endothelial growth factor (VEGF) inhibitors" or "anti-VEGF antibody or antigen-binding fragment thereof" means agents that inhibit the activity of VEGF and VEGFR. VEGR and VEGFR (a tyrosine kinase receptor) signaling modulates angiogenesis, which involves making of new blood vessels from existing blood vessels. Abnormal angiogenesis is known to occur in cancer, degenerative eye conditions, and other conditions that involve inflammation. Specific monoclonal antibodies can be used as VEGF inhibitors or anti-VEGF antibodies and particular tyrosine kinase inhibitors are used as VEGFR inhibitors. Vascular endothelial growth factor (VEGF) / vascular endothelial growth factor receptor (VEGFR) inhibitors are used to treat various types of cancers.

[0082] VEGFR tyrosine kinase inhibitor (TKI) including, but not limited to: ziv-aflibercept, bevacizumab, pazopanib, sunitinib, sorafenib, lenvatinib, cabozantinib, regorafenib, ponatinib, ramucirumab, and vandetanib. In certain embodiments, combination treatment further includes administration of an anti-TIGIT antibody, monalizumab, oleanolic acid, and / or oleclumab. In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof is bevacizumab. Disclosure related to bevacizumab can be found in U.S. Patent Nos.6,407,213 and 7,365,166, which are incorporated herein by reference in their entirety.  16   AZ Ref.: B7H1-620-WO-PCT

[0083] As used herein, the term "PARP inhibitor" means any agents that inhibit the activity of the poly (ADP-ribose) polymerase (PARP) enzyme in cells. PARP helps repair DNA when it becomes damaged. DNA damage may be caused by many things, including exposure to UV light, radiation, certain anticancer drugs, or other substances in the environment. In cancer treatment, blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. In some embodiments, the PARP inhibitor is olaparib. Disclosure related to olaparib can be found in European Patent Nos.1330442 and 1633724, which are incorporated herein by reference in their entirety.

[0084] As used herein, "chemotherapy" or "chemotherapy agents" can include any chemotherapeutic agents. In some embodiments, the chemotherapy agents comprise one or more platinum-based chemotherapeutic agents. In some embodiments, the one or more platinum- based chemotherapeutic agents comprise carboplatin, cisplatin, oxaliplatin, or combinations thereof. In some embodiments, the chemotherapy agents comprise one or more taxane-based chemotherapeutic agents. In some embodiments, the one or more taxane-based chemotherapeutic agents comprise nab-paclitaxel, paclitaxel, docetaxel, cabazitaxel, abraxane, anthracycline (Pegylated Liposomal Doxorubicin), or combinations thereof. In some embodiments, the chemotherapy agents comprise one or more platinum-based chemotherapeutic agents in combination with one or more taxane-based chemotherapeutic agents. In various embodiments, the disclosure permits substitution of one or more chemotherapy agents for any other chemotherapy agent and at any time during administration. Substitution of chemotherapy agents may occur for any reason including, but not limited to, a reaction to, or development of hypersensitivity to one or more chemotherapy agents in the subject. In some embodiments, the chemotherapy agents comprise cisplatin and paclitaxel. In some embodiments, the patient is administered one or more doses of cisplatin, wherein the dose is about 25 mg / m2. In some embodiments, the patient is administered one or more doses of cisplatin at a dose that produces an Area Under of Curve (AUC) of AUC5 or AUC6. In some embodiments, the patient is administered a dose of cisplatin from 25 mg / m2to 100 mg / m2. In some embodiments, the patient is administered one or more doses of paclitaxel, wherein the dose is about 175 mg / m2. In various embodiments, the dose of the chemotherapy agent can be reduced.

[0085] In some embodiments, the number of doses of one or more chemotherapy agents is measured in cycles. The number of treatment doses scheduled within each cycle depends on the 17   AZ Ref.: B7H1-620-WO-PCT   chemotherapy agent. In some embodiments, each cycle may contain only 1 dose. In one, non- limiting embodiment, the cycle may contain 1 dose administered on day 1 of the cycle. In other embodiments, a cycle may contain more than 1 dose. In one, non-limiting embodiment, the cycle may contain more than 1 dose given daily or weekly.

[0086] In some embodiments, the number of doses of the anti-VEGF antibody or antigen- binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and / or the PARP inhibitor is measured in cycles. The number of treatment doses scheduled within each cycle depends on the antibody or inhibitor. In some embodiments, each cycle may contain only 1 dose. In one, non-limiting embodiment, the cycle may contain 1 dose administered on day 1 of the cycle. In other embodiments, a cycle may contain more than 1 dose. In one, non-limiting embodiment, the cycle may contain more than 1 dose given daily or weekly.

[0087] The term "subject" as used herein is a human patient.

[0088] In some embodiments, the methods, compositions, and combinations disclosed herein are used for treating a subject with ovarian cancer or an ovarian tumor disorder. In some embodiments, the tumor is a solid tumor. The term "solid tumor," as used herein, refers to an abnormal mass of tissue that normally does not contain cysts or liquid areas.

[0089] The terms "treatment" or "treat," as used herein, refer to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include subjects having cancer as well as those prone to having cancer or those in cancer is to be prevented. In some embodiments, the methods, compositions, and combinations disclosed herein can be used for the treatment of ovarian cancer. In other embodiments, those in need of treatment include subjects having a tumor as well as those prone to have a tumor or those in which a tumor is to be prevented. In certain embodiments, the methods, compositions, and combinations disclosed herein can be used for the treatment of tumors. In other embodiments, treatment of a tumor includes inhibiting tumor growth, promoting tumor reduction, or both inhibiting tumor growth and promoting tumor reduction.

[0090] In some embodiments, the methods, compositions, and combinations disclosed herein provide an increase in progression free survival (PFS) relative to placebo. In some embodiments, the methods, compositions, and combinations disclosed herein provide an increase in overall survival (OS) versus placebo. 18   AZ Ref.: B7H1-620-WO-PCT

[0091] Overall Survival (OS) relates to the time period beginning on the date of treatment until death due to any cause. OS may refer to overall survival within a period of time such as, for example, 2 months, 3 months, 4 months, 6 months, 8 months, 12 months, 18 months, 24 months, and the like. Such periods of time can be identified, for example, as "OS24" which refers to the number (%) of patients who are alive at 24 months after treatment onset per the Kaplan-Meier estimate of overall survival at 24 months. In some embodiments, the overall survival is measured as compared to a patient who has only received bevacizumab and chemotherapy or has only received chemotherapy. In other embodiments, the overall survival is measured as compared to a patient who has not received treatment.

[0092] Progression-Free Survival (PFS) relates to the time period beginning on the date of treatment until the date of objective disease progression (RECIST 1.1) or death (by any cause in the absence of progression). In some embodiments, the methods, compositions, and combinations of the disclosure provide for (statistically significant and / or clinically meaningful) increase in PFS. In some embodiments, the methods, compositions, and combinations of the disclosure provide for PFS of at least 9 months to at least about 24 months (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or more than 24 months, and up to about 5 years). In some embodiments the progression-free survival is measured as compared to a patient who has only received bevacizumab and chemotherapy or has only received chemotherapy. In other embodiments, the overall survival is measured as compared to a patient who has not received treatment.

[0093] The terms "administration" or "administering," as used herein, refer to providing, contacting, and / or delivering a compound or compounds by any appropriate route to achieve the desired effect. Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intracutaneous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection), transdermal, topical, buccal, rectal, vaginal, nasal, ophthalmic, via inhalation, and implants.

[0094] In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the one or more chemotherapy agents are administered intravenously. In some embodiments, the PARP inhibitor is administered orally. 19   AZ Ref.: B7H1-620-WO-PCT

[0095] Provided herein are methods, compositions, and combinations for treating ovarian cancer or an ovarian tumor in a subject in need thereof. The subject may be PARP inhibitor and immune-mediated therapy naïve. As used herein "ovarian cancer" refers to any cancer or tumor which originates in the ovaries, or in the related areas of the fallopian tubes and the peritoneum. These include but are not limited to epithelial ovarian cancer, germ cell ovarian tumors, sex cord stromal tumors, and borderline ovarian tumors. The severity of ovarian cancer is measured in stages and grades.

[0096] As used herein, "stages" refers to an international system used to assess how far the cancer has spread. In Stage I, the cancer is confined to one or both ovaries and can be further subdivided into Stage IA: Growth is limited to 1 ovary with no tumor on external surfaces; Stage IB: Growth is limited to both ovaries with no tumor on external surfaces; and Stage IC: Tumor is either stage IA or IB, but with tumor on surface of one or both ovaries. In Stage II, the cancer has spread to the uterus or other nearby organs and can be further subdivided into Stage IIA: Extension and / or metastases of cancer to the uterus and / or fallopian tubes; Stage IIB: Extension of the cancer to other pelvic tissues; and Stage IIC: Tumor is at either stage IIA or IIB, but with tumor on surface of one or both ovaries. In Stage III, the cancer has spread to the lymph nodes or abdominal lining and can be further subdivided into Stage IIIA: Tumor limited to the true pelvis; Stage IIIB: Metastasis of abdominal peritoneal surfaces ≤ 2 cm in diameter; and Stage IIIC: Peritoneal metastasis beyond the pelvis > 2 cm in diameter. In Stage IV, the cancer has spread to distant organs, such as the lungs or liver.

[0097] As used herein "grades" or "grading" refers to how similar cancer cells look to normal cells and can help predict how the cancer will behave. Ovarian tumors that rarely spread are referred to as borderline or atypically proliferative tumors. In most ovarian cancer, tumors are divided into low-grade and high-grade and a grading number is not given. The most common type of ovarian cancer is high-grade serous carcinoma. There is also low-grade serous, which is less common. High grade tumors are also more likely to respond to chemotherapy compared to low grade tumors. All other ovarian cancers are graded as 1, 2, and 3. Grade 1 tumors are well differentiated cancers that have cells that closely look like normal cells and are less likely to spread or recur. Grade 2 tumors are moderately differentiated cancers and Grade 3 tumors are poorly differentiated cancers. Grades 2 and 3 show increasing difference of appearance compared to normal cells. They are also more likely to spread and recur. In some embodiments, 20   AZ Ref.: B7H1-620-WO-PCT   the methods, compositions, and combinations of the disclosure are used for the treatment of a subject with high-grade epithelial ovarian cancer. The methods, compositions, and combinations of the disclosure are used for the treatment of a subject with a stage III-IV high-grade epithelial ovarian cancer. As used herein "advanced ovarian cancer" is ovarian cancer that has spread beyond ovaries.

[0098] Ovarian cancer subjects are considered at higher risk for ovarian cancer due to Hereditary Breast and Ovarian Cancer Syndrome (HBOC). HBOC is an inherited genetic condition. There are 2 primary genes linked with most families who have HBOC: BRCA1 and BRCA2. A mutation in either BRCA1 or BRCA2 gives a woman an increased lifetime risk of developing breast and ovarian cancers. Men with these gene mutations also have an increased risk of breast cancer and prostate cancer. There is a slight increase in the risk of other cancers including pancreatic cancer and melanoma among subjects with BRCA1 or BRCA2 mutations. Mutations in the BRCA genes (BRCAm) can comprise either germline BRCA mutations (gBRCAm) or somatic / tumor BRCA mutations (tBRCAm).

[0099] BRCA mutations can result in homologous recombination deficiency (HRD). As used herein, "homologous recombination deficiency (HRD)" is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the homologous recombination repair (HRR) pathway. The majority of homologous recombination deficient (HRD) tumors will occur in patients with germline BRCA1 and BRCA2 mutations. However, there also are patients with germline mutations in other HR pathway genes and patients who do not carry an inherited germline mutation but have tumors with sporadic HRD mutations.

[0100] As used herein, "homologous recombination (HR)" refers to a process for repairing DNA double-strand breaks. Germline variants in the HR pathway, comprising at least 10 genes, such as BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, NBS1(NBN), PALB2, RAD51C, and RAD51D, lead to inherited susceptibility to specific types of cancers, including those of the breast, ovaries, prostate, and pancreas. In some embodiments, HRD status is assessed prospectively using the Myriad MyChoice CDx assay and a cutoff more than or equal to 42 for the genomic instability score can be used to determine if tumors are HRD-positive.

[0101] In some embodiments, the methods, compositions, and combinations of the disclosure are used for treating a subject with ovarian cancer wherein the ovarian cancer tumor lacks a BRCA1 / BRCA2 mutation (non-tBRCAm). The term "non-tBRCAm" may be defined as having 21   AZ Ref.: B7H1-620-WO-PCT   no detected or detectable deleterious mutation in BRCA1 or BRCA2. In other embodiments, the methods, compositions, and combinations of the disclosure are used for treating a subject with ovarian cancer wherein the ovarian cancer tumor comprises a BRCA1 / BRCA2 mutation (tBRCAm).

[0102] In some embodiments, the methods, compositions, and combinations of the disclosure are used for treating a subject with ovarian cancer wherein the ovarian cancer tumor is a homologous recombination deficiency (HRD) negative tumor. In other embodiments, the methods, compositions, and combinations of the disclosure are used for treating a subject with ovarian cancer wherein the ovarian cancer tumor is a homologous recombination deficiency (HRD) positive tumor.

[0103] Provided herein are methods of treating ovarian cancer in a subject in need thereof, comprising administering to the subject (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen- binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, a therapeutically effective amount of an anti- VEGF antibody or antigen-binding fragment thereof, and a therapeutically effective amount of a PARP inhibitor. In some embodiments herein, step (b) can exclude a therapeutically effective amount of a PARP inhibitor. In these embodiments, step (b) includes a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof.

[0104] In some embodiments, provided herein is a method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject an anti-VEGF antibody or antigen-binding fragment thereof at a dose of 10 mg / kg to 20 mg / kg, such as 15 mg / kg (or a flat dose of 800 mg to 1500 mg), the anti-PD-L1 antibody or antigen-binding fragment thereof at a dose of 10 mg / kg to 20 mg / kg (or a flat dose of 800 mg to 1500 mg, such as 1120 mg), and a PARP inhibitor at a dose of 100 mg to 300 mg.

[0105] Also provided herein are combinations for the treatment of ovarian cancer in a subject in need thereof, wherein the combination comprises (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF 22   AZ Ref.: B7H1-620-WO-PCT   antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof, and a therapeutically effective amount of a PARP inhibitor. In some embodiments herein, the combination of (b) can exclude a therapeutically effective amount of a PARP inhibitor. In these embodiments, the combination of (b) includes a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof and a therapeutically effective amount of an anti-VEGF antibody or antigen- binding fragment thereof.

[0106] In some embodiments, the combinations provided herein comprise an anti-VEGF antibody or antigen-binding fragment thereof at a dose of 10 mg / kg to 20 mg / kg, such as 15 mg / kg (or a flat dose of 800 mg to 1500 mg), the anti-PD-L1 antibody or antigen-binding fragment thereof at a dose of 10 mg / kg to 20 mg / kg (or a flat dose of 800 mg to 1500 mg, such as 1120 mg), and a PARP inhibitor at a dose of 100 mg to 300 mg.

[0107] The dose of the anti-VEGF antibody or antigen-binding fragment thereof, anti-PD-L1 antibody or antigen-binding fragment thereof, and the PARP inhibitor to be administered to the subject may vary depending, in part, upon the size (body weight, body surface, or organ size) and condition (the age and general health) of the subject.

[0108] In particular embodiments, the subject is administered one or more doses of the anti- VEGF antibody or antigen-binding fragment thereof, wherein the dose is 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 20 mg / kg, or 25 mg / kg. In some embodiments, the subject is administered one or more doses of the anti-VEGF antibody or antigen-binding fragment thereof wherein the dose is 15 mg / kg.

[0109] In particular embodiments, the subject is administered one or more flat doses of the anti-VEGF antibody or antigen-binding fragment thereof, wherein the dose is 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1120 mg, 1125mg, 1150 mg, 1175 mg, 1180 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575 mg, 1600 mg, 1625 mg, 1650 mg, 1675 mg, 1700 mg 1725 mg, 1750 mg, 1775 mg, 1800 mg, 1825 mg, 1850 mg, or 1875 mg. In some embodiments, the subject is administered one or more flat doses of the anti-VEGF antibody or antigen-binding fragment thereof wherein the dose is 1120 mg. 23   AZ Ref.: B7H1-620-WO-PCT

[0110] In particular embodiments, the subject is administered one or more doses of the anti- PD-L1 antibody or antigen-binding fragment thereof, wherein the dose is 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, or 15 mg / kg, 20 mg / kg, or 25 mg / kg. In some embodiments, the subject is administered one or more doses of the anti-PD-L1 antibody or antigen-binding fragment thereof wherein the dose is 15 mg / kg.

[0111] In particular embodiments, the subject is administered one or more flat doses of the anti-PD-L1 antibody or antigen-binding fragment thereof, wherein the dose is 500 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1120 mg, 1125mg, 1150 mg, 1175 mg, 1180 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575 mg, 1600 mg, 1625 mg, 1650 mg, 1675 mg, 1700 mg 1725 mg, 1750 mg, 1775 mg, 1800 mg, 1825 mg, 1850 mg, or 1875 mg. In some embodiments, the subject is administered one or more flat doses of the anti- PD-L1 antibody or antigen-binding fragment thereof wherein the dose is 1120 mg.

[0112] In particular embodiments, the subject is administered one or more flat doses of the PARP inhibitor, wherein the dose is 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg. In some embodiments, the subject is administered one or more flat doses of the PARP inhibitor wherein the dose is 300 mg. In some embodiments, a dose of from 100 mg to 300 mg of the PARP inhibitor is administered twice daily, thus, the PARP inhibitor is administered at a daily dose of from 200 mg to 600 mg. In other embodiments, the PARP inhibitor daily dose can be reduced.

[0113] In one particular non-limiting embodiment, step (a) comprises administration of 15 mg / kg of the anti-VEGF antibody or antigen-binding fragment thereof; and 1120 mg of the anti- PD-L1 antibody or antigen-binding fragment thereof.

[0114] In one particular non-limiting embodiment, step (b) comprises administration of 15 mg / kg of the anti-VEGF antibody or antigen-binding fragment thereof; 1120 mg of the anti-PD- L1 antibody or antigen-binding fragment thereof; and 300 mg of the PARP inhibitor.

[0115] The terms "co-administered," "in combination," or "combination therapy," as used herein, refer to simultaneous or sequential administration of multiple compounds or agents. A first compound or agent may be administered before, concurrently with, or after administration 24   AZ Ref.: B7H1-620-WO-PCT   of a second compound or agent; a third compound or agent may be administered before, concurrently with, or after administration of a first and / or second compound or agent; a fourth compound or agent may be administered before, concurrently with, or after administration of a first, second, and / or third compound or agent. The first compound or agent, the second compound or agent, the third compound or agent, and the fourth compound or agent may be simultaneously or sequentially administered on the same day, or may be sequentially administered within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, or 1 month of each other. In some embodiments, compounds or agents are co-administered during the period in which each of the compounds or agents are exerting at least some physiological effect and / or has remaining efficacy. In some embodiments, the anti-VEGF antibody or antigen- binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the one or more chemotherapy agents of step (a) are administered to the subject simultaneously, separately, and / or sequentially (e.g., separately, and sequentially). In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen- binding fragment thereof, and the PARP inhibitor of step (b) are administered to the subject simultaneously, separately, and / or sequentially (e.g., separately, and sequentially). In some embodiments, the anti-VEGF antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof of step (b) are administered to the subject simultaneously, separately, and / or sequentially (e.g., separately, and sequentially).

[0116] In particular embodiments, an initial step (step (a)) of the methods disclosed herein or an initial component of the combinations disclosed herein comprises a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD- L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof administered over a two week treatment period, over a three week treatment period, over a four week treatment period, over a five week treatment period, over a six week treatment period, over an eight week treatment period, over a twelve week treatment period, over a fourteen week treatment period, over a sixteen week treatment period, over an eighteen week treatment period, over a twenty-four week treatment period, or over a one-year or more treatment period. In particular embodiments, an initial step (step (a)) of the methods disclosed herein or an initial component of the combinations disclosed herein comprises a therapeutically effective amount of one or more chemotherapy 25   AZ Ref.: B7H1-620-WO-PCT   agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen- binding fragment thereof administered over a nine to fifteen-week treatment period.

[0117] In certain embodiments, a subsequent step (step (b)) of the methods disclosed herein or a subsequent component of the combinations disclosed herein comprises a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof, and optionally a therapeutically effective amount of a PARP inhibitor administered over a two week treatment period, over a three week treatment period, over a four week treatment period, over a five week treatment period, over a six week treatment period, over an eight week treatment period, over a twelve week treatment period, over a fourteen week treatment period, over a sixteen week treatment period, over an eighteen week treatment period, over a twenty-four week treatment period, over a six month treatment period, over an eight month treatment period, over a twelve month treatment period, over a fourteen month treatment period, over a fifteen month treatment period, over a sixteen month treatment period, over a eighteen month treatment period, over a twenty month treatment period, over a twenty four month treatment period or more. In certain embodiments, the anti-VEGF antibody or antigen-binding fragment thereof is administered over a one month to sixteen month or more treatment period; and the anti-PD-L1 antibody or antigen-binding fragment thereof and the optional PARP inhibitor is administered over a one month to twenty-four month or more treatment period. In certain embodiments, the anti-VEGF antibody or antigen-binding fragment thereof is administered over a fifteen month treatment period; and the anti-PD-L1 antibody or antigen-binding fragment thereof and PARP inhibitor is administered over a twenty-four month treatment period.

[0118] In particular embodiments of (a) of the methods, compositions, and combinations of the disclosure, a therapeutically effective amount of one or more chemotherapy agents is administered every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every ten weeks, or every twelve weeks; a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof is administered every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every ten weeks, or every twelve weeks; and a therapeutically effective amount of an anti-VEGF antibody 26   AZ Ref.: B7H1-620-WO-PCT   or antigen-binding fragment thereof is administered every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every ten weeks, or every twelve weeks.

[0119] In one particular embodiment of (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen- binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof is administered every three weeks.

[0120] In another particular embodiment of (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof is administered every three weeks for a minimum of three cycles and a maximum of five cycles. In another particular embodiment of (a), a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof is administered every three weeks for nine to fifteen weeks.

[0121] In particular embodiments of (b) of the methods, compositions, and combinations of the disclosure, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof is administered every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every ten weeks, or every twelve weeks; a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof is administered every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every ten weeks, or every twelve weeks; and a therapeutically effective amount of a PARP inhibitor is administered once, twice, or thrice daily.

[0122] In one particular embodiment of (b), a therapeutically effective amount of an anti-PD- L1 antibody or antigen-binding fragment thereof and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof is administered every three weeks.

[0123] In another particular embodiment of (b), a therapeutically effective amount of an anti- PD-L1 antibody or antigen-binding fragment thereof and a therapeutically effective amount of an 27   AZ Ref.: B7H1-620-WO-PCT   anti-VEGF antibody or antigen-binding fragment thereof is administered every three weeks; and a therapeutically effective amount of a PARP inhibitor is administered twice daily.

[0124] In another particular embodiment of (b), a therapeutically effective amount of an anti- PD-L1 antibody or antigen-binding fragment thereof is administered every three weeks for twenty-four months; and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof is administered every three weeks for fifteen months.

[0125] In another particular embodiment of (b), a therapeutically effective amount of an anti- PD-L1 antibody or antigen-binding fragment thereof is administered every three weeks for twenty-four months, and a therapeutically effective amount of a PARP inhibitor is administered twice daily for twenty-four months; and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof is administered every three weeks for fifteen months.

[0126] In particular embodiments, a therapeutically effective amount of one or more chemotherapy agents is administered for a minimum of four cycles and a maximum of six cycles. In one embodiment, the first cycle of the one or more chemotherapy agents alone or in combination with an anti-VEGF antibody or antigen-binding fragment thereof; is administered prior to (a). Therefore, in a particular embodiment, the therapeutically effective amount of one or more chemotherapy agents is administered for a minimum of three cycles and a maximum of six cycles. In particular embodiments, a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof (e.g., bevacizumab) is administered starting at the first cycle, alone or in combination with one or more chemotherapy agents, or starting at the second cycle and is given for up to 15 months for a total of up to 23 cycles. In particular embodiments, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof (e.g., durvalumab) is administered for a total of up to 24 months for a total of up to 35 cycles. In particular embodiments, a therapeutically effective amount of a PARP inhibitor (e.g., olaparib) is administered for a total of up to 24 months.

[0127] In particular embodiments, provided herein are methods, compositions, and combinations for the treatment of ovarian cancer in a subject in need thereof, wherein (a) a therapeutically effective amount of one or more chemotherapy agents is administered every three weeks for nine to fifteen weeks, an anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 1120 mg every three weeks for nine to fifteen weeks, and an anti- 28   AZ Ref.: B7H1-620-WO-PCT   VEGF antibody or antigen-binding fragment thereof is administered at a dose of 15 mg / kg every three weeks for nine to fifteen weeks; and (b) an anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 1120 mg every three weeks for twenty-four months, an anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose of 15 mg / kg every three weeks for a total of fifteen months, and an optional PARP inhibitor is administered at a dose of 300 mg twice daily for a total of twenty-four months.

[0128] In particular embodiments, provided herein are methods, compositions, and combinations for the treatment of ovarian cancer in a subject in need thereof, wherein (a) paclitaxel at a dose of 175 mg / m2and carboplatin at a dose of AUC5 or AUC6 are administered intravenously every three weeks for nine to fifteen weeks, durvalumab is administered intravenously at a dose of 1120 mg every three weeks for nine to fifteen weeks, and bevacizumab is administered intravenously at a dose of 15 mg / kg every three weeks for nine to fifteen weeks; and followed by (b) durvalumab is administered intravenously at a dose of 1120 mg every three weeks for twenty-four months, bevacizumab is administered intravenously at a dose of 15 mg / kg every three weeks for a total of fifteen months, and optionally olaparib is administered orally at a dose of 300 mg twice daily for a total of twenty-four months.

[0129] In particular embodiments, provided herein are methods, compositions, and combinations for the treatment of ovarian cancer in a subject in need thereof, wherein an initial step (step (a)) of the methods disclosed herein or an initial component of the combinations disclosed herein comprises administration of three to five doses of the anti-VEGF antibody or antigen-binding fragment thereof, three to five doses of the anti-PD-L1 antibody or antigen- binding fragment thereof, and three to five cycles of the one or more chemotherapy agents.

[0130] In particular embodiments, provided herein are methods, compositions, and combinations for the treatment of ovarian cancer in a subject in need thereof, wherein a subsequent step (step (b)) of the methods disclosed herein or a subsequent component of the combinations disclosed herein comprises administration of a dose of the anti-VEGF antibody or antigen-binding fragment thereof every three weeks for up to 15 months, a dose of the anti-PD- L1 antibody or antigen-binding fragment thereof every three weeks for up to 24 months, and optional twice daily doses of the PARP inhibitor for up to 24 months. 29   AZ Ref.: B7H1-620-WO-PCT

[0131] In certain embodiments of the disclosed methods, compositions, and / or combinations, step / combination (a) is administered prior to step / combination (b). In another embodiment, step / combination (b) is not administered until after completion of step / combination (a).

[0132] In certain embodiments the subject has completed one or more cycles of chemotherapy prior to administration of the disclosed methods, compositions, and / or combinations. In some embodiments, the subject has completed one, two, three, four or five cycles of chemotherapy prior to administration of the disclosed methods, compositions, and combinations. In another embodiment, one or more chemotherapeutic agents are administered prior to (a). In one non-limiting embodiment, the one or more chemotherapeutic agents administered prior to (a) are administered for 1 cycle. In one non-limiting embodiment, the one or more chemotherapeutic agents, alone or in combination with the anti-VEGF antibody or antigen-binding fragment thereof, administered prior to (a) are administered 3 weeks prior to the initiation of (a).

[0133] The terms "pharmaceutical composition" or "therapeutic composition," as used herein, refer to a compound or composition capable of inducing a desired therapeutic effect when properly administered to a subject. In some embodiments, the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one antibody of the disclosure.

[0134] The terms "pharmaceutically acceptable carrier" or "physiologically acceptable carrier," as used herein, refer to one or more formulation materials suitable for accomplishing or enhancing the delivery of one or more antibodies of the disclosure.

[0135] When used for in vivo administration, the formulations of the disclosure should be sterile. The formulations of the disclosure may be sterilized by various sterilization methods, including, for example, sterile filtration or radiation. In one embodiment, the formulation is filter sterilized with a presterilized 0.22-micron filter. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice as described in "Remington: The Science & Practice of Pharmacy," 21st ed., Lippincott Williams & Wilkins, (2005).

[0136] In some embodiments, antibodies can be formulated for particular routes of administration, such as oral, nasal, pulmonary, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The terms "parenteral administration" and "administered parenterally," as used herein, refer to modes of administration other than enteral 30   AZ Ref.: B7H1-620-WO-PCT   and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection, and infusion. Formulations of the disclosure that are suitable for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The antibodies and other actives may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required (see, e.g., U.S. Patent Nos.7,378,110; 7,258,873; and 7,135,180; U.S. Patent Application Publication Nos. 2004 / 0042972 and 2004 / 0042971).

[0137] The formulations can be presented in unit dosage form and can be prepared by any method known in the art of pharmacy. Actual dosage levels of the active ingredients in the formulation of the present disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject (e.g., "a therapeutically effective amount"). Dosages can also be administered via continuous infusion (such as through a pump). The administered dose may also depend on the route of administration. For example, subcutaneous administration may require a higher dosage than intravenous administration.

[0138] Without limiting the disclosure, a number of embodiments of the disclosure are described herein for purpose of illustration.

[0139] Embodiment 1. A method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject: (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen- binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, a therapeutically effective amount of an anti- VEGF antibody or antigen-binding fragment thereof, and a therapeutically effective amount of a PARP inhibitor.

[0140] Embodiment 2. A method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject: (a) a therapeutically effective amount of one or more 31   AZ Ref.: B7H1-620-WO-PCT   chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen- binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof and a therapeutically effective amount of an anti- VEGF antibody or antigen-binding fragment thereof.

[0141] Embodiment 3. The method of either embodiment 1 or embodiment 2, wherein step (b) occurs after completion of step (a).

[0142] Embodiment 4. The method of any one of embodiments 1-3, further comprising administering to the subject prior to step (a): (i) a therapeutically effective amount of one or more chemotherapy agents; or (ii) a therapeutically effective amount of one or more chemotherapy agents and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof.

[0143] Embodiment 5. The method of embodiment 4, further comprising administering to the subject prior to step (a): (i) at least 1 dose of a therapeutically effective amount of one or more chemotherapy agent; or (ii) at least 1 dose of a therapeutically effective amount of one or more chemotherapy agents and at least 1 dose of a therapeutically effective amount of an anti- VEGF antibody or antigen-binding fragment thereof.

[0144] Embodiment 6. The method according to any one of embodiments 1-5, wherein the anti-VEGF antibody or antigen-binding fragment thereof is bevacizumab.

[0145] Embodiment 7. The method according to any one of embodiments 1-6, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is durvalumab.

[0146] Embodiment 8. The method according to any one of embodiments 1-7, wherein the PARP inhibitor is olaparib.

[0147] Embodiment 9. The method according to any one of embodiments 1-8, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose of from 5 mg / kg to 20 mg / kg.

[0148] Embodiment 10. The method according to embodiment 9, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose of 15 mg / kg.

[0149] Embodiment 11. The method according to any one of embodiments 1-10, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of from 800 mg to 1500 mg. 32   AZ Ref.: B7H1-620-WO-PCT

[0150] Embodiment 12. The method according to embodiment 11, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 1120 mg.

[0151] Embodiment 13. The method according to any one of embodiments 1-10, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of from 10 mg / kg to 20 mg / kg.

[0152] Embodiment 14. The method according to embodiment 13, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 15 mg / kg.

[0153] Embodiment 15. The method according to any one of embodiments 1-14, wherein the PARP inhibitor is administered at a dose of between 100 mg and 300 mg.

[0154] Embodiment 16. The method according to embodiment 15, wherein the PARP inhibitor is administered at a dose of 300 mg.

[0155] Embodiment 17. The method according to any one of embodiments 1-16, wherein the one or more chemotherapy agents is paclitaxel and / or carboplatin.

[0156] Embodiment 18. The method according to any one of embodiments 1-17, wherein paclitaxel is administered at a dose of 175 mg / m2.

[0157] Embodiment 19. The method according to either embodiment 16 or embodiment 18, wherein carboplatin is administered at a dose that produces an Area Under of Curve (AUC) of AUC5 or AUC6.

[0158] Embodiment 20. The method according to any one of embodiments 1-19, wherein step (a) comprises administration of the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the one or more chemotherapy agents every two to four weeks.

[0159] Embodiment 21. The method according to embodiment 20, wherein step (a) comprises administration of a dose of the anti-VEGF antibody or antigen-binding fragment thereof, a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof, and a cycle of the one or more chemotherapy agents every two to four weeks for nine to eighteen weeks.

[0160] Embodiment 22. The method according to any one of embodiments 1 to 19, wherein step (a) comprises administration of a dose of the anti-VEGF antibody or antigen-binding fragment thereof, a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof, and a cycle of the one or more chemotherapy agents every three weeks. 33   AZ Ref.: B7H1-620-WO-PCT

[0161] Embodiment 23. The method according to embodiment 22, wherein step (a) comprises administration of a dose of the anti-VEGF antibody or antigen-binding fragment thereof, a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof, and a cycle of the one or more chemotherapy agents every three weeks for nine to fifteen weeks.

[0162] Embodiment 24. The method according to any one of embodiments 1-23, wherein step (a) comprises administration of three to five doses of the anti-VEGF antibody or antigen- binding fragment thereof, three to five doses of the anti-PD-L1 antibody or antigen-binding fragment thereof, and three to five cycles of the one or more chemotherapy agents.

[0163] Embodiment 25. The method according to any one of embodiments 1-24, wherein step (a) comprises administration of: 15 mg / kg of the anti-VEGF antibody or antigen-binding fragment thereof; and 1120 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof.

[0164] Embodiment 26. The method according to embodiment 25, wherein step (a) comprises administration of: 15 mg / kg of bevacizumab; and 1120 mg of durvalumab.

[0165] Embodiment 27. The method according to embodiment 26, wherein step (a) comprises administration of: 15 mg / kg of bevacizumab every 3 weeks; and 1120 mg of durvalumab every 3 weeks.

[0166] Embodiment 28. The method according to any one of embodiments 25-27, wherein step (a) further comprises administration of: 175 mg / m2of paclitaxel; and / or 25 mg / m2of cisplatin.

[0167] Embodiment 29. The method according to any one of embodiments 1-28, wherein step (b) comprises administration of a dose of the anti-VEGF antibody or antigen-binding fragment thereof and a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every two to four weeks.

[0168] Embodiment 30. The method according to any one of embodiments 1-29, wherein step (b) comprises administration of a dose of the anti-VEGF antibody or antigen-binding fragment thereof and a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every three weeks.

[0169] Embodiment 31. The method according to any one of embodiments 1-28, wherein step (b) comprises administration of: a dose of the anti-VEGF antibody or antigen-binding fragment thereof and a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every two to four weeks; and a dose of the PARP inhibitor twice daily. 34   AZ Ref.: B7H1-620-WO-PCT

[0170] Embodiment 32. The method according to any one of embodiments 1-29, wherein step (b) comprises administration of: a dose of the anti-VEGF antibody or antigen-binding fragment thereof and a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every three weeks; and a dose of the PARP inhibitor twice daily.

[0171] Embodiment 33. The method according to embodiment 22, wherein step (b) comprises administration of: a dose of the anti-VEGF antibody or antigen-binding fragment thereof every three weeks for up to 15 months; and a dose of the anti-PD-L1 antibody or antigen- binding fragment thereof every three weeks for up to 24 months.

[0172] Embodiment 34. The method according to embodiment 22, wherein step (b) comprises administration of: a dose of the anti-VEGF antibody or antigen-binding fragment thereof every three weeks for up to 15 months; a dose of the anti-PD-L1 antibody or antigen- binding fragment thereof every three weeks for up to 24 months; and twice daily doses of the PARP inhibitor for up to 24 months.

[0173] Embodiment 35. The method according to any one of embodiments 1-30 or 33, wherein step (b) comprises administration of: 15 mg / kg of the anti-VEGF antibody or antigen- binding fragment thereof; and 1120 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof.

[0174] Embodiment 36. The method according to embodiment 35, wherein step (b) comprises administration of: 15 mg / kg of bevacizumab every 3 weeks; and 1120 mg of durvalumab every 3 weeks.

[0175] Embodiment 37. The method according to any one of embodiments 1-28, 31, 32, or 34, wherein step (b) comprises administration of: 15 mg / kg of the anti-VEGF antibody or antigen-binding fragment thereof; 1120 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof; and 300 mg of the PARP inhibitor.

[0176] Embodiment 38. The method according to embodiment 37, wherein step (b) comprises administration of: 15 mg / kg of bevacizumab; 1120 mg of durvalumab; and 300 mg olaparib.

[0177] Embodiment 39. The method according to embodiment 38, wherein step (b) comprises administration of: 15 mg / kg of bevacizumab every 3 weeks; 1120 mg of durvalumab every 3 weeks; and 300 mg olaparib twice a day. 35   AZ Ref.: B7H1-620-WO-PCT

[0178] Embodiment 40. The method according to any one of embodiments 1-39, wherein the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen- binding fragment thereof, and the one or more chemotherapy agents are administered intravenously.

[0179] Embodiment 41. The method according to any one of embodiments 1-40, wherein the PARP inhibitor is administered orally.

[0180] Embodiment 42. The method according to any one of embodiments 1-41, wherein the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen- binding fragment thereof, and the one or more chemotherapy agents in step (a) are administered to the subject simultaneously, separately, and / or sequentially.

[0181] Embodiment 43. The method according to any one of embodiments 1-42, wherein the anti-VEGF antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof in step (b) are administered to the subject simultaneously, separately, and / or sequentially.

[0182] Embodiment 44. The method according to any one of embodiments 1-42, wherein the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen- binding fragment thereof, and the PARP inhibitor of step (b) are administered to the subject simultaneously, separately, and / or sequentially.

[0183] Embodiment 45. The method according to any one of embodiments 1-44, wherein the ovarian cancer is advanced ovarian cancer.

[0184] Embodiment 46. The method according to any one of embodiments 1-45, wherein the ovarian cancer is high-grade epithelial ovarian cancer.

[0185] Embodiment 47. The method according to any one of embodiments 1-46, wherein the ovarian cancer is an ovarian cancer tumor lacking a BRCA1 / BRCA2 mutation (non-tBRCAm).

[0186] Embodiment 48. The method according to any one of embodiments 1-47, wherein the ovarian cancer is an ovarian cancer tumor that is a homologous recombination deficiency (HRD) positive tumor.

[0187] Embodiment 49. The method according to any one of embodiments 1-47, wherein the ovarian cancer is an ovarian cancer tumor that is a homologous recombination deficiency (HRD) negative tumor. 36   AZ Ref.: B7H1-620-WO-PCT

[0188] Embodiment 50. The method according to any one of embodiments 1-49, wherein the treatment produces an increase in progression free survival in the subject compared to a patient who has only received bevacizumab and chemotherapy.

[0189] Embodiment 51. The method according to embodiment 50, wherein the treatment produces an increase in progression free survival for at least 4 months.

[0190] Embodiment 52. The method according to any one of embodiments 1-50, wherein the treatment produces an increase in overall survival in the subject compared to a patient who has only received bevacizumab and chemotherapy.

[0191] Embodiment 53. The method according to embodiment 52, wherein the treatment produces an increase in overall survival for at least 4 months.

[0192] Embodiment 54. A combination for use in the treatment of ovarian cancer in a subject in need thereof, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof, and a therapeutically effective amount of a PARP inhibitor.

[0193] Embodiment 55. A combination for use in the treatment of ovarian cancer in a subject in need thereof, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof.

[0194] Embodiment 56. The combination for use according to either embodiment 54 or embodiment 55, wherein the anti-VEGF antibody or antigen-binding fragment thereof is bevacizumab.

[0195] Embodiment 57. The combination for use according to any one of embodiments 54- 56, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is durvalumab. 37   AZ Ref.: B7H1-620-WO-PCT

[0196] Embodiment 58. The combination for use according to any one of embodiments 54, 56, or 57, wherein the PARP inhibitor is olaparib.

[0197] Embodiment 59. The combination for use according to any one of embodiments 54- 58, wherein the therapeutically effective amount of the anti-VEGF antibody or antigen-binding fragment thereof comprises a dose of from 5 mg / kg to 20 mg / kg.

[0198] Embodiment 60. The combination for use according to embodiment 59, wherein the dose of anti-VEGF antibody or antigen-binding fragment thereof is 15 mg / kg.

[0199] Embodiment 61. The combination for use according to any one of embodiments 54- 60, wherein the therapeutically effective amount of the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a dose of from 800 mg to 1500 mg.

[0200] Embodiment 62. The combination for use according to embodiment 61, wherein the dose of anti-PD-L1 antibody or antigen-binding fragment thereof is 1120 mg.

[0201] Embodiment 63. The combination for use according to any one of embodiments 54- 62, wherein the therapeutically effective amount of the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a dose of from 10 mg / kg to 20 mg / kg.

[0202] Embodiment 64. The combination for use according to embodiment 63, wherein the dose of anti-PD-L1 antibody or antigen-binding fragment thereof is 15 mg / kg.

[0203] Embodiment 65. The combination for use according to any one of embodiments 54- 64, wherein the therapeutically effective amount of PARP inhibitor comprises a dose of from 100 mg to 300 mg.

[0204] Embodiment 66. The combination for use according to embodiment 65, wherein the dose of PARP inhibitor is 300 mg.

[0205] Embodiment 67. The combination for use according to any one of embodiments 54- 66, wherein the one or more chemotherapy agents is paclitaxel and / or carboplatin.

[0206] Embodiment 68. The combination for use according to embodiment 67, wherein the therapeutically effective amount of paclitaxel comprises a dose of 175 mg / m2.

[0207] Embodiment 69. The combination for use according to either embodiment 67 or embodiment 68, wherein the therapeutically effective amount of carboplatin comprises a dose that produces an Area Under of Curve (AUC) of AUC5 or AUC6.

[0208] Embodiment 70. The combination for use according to any one of embodiments 54- 69, wherein administration of the anti-VEGF antibody or antigen-binding fragment thereof, the 38   AZ Ref.: B7H1-620-WO-PCT   anti-PD-L1 antibody or antigen-binding fragment thereof, and the one or more chemotherapy agents is every two to four weeks.

[0209] Embodiment 71. The combination for use according to embodiment 70, wherein administration is every two to four weeks for nine to eighteen weeks.

[0210] Embodiment 72. The combination for use according to either embodiment 70 or embodiment 71, wherein administration is every three weeks.

[0211] Embodiment 73. The combination for use according to embodiment 72, wherein administration is every three weeks for nine to fifteen weeks.

[0212] Embodiment 74. The combination for use according to any one of embodiments 54- 73, wherein administration of the anti-VEGF antibody or antigen-binding fragment thereof is four to six doses, administration of the anti-PD-L1 antibody or antigen-binding fragment thereof is three to five doses, and administration of the one or more chemotherapy agents is four to six doses.

[0213] Embodiment 75. The combination for use according to any one of embodiments 54- 74, wherein prior to administration of the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the one or more chemotherapy agents, the subject received: (i) the one or more chemotherapy agents; or (ii) the one or more chemotherapy agents and the anti-VEGF antibody or antigen-binding fragment thereof.

[0214] Embodiment 76. The combination for use according to embodiment 75, wherein prior to administration of the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the one or more chemotherapy agents, the subject received: (i) at least 1 dose of the one or more chemotherapy agents; or (ii) at least 1 dose of the one or more chemotherapy agents and at least 1 dose of the anti-VEGF antibody or antigen-binding fragment thereof, are administered to the subject.

[0215] Embodiment 77. The combination for use according to any one of embodiments 54- 76, wherein (a) comprises administration of: the anti-VEGF antibody or antigen-binding fragment thereof at a dose of 15 mg / kg; and the anti-PD-L1 antibody or antigen-binding fragment thereof at a dose of 1120 mg.

[0216] Embodiment 78. The combination for use according to embodiment 77, wherein: the anti-VEGF antibody or antigen-binding fragment thereof is bevacizumab and administration of 39   AZ Ref.: B7H1-620-WO-PCT   bevacizumab is at a dose of 15 mg / kg; and the anti-PD-L1 antibody or antigen-binding fragment thereof is durvalumab and administration of durvalumab is at a dose of 1120 mg.

[0217] Embodiment 79. The combination for use according to either embodiment 77 or embodiment 78, wherein: the anti-VEGF antibody or antigen-binding fragment thereof is bevacizumab and administration of bevacizumab is at a dose of 15 mg / kg every 3 weeks; and the anti-PD-L1 antibody or antigen-binding fragment thereof is durvalumab and administration of durvalumab is at a dose of 1120 mg every 3 weeks.

[0218] Embodiment 80. The combination for use according to any one of embodiments 77- 79, wherein (a) further comprises: 175 mg / m2of paclitaxel; and 25 mg / m2of cisplatin.

[0219] Embodiment 81. The combination for use according to any one of embodiments 54- 80, wherein (b) comprises administration of the anti-VEGF antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof every two to four weeks.

[0220] Embodiment 82. The combination for use according to any one of embodiments 54- 80, wherein (b) comprises administration of the anti-VEGF antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof every three weeks.

[0221] Embodiment 83. The combination for use according to any one of embodiments 54- 80, wherein (b) comprises administration of: the anti-VEGF antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof every two to four weeks; and the PARP inhibitor twice daily.

[0222] Embodiment 84. The combination for use according to any one of embodiments 54- 83, wherein (b) comprises administration of: the anti-VEGF antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof every three weeks; and the PARP inhibitor twice daily.

[0223] Embodiment 85. The combination for use according to any one of embodiments 54- 82, wherein (b) comprises administration of: the anti-VEGF antibody or antigen-binding fragment thereof at a dose of 15 mg / kg; and the anti-PD-L1 antibody or antigen-binding fragment thereof at a dose of 1120 mg.

[0224] Embodiment 86. The method according to embodiment 85, wherein (b) comprises administration of: a dose of the anti-VEGF antibody or antigen-binding fragment thereof every 40   AZ Ref.: B7H1-620-WO-PCT   three weeks for up to 15 months; and a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every three weeks for up to 24 months.

[0225] Embodiment 87. The combination for use according to embodiment 85, wherein: the anti-VEGF antibody or antigen-binding fragment thereof of (b) is bevacizumab and administration of bevacizumab is at a dose of 15 mg / kg; and the anti-PD-L1 antibody or antigen- binding fragment thereof of (b) is durvalumab and administration of durvalumab is at a dose of 1120 mg.

[0226] Embodiment 88. The combination for use according to either embodiment 85 or embodiment 86, wherein: the anti-VEGF antibody or antigen-binding fragment thereof of (b) is bevacizumab and administration of bevacizumab is at a dose of 15 mg / kg every 3 weeks; and the anti-PD-L1 antibody or antigen-binding fragment thereof of (b) is durvalumab and administration of durvalumab is at a dose of 1120 mg every 3 weeks.

[0227] Embodiment 89. The combination for use according to any one of embodiments 54- 80, 83, or 84, wherein: the anti-VEGF antibody or antigen-binding fragment thereof at a dose of 15 mg / kg; the anti-PD-L1 antibody or antigen-binding fragment thereof at a dose of 1120 mg; and the PARP inhibitor at a dose of 300 mg.

[0228] Embodiment 90. The combination according to embodiment 89, wherein (b) comprises administration of: a dose of the anti-VEGF antibody or antigen-binding fragment thereof every three weeks for up to 15 months; a dose of the anti-PD-L1 antibody or antigen- binding fragment thereof every three weeks for up to 24 months; and twice daily doses of the PARP inhibitor for up to 24 months.

[0229] Embodiment 91. The combination for use according to embodiment 89, wherein: the anti-VEGF antibody or antigen-binding fragment of (b) is bevacizumab and administration of bevacizumab is at a dose of 15 mg / kg; the anti-PD-L1 antibody or antigen-binding fragment thereof of (b) is durvalumab and administration of durvalumab is at a dose of 1120 mg; and the PARP inhibitor of (b) is olaparib and administration of olaparib is at a dose of 300 mg.

[0230] Embodiment 92. The combination for use according to either embodiment 89 or embodiment 90, wherein: the anti-VEGF antibody or antigen-binding fragment of (b) is bevacizumab and administration of bevacizumab is at a dose of 15 mg / kg every 3 weeks; the anti-PD-L1 antibody or antigen-binding fragment thereof of (b) is durvalumab and 41   AZ Ref.: B7H1-620-WO-PCT   administration of durvalumab is at a dose of 1120 mg every 3 weeks; and the PARP inhibitor of (b) is olaparib and administration of olaparib is at a dose of 300 mg twice a day.

[0231] Embodiment 93. The combination for use according to any one of embodiments 54- 92, wherein administration of the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the one or more chemotherapy agents is intravenous.

[0232] Embodiment 94. The combination for use according to any one of embodiments 54- 93, wherein administration of the PARP inhibitor is oral.

[0233] Embodiment 95. The combination for use according to any one of embodiments 54- 94, wherein administration of the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the one or more chemotherapy agents of (a) occurs simultaneously, separately, and / or sequentially.

[0234] Embodiment 96. The combination for use according to any one of embodiments 54- 95, wherein administration of the anti-VEGF antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof of (b) occurs simultaneously, separately, and / or sequentially.

[0235] Embodiment 97. The combination for use according to any one of embodiments 54- 95, wherein administration of the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the PARP inhibitor of (b) occurs simultaneously, separately, and / or sequentially.

[0236] Embodiment 98. The combination for use according to any one of embodiments 54- 97, wherein the ovarian cancer is advanced ovarian cancer.

[0237] Embodiment 99. The combination for use according to any one of embodiments 54- 98, wherein the ovarian cancer is high-grade epithelial ovarian cancer.

[0238] Embodiment 100. The combination for use according to any one of embodiments 54- 99, wherein the ovarian cancer is an ovarian cancer tumor lacking a BRCA1 / BRCA2 mutation (non-tBRCAm).

[0239] Embodiment 101. The combination for use according to any one of embodiments 54- 100, wherein the ovarian cancer is an ovarian cancer tumor that is a homologous recombination deficiency (HRD) positive tumor. 42   AZ Ref.: B7H1-620-WO-PCT

[0240] Embodiment 102. The combination for use according to any one of embodiments 54- 100, wherein the ovarian cancer is an ovarian cancer tumor that is a homologous recombination deficiency (HRD) negative tumor.

[0241] Embodiment 103. The combination for use according to any one of embodiments 54- 102, wherein treatment with the combination produces an increase in progression free survival in the subject compared to a patient who has only received bevacizumab and chemotherapy.

[0242] Embodiment 104. The combination for use according to embodiment 103, wherein the treatment produces an increase in progression free survival for at least 4 months.

[0243] Embodiment 105. The combination for use according to any one of embodiments 54- 102, wherein treatment with the combination produces an increase in overall survival in the subject compared to a patient who has only received bevacizumab and chemotherapy.

[0244] Embodiment 106. The combination for use according to embodiment 105, wherein the treatment produces an increase in overall survival for at least 4 months.

[0245] Embodiment 107. Use of a combination in the manufacture of a medicament for the treatment of ovarian cancer in a subject in need thereof, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, a therapeutically effective amount of an anti-VEGF antibody or antigen- binding fragment thereof, and a therapeutically effective amount of a PARP inhibitor.

[0246] Embodiment 108. Use of a combination in the manufacture of a medicament for the treatment of ovarian cancer in a subject in need thereof, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof and a therapeutically effective amount of an anti-VEGF antibody or antigen- binding fragment thereof. 43   AZ Ref.: B7H1-620-WO-PCT   EXAMPLES

[0247] The Examples that follow are illustrative of specific embodiments of the disclosure, and various uses thereof. They are set forth for explanatory purposes only and should not be construed as limiting the scope of the disclosure in any way.   Example 1: Interim Analysis 1 (DCO - 5 Dec 2022) -Durvalumab with paclitaxel / carboplatin and bevacizumab followed by maintenance with durvalumab, bevacizumab and olaparib in patients with newly diagnosed advanced ovarian cancer without a tumor BRCA1 / BRCA2 mutation

[0248] The Phase III DUO-O study evaluates paclitaxel / carboplatin + bevacizumab + durvalumab followed by maintenance therapy with bevacizumab + durvalumab + olaparib in patients with newly diagnosed non-tBRCAm advanced OC including progression free survival analysis from the DUO-O study.

[0249] DUO-O enrolled patients who had not previously received systemic therapy and were PARP inhibitor and immune-mediated therapy naïve. Additionally, patients with no tumor BRCA mutation could be enrolled if they had stable disease. 1. Methods

[0250] As shown in Figure 1, following completion of one cycle of chemotherapy, patients were randomized 1:1:1 to Arms 1, 2 or 3. Randomization was stratified by timing and outcome of cytoreductive surgery and geographical region. Homologous recombination deficiency, or HRD, status was not a stratification factor at randomization in DUO-O. Arm 1, the control arm, consisted of paclitaxel / carboplatin plus bevacizumab followed by maintenance bevacizumab. Arm 2 consisted of paclitaxel / carboplatin plus bevacizumab plus durvalumab followed by maintenance bevacizumab plus durvalumab. Arm 3 consisted of paclitaxel / carboplatin plus bevacizumab plus durvalumab followed by maintenance bevacizumab plus durvalumab plus olaparib.

[0251] All patients who completed the chemotherapy phase could proceed to the maintenance phase and treatment continued until investigator-assessed disease progression, study treatment completion or other discontinuation criteria were met. 44   AZ Ref.: B7H1-620-WO-PCT

[0252] As shown in Figure 2, the primary endpoints in DUO-O were PFS as assessed by the investigator in Arm 3, the olaparib containing arm, versus Arm 1, the chemotherapy plus bevacizumab backbone arm, first in the non-tumor BRCA-mutated HRD-positive population, and then in the intent-to-treat, or ITT population. HRD status was assessed prospectively using the Myriad MyChoice CDx assay and a cutoff more than or equal to 42 for the genomic instability score was used to determine HRD if tumors were HRD-positive.

[0253] Key secondary endpoints included PFS in Arm 2, the durvalumab arm versus Arm 1, the chemotherapy plus bevacizumab backbone in the ITT population, overall survival, or OS, and safety.

[0254] As shown in Figure 3, the planned sample size was approximately 1,104 and the superiority interim PFS analysis was planned for when approximately 86% of target PFS events had occurred for Arm 3 versus Arm 1 in both the non-tumor BRCA-mutated HRD-positive and ITT populations.

[0255] Non-tBRCAm cohort

[0256] Approximately 1104 patients with no deleterious / suspected deleterious mutation in BRCA1and BRCA2 will be randomized 1:1:1 to receive a further 5 cycles of platinum-based chemotherapy (in combination with berncizumab followed by bevacizumab maintenance for up to a total of cycles (15 months) of treatment. For the China cohort, approximately 120 non- tBRCAm patient randomized (1:1:1) from sites in China will be required. If necessary, the China cohort will continue recruiting patient after recruitment to the Global population closes at approximately 1104 patients. Investigational treatment will be given as specified below:

[0257] (i) Arm 1 (SoC): Patient in Arm 1 will receive saline IV Q3W as a placebo for durvalumab from Day 1 of Cycle 2 for up to a total of 35 cycles (24 months) of treatment. At the end of chemotherapy, patients will also receive placebo tablet, matched to olaparib for up to a total of 24 months.

[0258] (ii) Arm 2: Patient in Arm 2 will receive durvalumab 1120 mg Q3W from Day 1 of Cycle 2 for up to a total of 35 cycles (24 months) of treatment. At the end of chemotherapy, patients will also receive placebo tablets, matched to olaparib for up to a total of 24 months.

[0259] (iii) Arm 3: Patients in Arm 3 will receive durvalumab 1120 mg Q3W from Day 1 of Cycle 2 for up to a total of 35 cycles (24 months) of treatment. At the end of chemotherapy, patients will also receive olaparib tablets, 300 mg mice daily (bd) for up to a total of 24 months. 45   AZ Ref.: B7H1-620-WO-PCT

[0260] The DUO-O trial used a multiple testing procedure. 5% alpha was allocated to comparing PFS in Arm 3, the olaparib arm versus Arm 1, the chemotherapy plus bevacizumab backbone, in the non-tumor BRCA mutated HRD positive population. As statistical significance was reached, 5% alpha was allocated to comparing PFS in Arm 3 versus Arm 1 in the ITT population. PFS in Arm 2, the durvalumab arm versus Arm 1 in the ITT population was assessed but will be reassessed at the final PFS analysis. As shown in Figure 4, in DUO-O, over 90% of patients had known HRD status. At baseline, patient characteristics were well balanced between treatment arms. Across all arms, approximately 90% of patients completed all planned cycles of chemotherapy. 88%, 86% and 80% of patients in Arms 1, 2 and 3, respectively started the maintenance phase (Figure 5).

[0261] In the HRD-positive population, the median duration of follow-up in censored patients was 25.6 months in Arm 3 versus 28.8 months in Arm 1 and data maturity was 35% and 60%, respectively. 2. Results

[0262] DUO-O met its primary endpoint at the planned progression free survival interim analysis, demonstrating statistically significant and clinically meaningful improvement in progression free survival with first line chemotherapy + bevacizumab + durvalumab followed by maintenance bevacizumab + durvalumab + olaparib compared with control in patients with advanced OC.

[0263] Non-tBRCAm HRD-positive: HR 0.49 (0.34–0.69); P<0.0001.

[0264] Non-tBRCAm ITT: HR 0.63 (0.52–0.76); P<0.0001.

[0265] Consistent progression free survival benefit was observed across subgroups, including those patients with HRD-negative disease (HR 0.68 [0.54–0.86]).

[0266] A numerical, but not statistical improvement in PFS was shown with chemotherapy + bevacizumab + durvalumab followed by maintenance bevacizumab + durvalumab compared with control in the non-tBRCAm ITT population at the time of the PFS interim analysis.

[0267] Safety was generally consistent with the known profiles of each individual agent.

[0268] A statistically significant improvement in PFS was observed between Arm 3 and Arm 1. Median PFS was 37.3 months and 23.0 months, respectively and the hazard ratio, or HR, was 0.49. At 18 months, the PFS rates were 84% in Arm 3 compared with 69% in Arm 1 (Figure 6). Similarly, in the ITT population a statically significant improvement in PFS was observed 46   AZ Ref.: B7H1-620-WO-PCT   between Arm 3 and Arm 1. Median PFS was 24.2 months in Arm 3, compared with 19.3 months in Arm 1 and the HR was 0.63. Results for the ITT population were slightly more mature than for the HRD positive population, with data maturity of 51% and 69% in Arms 3 and 1, respectively (Figure 7). A numerical improvement in PFS was observed in Arm 2 versus Arm 1, but statistical significance was not reached. At 18 months, the PFS rates were 71% in Arm 3, 56% in Arm 2 and 55% in Arm 1 (Figure 8).

[0269] As an unstratified Cox proportional hazard model was used for these analyses, there are numerical differences between the HR and 95% CI for the HRD-positive data presented here and the analysis for the primary endpoint shown earlier. A PFS benefit was observed in the HRD-negative population with median PFS of 17.4 months in Arm 1, and 20.9 months in Arm 3. For the PFS comparison between Arms 3 and 1, the HR was 0.68 in the HRD negative subgroup (Figure 9). In Arm 2, median PFS was 15.4 months in the HRD-negative population (Figure 9)

[0270] The forest plot shows a consistent PFS effect across subgroups for the ITT population in Arms 3 versus 1 (Figure 10).

[0271] During both the chemotherapy phase and maintenance phase, the incidence of serious adverse events was similar across all treatment arms (Figure 11). The incidence of myelodysplastic syndrome and acute myeloid leukemia, which are adverse events of special interest for olaparib, was low, consistent with previous Phase III trials in the first-line setting. The incidence of new primary malignancies and pneumonitis were also low. Immune-mediated adverse events were reported throughout the study, with a higher numerical proportion of patients in Arms 2 and 3 experiencing such events (Figure 11).

[0272] Overall, the discontinuation rates differed between the treatment arms, with a numerically higher proportion of patients discontinuing any treatment because of an adverse event in Arm 3. 35% of patients in Arm 3, 26% in Arm 2 and 20% in Arm 1 discontinued any treatment because of an adverse event (Figure 11).

[0273] Figure 12 shows adverse events of any grade with a frequency of greater than or equal to 20%. During the maintenance phase in Arm 3, the most common adverse events were nausea and anemia, reported in 52% and 41% of patients, respectively. During the same period in Arm 2, nausea and anemia were reported in 17% and 10% of patients, respectively, and in Arm 1, were reported in 15% and 5% of patients, respectively. 47   AZ Ref.: B7H1-620-WO-PCT

[0274] Similarly, when looking at adverse events of grade 3 or higher with an overall incidence of greater than or equal to 5%, neutropenia and anemia were the most common event in Arm 3 (Figure 13). During the maintenance phase, anemia of grade 3 or higher was reported in 21% of patients, compared with less than 1% in both Arms 2 and 1. Other adverse events of grade 3 or higher included leukopenia, hypertension and thrombocytopenia. These adverse events align with those anticipated for the DUO-O treatment regimens (Figure 13).

[0275] DUO-O demonstrated a statistically significant and clinically meaningful improvement in PFS with first-line chemotherapy plus bevacizumab plus durvalumab followed by maintenance bevacizumab plus durvalumab plus olaparib, Arm 3 versus chemotherapy plus bevacizumab followed by maintenance bevacizumab, Arm 1 in patients with non-tumor BRCA- mutated advanced ovarian cancer. In the non-tumor BRCA-mutated HRD-positive population, the HR for PFS for Arm 3 versus Arm 1 was 0.49 and in the ITT population, the HR for PFS was 0.63. A consistent PFS benefit for Arm 3 versus Arm 1 across subgroup analyses, including for patients with HRD-negative disease is reported. The HR for PFS for Arm 3 versus Arm 1 was 0.68 in the HRD-negative subgroup.

[0276] A numerical, but not statistically significant, improvement in PFS was shown with chemotherapy plus bevacizumab plus durvalumab followed by maintenance bevacizumab plus durvalumab, Arm 2, versus chemotherapy plus bevacizumab followed by maintenance bevacizumab, Arm 1 in the ITT population.

[0277] The safety and tolerability of these combinations was generally consistent with that observed in prior clinical trials and the known profiles of the individual agents.

[0278] The DUO-O trial provide encouraging evidence for the combination chemotherapy plus bevacizumab plus durvalumab, followed by maintenance therapy with bevacizumab plus durvalumab plus olaparib in patients with non-tumor BRCA-mutated advanced ovarian cancer. Example 2: Updated Analysis: Durvalumab with paclitaxel / carboplatin and bevacizumab followed by maintenance with durvalumab, bevacizumab and olaparib in patients with newly diagnosed advanced ovarian cancer without a tumor BRCA1 / BRCA2 mutation

[0279] DUO-O met its primary endpoints, with carboplatin / paclitaxel, bevacizumab plus durvalumab followed by maintenance bevacizumab, durvalumab plus olaparib providing a statistically significant and clinically meaningful progression-free survival benefit over 48   AZ Ref.: B7H1-620-WO-PCT   carboplatin / paclitaxel plus bevacizumab followed by maintenance bevacizumab in both the non- tBRCAm homologous recombination deficiency-positive and intention-to-treat populations. The safety profiles observed in the experimental arms were generally consistent with the individual agents. 1. Methods

[0280] Materials and methods are as outlined in Example 1

[0281] Randomization and Treatment

[0282] All patients received Cycle 1 of chemotherapy while tBRCAm status was determined (Figure 15). During Cycle 1 of chemotherapy, patients received carboplatin area under the serum-concentration-time curve (AUC) of 5 or 6 intravenously and intravenous paclitaxel 175 mg / m2. Cycle 1 could also include intravenous bevacizumab 15 mg / kg according to local practice.

[0283] Once BRCAm status was known, and prior to Cycle 2 of chemotherapy, non-tBRCA patients were randomized (1:1:1) to receive paclitaxel 175 mg / m2every 3 weeks, carboplatin at an AUC of 5 or 6 every 3 weeks (six cycles in total) and bevacizumab 15 mg / kg every 3 weeks plus durvalumab placebo followed by maintenance bevacizumab 15 mg / kg every 3 weeks (total of 15 months), durvalumab placebo plus olaparib placebo (control arm); carboplatin / paclitaxel, bevacizumab plus intravenous durvalumab 1120 mg every 3 weeks followed by maintenance bevacizumab, durvalumab 1120 mg every 3 weeks (total of 24 months) plus olaparib placebo (durvalumab arm); or carboplatin / paclitaxel, bevacizumab plus durvalumab followed by maintenance bevacizumab, durvalumab plus olaparib tablets 300 mg twice daily (total of 24 months) (durvalumab+olaparib arm). Randomization was stratified according to the timing and outcome of debulking surgery (no macroscopic residual disease after upfront surgery v macroscopic residual disease after upfront or planned interval debulking surgery) and geographic region (North America v Europe v rest-of-world).

[0284] Study treatment continued until patients experienced objective radiologic disease progression (modified RECIST v1.1), met other discontinuation criteria, or had completed the stated duration(s) of study treatment(s). Patients without objective disease progression during the chemotherapy phase who met other prespecified requirements could start maintenance therapy. Patients who discontinued one or more study treatment(s) because of an adverse event 49   AZ Ref.: B7H1-620-WO-PCT   (AE) considered attributable to one of the study treatments but not the others could continue to receive the remaining study treatment(s).

[0285] Patients who were unable to start maintenance olaparib / placebo within 9 weeks from the last day of chemotherapy infusion continued durvalumab / placebo and bevacizumab as maintenance therapy. Durvalumab / placebo also continued during the 3- to 9-week window after the last day of chemotherapy infusion, if the olaparib / placebo start criteria had not yet been met.

[0286] Patients with stable disease at the end of maintenance therapy could continue to receive study treatment.

[0287] Outcomes and Assessments

[0288] During study conduct, in response to the publication of results from other studies6,10,14,15together with the establishment of homologous recombination deficiency (HRD) status as a clinically relevant biomarker in newly diagnosed ovarian cancer, the durvalumab+olaparib arm was prioritized and the primary endpoint was amended on June 11, 2021 to progression-free survival (PFS; the time from randomization to investigator-assessed progression [modified RECIST v1.1] or death) in the durvalumab+olaparib versus control arms; PFS was formally statistically tested in a fixed hierarchal sequence in the non-tBRCAm HRD- positive population (defined as a GIS of ≥42) and then in the intention-to-treat population. PFS in the durvalumab versus control arms in the intention-to-treat population was a key secondary endpoint included in the hierarchical testing procedure. Prespecified sensitivity and subgroup analyses of PFS were conducted.

[0289] Secondary endpoints included investigator-assessed PFS in the durvalumab versus control arms in the intention-to-treat population; overall survival (OS; the time from randomization to death) in the durvalumab+olaparib versus control arms in the non-tBRCAm HRD-positive and intention-to-treat populations and in the durvalumab versus control arms in the intention-to-treat population; time from randomization to second progression (investigator assessment of radiologic, clinical, or CA-125 progression) or death (PFS2)

[0290] Tumor Assessments

[0291] Patients' tumors were assessed by CT or magnetic resonance imaging (MRI), according to modified RECIST v1.1. Baseline scans were performed no more than 28 days before the start of Cycle 1 of chemotherapy (patients undergoing primary debulking surgery had the baseline scan after surgery) and patients undergoing interval debulking surgery had an 50   AZ Ref.: B7H1-620-WO-PCT   additional scan prior to surgery. Subsequent scans were performed within 3 weeks (±1 week) after the last dose of chemotherapy but before the start of maintenance therapy, then every 12 weeks (±2 weeks) for up to 3 years, and then every 24 weeks (±2 weeks), relative to the date of the end of chemotherapy assessment scan, until objective radiologic disease progression. All treatment decisions were based on site assessment of scans. Following disease progression assessment of disease was as per local clinical practice. 2. Results

[0292] 1,130 non-tBRCAm patients were randomized between January 30, 2019 and June 17, 2021. 376 of 378 patients assigned to the control arm, 373 of 374 patients assigned to the durvalumab arm, and 378 of 378 patients assigned to the durvalumab+olaparib arm received at least one dose of investigational treatment; 331, 323, and 336 patients, respectively, started the maintenance phase (Figure 14).

[0293] The DCOs for the interim and final PFS analyses occurred per-protocol on December 5, 2022 and September 18, 2023, respectively. The number of patients still receiving investigational treatment at DCO is shown in Figures 14A and 14B.

[0294] Baseline characteristics were well balanced between treatment arms in the intention- to-treat (Table 1) and non-tBRCAm HRD-positive (Table 1) populations.

[0295] The median (range) duration of follow-up for PFS in censored patients in the intention-to-treat population was 25.5 (0.0-44.8), 23.1 (0.0-42.6), and 23.3 (0.0-41.7) months in the control, durvalumab, and durvalumab+olaparib arm at the interim PFS analysis, and 34.5 (0.0-51.6), 33.1 (0.0-50.8), and 32.0 (0.0-51.3) months, respectively, at the final PFS analysis.

[0296] At the prespecified interim PFS analysis in the non-tBRCAm HRD-positive population, 135 of 283 patients had PFS events (data maturity, 47.7%); 135 (90.6%) of the 149 target PFS events had occurred. Median PFS was 37.3 months in the durvalumab+olaparib arm and 23.0 months in the control arm (HR, 0.49 [95% CI, 0.34-0.69]; P<.0001) (Figure 16A). In the intention-to-treat population, 452 of 756 patients had PFS events (data maturity, 59.8%); 452 (99.8%) of 453 target PFS events had occurred. Median PFS was 24.2 months in the durvalumab+olaparib arm and 19.3 months in the control arm (HR, 0.63 [95% CI, 0.52-0.76]; P<.0001) (Figure 16B).

[0297] As the primary endpoints were met, this interim PFS analysis (Example1) (DCO: December 5, 2022) was the primary analysis and the final PFS analysis in these treatment arms 51   AZ Ref.: B7H1-620-WO-PCT   (DCO: September 18, 2023) was descriptive. The improvement in PFS was sustained at the final descriptive PFS analysis, with HRs for PFS in the durvalumab+olaparib versus control arms of 0.46 (95% CI, 0.33-0.65) in the non-tBRCAm HRD-positive population (Figure 16C) and 0.61 (95% CI, 0.51-0.73) in the intention-to-treat population (Figure 16D).

[0298] PFS for the durvalumab arm in the intention-to-treat population at the interim / primary PFS analysis is shown in Figure 16B. This treatment arm was reassessed at the final PFS analysis, at which time median PFS was 20.6 and 19.3 months in the durvalumab versus control arms, respectively (HR, 0.87 [95% CI, 0.74-1.03]; P=.11) (Figure 16D).

[0299] The interim and final PFS analyses were supported by results of prespecified sensitivity analyses. In prespecified subgroup analyses, PFS favored the durvalumab+olaparib arm over control in all subgroups other than the tumor area positivity (TAP5; PD-L1 expression) unknown subgroup (Figure 18 and 19A). A PFS benefit was seen in the durvalumab+olaparib versus control arms in the subgroup of patients with HRD-negative tumors at both the interim (HR, 0.68 [95% CI, 0.58-0.86]) and final (HR, 0.68 [95% CI, 0.54-0.85]) PFS analyses (Figures 21A and 21B). Results of prespecified subgroup analyses comparing the durvalumab and control arms are shown in Figure 19B and 19C.

[0300] The HR (95% CI) for PFS2 was 0.82 (0.67-1.01) for the durvalumab+olaparib arm versus control and 0.91 (0.75-1.12) for the durvalumab arm versus control in the intention-to- treat population (Figure 20A) and 0.66 (0.43-1.00) in the durvalumab+olaparib arm versus control in the non-tBRCAm HRD-positive population (Figure 20B) (DCO: September 18, 2023). PFS2 in the HRD-negative subgroup is shown in Figure 21C. Interim OS data were immature (DCO: September 18, 2023). In the intention-to-treat population, 432 of 1,130 patients had died (data maturity, 38.2%). Median OS was 72.9 and 72.5 months in the durvalumab+olaparib versus control arms, respectively (HR, 0.95 [95% CI, 0.76-1.20]; P=.68) and 71.6 and 72.5 months in the durvalumab versus control arms, respectively (HR, 0.92 [95% CI, 0.73-1.16]) (Figure 20C). In the non-tBRCAm HRD-positive population, 65 of 283 patients had died (data maturity, 23.0%). Median OS was not reached in the durvalumab+olaparib and control arms (HR, 0.84 [95% CI, 0.51-1.37]) (Figure 20D). In the HRD-negative subgroup, median OS was 41.1 and 39.6 months in the durvalumab+olaparib versus control arms, respectively (HR, 0.99 [95% CI, 0.76-1.31]) (Figure 21D). 52   AZ Ref.: B7H1-620-WO-PCT

[0301] Overall, grade ≥3 AEs were reported in 62.0%, 66.0%, and 72.0% of patients in the control, durvalumab, and durvalumab+olaparib arms, respectively.

[0302] Serious AEs were reported in 35.1%, 44.2% and 39.7% of patients in the control, durvalumab, and durvalumab+olaparib arms, respectively, and AEs with an outcome of death regardless of causality were reported in 1.1%, 2.4%, and 2.1% of patients, respectively.

[0303] MDS / AML was reported in 1 (0.3%), 0, and 3 (0.8%) patients in the control, durvalumab, and durvalumab+olaparib arms, respectively; new primary malignancies were reported in 3 (0.8%), 1 (0.3%), and 5 (1.3%) patients, respectively, and pneumonitis was reported in 3 (0.8%), 5 (1.3%), and 7 (1.9%) of patients, respectively. Pure red cell aplasia and autoimmune hemolytic anemia were each reported in 2 (0.5%) patients in the durvalumab plus olaparib arm, with no cases reported in the durvalumab or control arms.

[0304] Immune-mediated AEs were reported in 35.1%, 56.6%, and 54.0% of patients in the control, durvalumab, and durvalumab+olaparib arms, respectively.

[0305] AEs were usually managed by dose modification rather than by discontinuation. Overall, discontinuation of study treatment because of AEs occurred in 21.5%, 26.3%, and 34.7% of patients in the control, durvalumab, and durvalumab+olaparib arms, respectively.

[0306] PC + bev + durva followed by bev + durva + ola mtx continued to demonstrate improvement in PFS, with the longest mPFS of 45.1 mo in the non-tBRCAm HRD positive population, and an associated favorable OS trend. 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Arm 1 Arm 2 Arm 3 (control arm) (durva arm) (durva + ola arm) PC + bev PC + bev + durva PC + bev + durva + ola mtx Non-tBRCAm HRD-positive* PFS events, n / N (%) 94 / 143 (65.7) 89 / 148 (60.1) 57 / 140 (40.7) Median PFS, mo 23.3 25.1 45.1 HR (95% CI)†0.89 (0.67–1.19) 0.46 (0.33–0.65) 24 mo PFS, % 46.5 50.9 72.9 OS events, n / N (%) 35 / 143 (24.5) 24 / 148 (16.2) 30 / 140 (21.4) Median OS, mo NR NR NR HR (95% CI)†0.69 (0.41–1.15) 0.84 (0.51–1.37) 24 mo OS, % 88.6 91.7 96.4 Non-tBRCAm ITT PFS events, n / N (%) 283 / 378 (74.9) 257 / 374 (68.7) 221 / 378 (58.5) Median PFS, mo 19.3 20.6 25.1 HR (95% CI)†0.87 (0.74–1.03) 0.61 (0.51–0.73) P=0.11§24 mo PFS, % 33.2 38.7 53.0 OS events, n / N (%) 150 / 378 (39.7) 137 / 374 (36.6) 145 / 378 (38.4) Median OS, mo 48.0 NR 48.5 HR (95% CI)†‖0.92 (0.73–1.16) 0.95 (0.76–1.20) P=0.68¶24 mo OS, % 79.8 81.2 83.3 HRD-negative** PFS events, n / N (%) 173 / 216 (80.1) 152 / 199 (76.4) 144 / 211 (68.2) Median PFS, mo 17.5 15.4 21.1 HR (95% CI)†‖0.92 (0.74–1.14) 0.68 (0.54–0.85) 24 mo PFS, % 26.1 30.9 41.1 59   AZ Ref.: B7H1-620-WO-PCT   OS events, n / N (%) 103 / 216 (47.7) 103 / 199 (51.8) 101 / 211 (47.9) Median OS, mo 39.6 37.9 41.1 HR (95% CI)†‖1.05 (0.80–1.38) 0.99 (0.76–1.31) 24 mo OS, % 76.9 73.0 76.4 *Defined as a GIS ≥42 (Myriad MyChoice®CDx assay).†vs Arm 1. HR and CI were estimated from a stratified Cox proportional hazards model (stratified by the timing and outcome of cytoreductive surgery [non-tBRCAm HRD-positive population] or by the timing and outcome of cytoreductive surgery and geographic region [non-tBRCAm ITT population]).§Testing boundary: 2-sided P<0.0248.‖HR and CI were estimated from an unstratified Cox proportional hazards model.¶Testing boundary: 2-sided P<0.0104. **Defined as a GIS <42 (Myriad MyChoice®CDx assay). CI, confidence interval; GIS, genomic instability score; HR, hazard ratio; ITT, intent-to-treat; NR, not reached; tBRCAm, tumor BRCA1 / BRCA mutation. Example 3: Interim Analysis 2 (DCO2 – 18 Sep 2023) PFS analysis for Durvalumab (D) + paclitaxel / carboplatin (PC) + bevacizumab (B) followed by D, B + olaparib (O) maintenance (mtx) for newly diagnosed advanced ovarian cancer (AOC) without a tumour BRCA1 / BRCA2 mutation (tBRCAm)

[0307] DUO-O, a placebo-controlled study, showed statistically significant, clinically meaningful PFS benefit with D + PC + B followed by D + B + O mtx vs PC + B followed by B in non-tBRCAm HRD+ and non-tBRCAm ITT populations 1. Methods

[0308] Patients (pts) had newly diagnosed high-grade epithelial AOC and primary or planned interval debulking surgery. After 1 cycle of PC ± B, pts with non-tBRCAm AOC were randomized 1:1:1, stratified by timing and outcome of cytoreductive surgery (no macroscopic residual disease after upfront primary surgery and all others), and geographic region (North America, Europe, and other regions), to Arm 1 (control): PC + B followed by B; Arm 2: PC + B + D followed by B + D; or Arm 3: PC + B + D followed by B + D + O mtx. We present final descriptive PFS and subgroup analyses (Arm 3 vs 1); secondary endpoints of PFS (Arm 2 vs 1; non-tBRCAm ITT) and interim OS (both formally tested per the predefined multiple testing procedure); and PFS2. 2. Results 60   AZ Ref.: B7H1-620-WO-PCT

[0309] At DCO2 (18 Sep 2023), PFS benefit for Arm 3 vs 1 was sustained in both non- tBRCAm HRD+ and non-tBRCAm ITT populations (Table 6), and was consistent across preplanned subgroups, including for the stratification factors. Interim OS analysis for Arm 3 vs 1 (non-tBRCAm ITT) was not statistically significant. A favorable OS trend was shown for Arm 3 vs 1 in the non-tBRCAm HRD+ population. In both populations, PFS2 was improved for Arm 3 vs 1 and Arm 2 vs 1 (Table 6). DCO2 safety findings were similar to DCO1 (Figure 25). The safety findings were consistent with the primary analysis. Overall, the most common grade ≥3 AEs in Arm 3 were neutropenia (31% vs 28% in Arm 2 and 26% in Arm 1) and anemia (25% vs 8% in Arm 2 and 8% in Arm 1). Grade ≥3 PRCA and / or AIHA events were reported in 3 patients in Arm 3 in the maintenance phase and all events resolved.

[0310] D + PC + B followed by D + B + O mtx continued to improve PFS vs control, including by subgroup; in the non-tBRCAm HRD+ population, median PFS was 45.1 mo, the longest seen for these pts in the first-line setting to date, with an associated favourable OS trend. PFS2 was improved in both the non-tBRCAm HRD+ and non-tBRCAm ITT populations (Figures 22-24). DUO-O continued to demonstrate clinically meaningful PFS benefit with first- line chemotherapy + bevacizumab + durvalumab followed by bevacizumab + durvalumab + olaparib maintenance (Arm 3) versus control (Arm 1). mPFS of 45.1 months in Arm 3 is the longest observed for non-tBRCAm HRD-positive patients in the first-line setting. Final PFS results for Arm 2 versus Arm 1 were also consistent with the previous findings, and show numerical improvement with a hazard ratio of 0.89. The DUO-O time-to-event data include the duration of the chemotherapy phase, which equates to approximately 4.5 months.

[0311] At this OS interim analysis, Arm 3 versus Arm 1 was not statistically significant in the non-tBRCAm. In the ITT population; however, a favorable trend was noted in the non- tBRCAm HRD-positive population. Safety continues to be generally consistent with the earlier analysis and known profiles of each agent. 61   TCP-O W-),0 )0) S26-8317 1 17. 52.810O16 2.1,:TH3 3 .7= 56.0–9–.08. –S Tn 2 0 1.50 67= 076B. . .OI(l: 0P0( , e.0( (Sf Fdoe PR:+mZ ) )DxoA3 6)2 RC T4TI 2736.70.1 1=08 11–.2 . 11. H[ de09 1–9.1–y ifin2.0 4.7=. 0 3 05r7e ta0P7. .gr(0(0( rutssn euvit ncaur8do) 3er]173 .=9ot Smn 1 y FcPf:ATCo TReI[ Btmn-o on) )ctigo5 7)5 u er N04 1 66.304 .912.odci3 1 . 4–8 60n h= 5n4.0 3. – . –3. 0 15004a pa0. .(0(0g(nrig 2miote6g2y4b d)9)5)6≥ dna*+ 811.1.3.er eifiytrD R241 .9= 58 12.0– 976.1191 o0–1.0–0csaertgrHn6.4 60.0.0yt s uil(ls( ( ( ibe eavt doitsimcnuix dco er3 Co1413.mo dtyc= 3 nn2 eeigfif,tyaoreatss msaaoctu†xmo oo)I†) †)DrfdCICICCd nm,n%ai 5%5% ®eta5ecgi anid9(9(9(o mieR R Rhtsmit. M H H HCyEy6M.1breldmo2 air] )baTmr S SrA2S2S AFSPOFyPMs* †vFPFPAZ Ref.: B7H1-620-WO-PCT   Example 4: Updated Analysis: Durvalumab With Carboplatin / Paclitaxel and Bevacizumab Followed by Durvalumab, Bevacizumab and Olaparib Maintenance in Newly Diagnosed Non-BRCA-Mutated Advanced Ovarian Cancer

[0312] An updated analysis of the PFS and OS in DUO-O: first-line durvalumab plus carboplatin / paclitaxel and bevacizumab followed by durvalumab, bevacizumab plus olaparib maintenance demonstrated a statistically significant, clinically meaningful PFS improvement, with greatest benefit seen in the non-tBRCAm HRD-positive population. 1. Methods

[0313] Material and methods are as outlined in Examples 1-3 above.

[0314] Determination of Homologous Recombination Repair Mutation (HRRm) Status

[0315] Tumor tissue samples were used for homologous recombination repair mutation (HRRm) testing. Tumor HRRm status was evaluated prospectively using the MyChoice® CDx assay. A sample was considered positive if a deleterious or suspected deleterious HRRm was detected in any one of the following prespecified genes associated with HRR: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. BRCA1 and BRCA2 were included in this list of prespecified genes, despite the study inclusion criteria for the non-tBRCAm cohort requiring patients to have no detected deleterious or suspected deleterious mutation in BRCA1 and BRCA2, so patients who were any mis-randomized were captured as being positive for HRRm. A negative HRRm status (non-HRRm) was defined as a sample with no deleterious or suspected deleterious mutations in any of the prespecified genes. Unknown HRRm status included cancelled or failed tests and the one patient recruited in China where HRR testing was not performed. 2. Results

[0316] Non-tBRCAm HRD-positive population

[0317] In the non-tBRCAm HRD-positive population at the prespecified interim PFS analysis, 135 of 283 patients in the durvalumab+olaparib arm and control arm had PFS events (data maturity, 47.7%). The durvalumab+olaparib arm demonstrated a statistically significant 51% lower risk of disease progression or death versus control (HR, 0.49 [95% CI, 0.34-0.69]; P<.0001; median PFS [mPFS] 37.3 v 23.0 months) (Figure 6 and Table 7).

[0318] At the final PFS analysis, the improvement in the durvalumab+olaparib arm versus control was sustained (HR, 0.46; 95% CI, 0.33-0.65; mPFS 45.1 v 23.3 months; 24-month PFS 63   AZ Ref.: B7H1-620-WO-PCT   rates 72.9% v 46.5%; descriptive analysis) (Figure 27 and Table 7). The HR for PFS in the durvalumab arm versus control was 0.89 (95% CI, 0.67-1.19; mPFS 25.1 v 23.3 months; 24- month PFS rates 50.9% v 46.5%) (Figure 27 and Table 7).

[0319] Consistent results were seen in prespecified sensitivity analyses, including PFS as assessed by blinded independent central review (BICR). A generally consistent treatment effect for the durvalumab+olaparib arm versus control was seen across prespecified subgroups (Figures 28 and 30).

[0320] Non-tBRCAm ITT population

[0321] In the non-tBRCAm ITT population at the prespecified interim PFS analysis, 452 of 756 patients in the durvalumab+olaparib and control arms had PFS events (data maturity, 59.8%). The durvalumab+olaparib arm demonstrated a statistically significant 37% lower risk of disease progression or death versus control (HR, 0.63 [95% CI, 0.52-0.76]; P<.0001; mPFS 24.2 v 19.3 months) (Figure 16B and Table 7). As both primary endpoints were met at the interim PFS analysis, it is hereafter described as the primary analysis. At the final PFS analysis, the improvement in the durvalumab+olaparib arm versus control was sustained (HR, 0.61 [95% CI, 0.51-0.73]; mPFS 25.1 v 19.3 months; 24-month PFS rates 53.0% v 33.2%; descriptive analysis) (Figure 16D and Table 7).

[0322] A statistically significant PFS benefit was not seen for the durvalumab arm versus control at the primary PFS analysis (Figure 16B and Table 7). Therefore, PFS in the durvalumab arm was retested at the final PFS analysis as per the MTP, with no statistically significant PFS benefit seen (HR, 0.87 [95% CI, 0.74-1.03]; P=.11; mPFS 20.6 v 19.3 months; 24-month PFS rates 38.7% v 33.2%) (Figure 16B and Table 7).

[0323] Consistent results were seen in prespecified sensitivity analyses, including PFS as assessed by BICR. A generally consistent treatment effect was seen across prespecified subgroups (Figures 18 and 19A-C).

[0324] HRD-negative subgroup

[0325] In the subgroup with HRD-negative tumors, a PFS benefit was seen in the durvalumab+olaparib arm versus control at both the primary (HR, 0.68 [95% CI, 0.54-0.86]; mPFS 20.9 v 17.4 months; 18-month PFS rates 64.0% v 47.6%) and final (HR, 0.68 [95% CI, 0.54-0.85]; mPFS 21.1 v 17.5 months; 24-month PFS rates 41.1% v 26.1%) PFS analyses (Table 7 and Figure 21A-B). 64   AZ Ref.: B7H1-620-WO-PCT

[0326] PFS2 analysis (DCO September 18, 2023)

[0327] PFS2 in the non-tBRCAm HRD-positive, non-tBRCAm ITT, and HRD-negative populations is reported in Table 2 (see also Figures 20A-B).

[0328] Interim OS analysis (DCO September 18, 2023)

[0329] Non-tBRCAm ITT population: In the non-tBRCAm ITT population at the interim OS analysis, 432 of 1,130 patients in the durvalumab+olaparib, durvalumab, and control arms had died (data maturity, 38.2%). The HR for OS in the durvalumab+olaparib arm versus control was 0.95 (95% CI, 0.76-1.20; P=.68; median OS [mOS] 48.5 v 48.0 months; 24-month OS rates 83.3% v 79.8%) and in the durvalumab arm versus control was 0.92 (95% CI, 0.73-1.16; mOS not reached (NR) v 48.0 months; 24-month OS rates 81.2% v 79.8%) (Figure 20C and Table 7). As no statistically significant improvement in OS was seen for the durvalumab+olaparib arm versus control no further testing was performed per the MTP. Subsequent PARP inhibitor therapy was received by 18.5%, 17.6%, and 7.1% of patients in the control, durvalumab, and durvalumab+olaparib arms, respectively, and 6.1%, 1.3%, and 0.8%, respectively, received subsequent immunotherapy (Table 7).

[0330] HRD-negative subgroup

[0331] In the HRD-negative subgroup, the HR for OS in the durvalumab+olaparib arm versus control was 0.99 (95% CI, 0.76-1.31; mOS 41.1 v 39.6 months; 24-month OS rates 76.4% v 76.9%) (Table 7 and Figure 21D). 3. Conclusions

[0332] DUO-O met its primary endpoints at the planned interim PFS analysis, demonstrating a statistically significant and clinically meaningful PFS improvement in women with newly diagnosed advanced ovarian cancer with the addition of durvalumab to a backbone of chemotherapy plus bevacizumab followed by bevacizumab, durvalumab, and olaparib maintenance compared with chemotherapy plus bevacizumab followed by bevacizumab alone in both the non-tBRCAm HRD-positive and non-tBRCAm ITT populations. PFS benefit was sustained at the final PFS analysis and was consistent across prespecified subgroups in both the non-tBRCAm HRD-positive and non-tBRCAm ITT populations, including in patients with HRD-negative tumors (55.4% of the DUO-O population) and the PD-L1 biomarker subgroups. 65   AZ Ref.: B7H1-620-WO-PCT

[0333] The mPFS of 45.1 months achieved in the durvalumab+olaparib arm of the non- tBRCAm HRD-positive population in DUO-O is the longest observed in any trial in the newly diagnosed, advanced ovarian cancer setting to date.

[0334] In DUO-O, OS maturity was 38% and 21% in the non-tBRCAm ITT and HRD- positive populations, respectively, at the time of the interim OS analysis, and a favorable OS trend was noted in the non-tBRCAm HRD-positive population. Of note, reported use of subsequent therapies such as PARP inhibitors and immunotherapy was low at the time that OS was assessed and were not accounted for in the interim OS analysis. DUO-O is ongoing with updated OS analyses planned with longer-term follow-up.

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Ledermann et al., "Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up," Ann. Oncol.24 Suppl 6: vi24-32 (2013). 2. Burger et al., "Incorporation of bevacizumab in the primary treatment of ovarian cancer." N. Engl. J. Med.365(26): 2473-83 (2011). 3. Tewari et al., "Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer," J. Clin. Oncol.37(26): 2317-28 (2019). 4. Perren et al., "A phase 3 trial of bevacizumab in ovarian cancer," N. Engl. J. Med.365(26): 2484- 96 (2011). 5. Oza et al., "Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial," Lancet Oncol. 16(8): 928-36 (2015). 6. Ray-Coquard et al., "Olaparib plus bevacizumab as first-line maintenance in ovarian cancer," N. Engl. J. Med.381(25): 2416-28 (2019). 7. Ray-Coquard et al., "Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1 / ENGOT-ov25 trial," Ann. Oncol.34(8): 681-92 (2023). 8. Moore et al., "Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer," N. Engl. J. Med.379(26): 2495-505 (2018). 9. DiSilvestro et al., "Overall survival with maintenance olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: the SOLO1 / GOG 3004 trial," J. Clin. Oncol.41(3): 609-17 (2023). 10. Gonzalez-Martin et al., "Niraparib in patients with newly diagnosed advanced ovarian cancer," N. Engl. J. Med.381(25): 2391-402 (2019). 11. Monk et al., "A randomized, Phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO / GOG-3020 / ENGOT- ov45)," J. Clin. Oncol.40(34): 3952-64 (2022). 12. 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Claims

AZ Ref.: B7H1-620-WO-PCT   WHAT IS CLAIMED IS: Claim 1. A combination for use in the treatment of ovarian cancer in a subject in need thereof, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, a therapeutically effective amount of an anti-VEGF antibody or antigen- binding fragment thereof, and a therapeutically effective amount of a PARP inhibitor. Claim 2. A combination for use in the treatment of ovarian cancer in a subject in need thereof, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof and a therapeutically effective amount of an anti-VEGF antibody or antigen- binding fragment thereof. Claim 3. The combination for use according to either claim 1 or claim 2, wherein the anti- VEGF antibody or antigen-binding fragment thereof is bevacizumab. Claim 4. The combination for use according to any one of claims 1-3, wherein the anti-PD- L1 antibody or antigen-binding fragment thereof is durvalumab. Claim 5. The combination for use according to any one of claims 1, 3, or 4, wherein the PARP inhibitor is olaparib. 72   AZ Ref.: B7H1-620-WO-PCT   Claim 6. The combination for use according to any one of claims 1-5, wherein the therapeutically effective amount of the anti-VEGF antibody or antigen-binding fragment thereof comprises a dose of from 5 mg / kg to 20 mg / kg. Claim 7. The combination for use according to claim 6, wherein the dose of anti-VEGF antibody or antigen-binding fragment thereof is 15 mg / kg. Claim 8. The combination for use according to any one of claims 1-7, wherein the therapeutically effective amount of the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a dose of from 800 mg to 1500 mg. Claim 9. The combination for use according to claim 8, wherein the dose of anti-PD-L1 antibody or antigen-binding fragment thereof is 1120 mg. Claim 10. The combination for use according to any one of claims 1-9, wherein the therapeutically effective amount of the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a dose of from 10 mg / kg to 20 mg / kg. Claim 11. The combination for use according to claim 10, wherein the dose of anti-PD-L1 antibody or antigen-binding fragment thereof is 15 mg / kg. Claim 12. The combination for use according to any one of claims 1-11, wherein the therapeutically effective amount of the PARP inhibitor comprises a dose of from 100 mg to 300 mg. Claim 13. The combination for use according to claim 12, wherein the dose of PARP inhibitor is 300 mg. Claim 14. The combination for use according to any one of claims 1-13, wherein the one or more chemotherapy agents is paclitaxel and / or carboplatin. 73   AZ Ref.: B7H1-620-WO-PCT   Claim 15. The combination for use according to claim 14, wherein the therapeutically effective amount of paclitaxel comprises a dose of 175 mg / m2. Claim 16. The combination for use according to either claim 14 or claim 15, wherein the therapeutically effective amount of carboplatin comprises a dose that produces an Area Under of Curve (AUC) of AUC5 or AUC6. Claim 17. The combination for use according to any one of claims 1-16, wherein administration of the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the one or more chemotherapy agents is every two to four weeks. Claim 18. The combination for use according to claim 17, wherein administration is every two to four weeks for nine to eighteen weeks. Claim 19. The combination for use according to either claim 17 or claim 18, wherein administration is every three weeks. Claim 20. The combination for use according to claim 19, wherein administration is every three weeks for nine to fifteen weeks. Claim 21. The combination for use according to any one of claims 1-20, wherein administration of the anti-VEGF antibody or antigen-binding fragment thereof is four to six doses, administration of the anti-PD-L1 antibody or antigen-binding fragment thereof is three to five doses, and administration of the one or more chemotherapy agents is four to six doses. Claim 22. The combination for use according to any one of claims 1-21, wherein prior to administration of the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the one or more chemotherapy agents, the subject received: (i) the one or more chemotherapy agents; or 74   AZ Ref.: B7H1-620-WO-PCT   (ii) the one or more chemotherapy agents and the anti-VEGF antibody or antigen- binding fragment thereof. Claim 23. The combination for use according to claim 22, wherein prior to administration of the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the one or more chemotherapy agents, the subject received: (i) at least 1 dose of the one or more chemotherapy agents; or (ii) at least 1 dose of the one or more chemotherapy agents and at least 1 dose of the anti-VEGF antibody or antigen-binding fragment thereof. Claim 24. The combination for use according to any one of claims 1 to 23, wherein (a) comprises administration of: the anti-VEGF antibody or antigen-binding fragment thereof at a dose of 15 mg / kg; and the anti-PD-L1 antibody or antigen-binding fragment thereof at a dose of 1120 mg. Claim 25. The combination for use according to claim 24, wherein: the anti-VEGF antibody or antigen-binding fragment thereof is bevacizumab and administration of bevacizumab is at a dose of 15 mg / kg; and the anti-PD-L1 antibody or antigen-binding fragment thereof is durvalumab and administration of durvalumab is at a dose of 1120 mg. Claim 26. The combination for use according to either claim 24 or claim 25, wherein: the anti-VEGF antibody or antigen-binding fragment thereof is bevacizumab and administration of bevacizumab is at a dose of 15 mg / kg every 3 weeks; and the anti-PD-L1 antibody or antigen-binding fragment thereof is durvalumab and administration of durvalumab is at a dose of 1120 mg every 3 weeks. Claim 27. The combination for use according to any one of claims 24-26, wherein (a) further comprises: 175 mg / m2of paclitaxel; and 75   AZ Ref.: B7H1-620-WO-PCT   25 mg / m2of cisplatin. Claim 28. The combination for use according to any one of claims 1-27, wherein (b) comprises administration of the anti-VEGF antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof every two to four weeks. Claim 29. The combination for use according to any one of claims 1-27, wherein (b) comprises administration of the anti-VEGF antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof every three weeks. Claim 30. The combination for use according to any one of claims 1-27, wherein (b) comprises administration of: the anti-VEGF antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof every two to four weeks; and the PARP inhibitor twice daily. Claim 31. The combination for use according to any one of claims 1-30, wherein (b) comprises administration of: the anti-VEGF antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof every three weeks; and the PARP inhibitor twice daily. Claim 32. The combination for use according to any one of claims 1-29, wherein (b) comprises administration of: the anti-VEGF antibody or antigen-binding fragment thereof at a dose of 15 mg / kg; and the anti-PD-L1 antibody or antigen-binding fragment thereof at a dose of 1120 mg. Claim 33. The method according to claim 32, wherein (b) comprises administration of: a dose of the anti-VEGF antibody or antigen-binding fragment thereof every three weeks for up to 15 months; and 76   AZ Ref.: B7H1-620-WO-PCT   a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every three weeks for up to 24 months. Claim 34. The combination for use according to claim 32, wherein: the anti-VEGF antibody or antigen-binding fragment thereof of (b) is bevacizumab and administration of bevacizumab is at a dose of 15 mg / kg; and the anti-PD-L1 antibody or antigen-binding fragment thereof of (b) is durvalumab and administration of durvalumab is at a dose of 1120 mg. Claim 35. The combination for use according to either claim 32 or claim 33, wherein: the anti-VEGF antibody or antigen-binding fragment thereof of (b) is bevacizumab and administration of bevacizumab is at a dose of 15 mg / kg every 3 weeks; and the anti-PD-L1 antibody or antigen-binding fragment thereof of (b) is durvalumab and administration of durvalumab is at a dose of 1120 mg every 3 weeks. Claim 36. The combination for use according to any one of claims 1-27, 30, or 31, wherein (b) comprises administration of: the anti-VEGF antibody or antigen-binding fragment thereof at a dose of 15 mg / kg; the anti-PD-L1 antibody or antigen-binding fragment thereof at a dose of 1120 mg; and the PARP inhibitor at a dose of 300 mg. Claim 37. The method according to claim 36, wherein (b) comprises administration of: a dose of the anti-VEGF antibody or antigen-binding fragment thereof every three weeks for up to 15 months; a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every three weeks for up to 24 months; and twice daily doses of the PARP inhibitor for up to 24 months. Claim 38. The combination for use according to claim 36, wherein: the anti-VEGF antibody or antigen-binding fragment of (b) is bevacizumab and administration of bevacizumab is at a dose of 15 mg / kg; 77   AZ Ref.: B7H1-620-WO-PCT   the anti-PD-L1 antibody or antigen-binding fragment thereof of (b) is durvalumab and administration of durvalumab is at a dose of 1120 mg; and the PARP inhibitor of (b) is olaparib and administration of olaparib is at a dose of 300 mg. Claim 39. The combination for use according to either claim 36 or claim 37, wherein: the anti-VEGF antibody or antigen-binding fragment of (b) is bevacizumab and administration of bevacizumab is at a dose of 15 mg / kg every 3 weeks; the anti-PD-L1 antibody or antigen-binding fragment thereof of (b) is durvalumab and administration of durvalumab is at a dose of 1120 mg every 3 weeks; and the PARP inhibitor of (b) is olaparib and administration of olaparib is at a dose of 300 mg twice a day. Claim 40. The combination for use according to any one of claims 1-39, wherein administration of the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the one or more chemotherapy agents is intravenous. Claim 41. The combination for use according to any one of claims 1-40, wherein administration of the PARP inhibitor is oral. Claim 42. The combination for use according to any one of claims 1-41, wherein administration of the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the one or more chemotherapy agents of (a) occurs simultaneously, separately, and / or sequentially. Claim 43. The combination for use according to any one of claims 1-42, wherein administration of the anti-VEGF antibody or antigen-binding fragment thereof and the anti-PD- L1 antibody or antigen-binding fragment thereof of (b) occurs simultaneously, separately, and / or sequentially. 78   AZ Ref.: B7H1-620-WO-PCT   Claim 44. The combination for use according to any one of claims 1-42, wherein administration of the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the PARP inhibitor of (b) occurs simultaneously, separately, and / or sequentially. Claim 45. The combination for use according to any one of claims 1-44, wherein the ovarian cancer is advanced ovarian cancer. Claim 46. The combination for use according to any one of claims 1-45, wherein the ovarian cancer is high-grade epithelial ovarian cancer. Claim 47. The combination for use according to any one of claims 1-46, wherein the ovarian cancer is an ovarian cancer tumor lacking a BRCA1 / BRCA2 mutation (non-tBRCAm). Claim 48. The combination for use according to any one of claims 1-47, wherein the ovarian cancer is an ovarian cancer tumor that is a homologous recombination deficiency (HRD) positive tumor. Claim 49. The combination for use according to any one of claims 1-47, wherein the ovarian cancer is an ovarian cancer tumor that is a homologous recombination deficiency (HRD) negative tumor. Claim 50. The combination for use according to any one of claims 1-49, wherein treatment with the combination produces an increase in progression free survival in the subject compared to a patient who has only received bevacizumab and chemotherapy. Claim 51. The combination for use according to claim 50, wherein the treatment produces an increase in progression free survival for at least 4 months. 79   AZ Ref.: B7H1-620-WO-PCT   Claim 52. The combination for use according to any one of claims 1-49, wherein treatment with the combination produces an increase in overall survival in the subject compared to a patient who has only received bevacizumab and chemotherapy. Claim 53. The combination for use according to claim 52, wherein the treatment produces an increase in overall survival for at least 4 months. Claim 54. A method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject: (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, a therapeutically effective amount of an anti-VEGF antibody or antigen- binding fragment thereof, and a therapeutically effective amount of a PARP inhibitor. Claim 55. A method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject: (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof and a therapeutically effective amount of an anti-VEGF antibody or antigen- binding fragment thereof. Claim 56. The method of either claim 54 or claim 55, wherein step (b) occurs after completion of step (a). 80   AZ Ref.: B7H1-620-WO-PCT   Claim 57. The method of any one of claims 54-56, further comprising administering to the subject prior to step (a): (i) a therapeutically effective amount of one or more chemotherapy agents; or (ii) a therapeutically effective amount of one or more chemotherapy agents and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof. Claim 58. The method of claim 57, further comprising administering to the subject prior to step (a): (i) at least 1 dose of a therapeutically effective amount of one or more chemotherapy agents; or (ii) at least 1 dose of a therapeutically effective amount of one or more chemotherapy agents and at least 1 dose of a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof. Claim 59. The method according to any one of claims 54-58, wherein the anti-VEGF antibody or antigen-binding fragment thereof is bevacizumab. Claim 60. The method according to any one of claims 54-59, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is durvalumab. Claim 61. The method according to any one of claims 54-60, wherein the PARP inhibitor is olaparib. Claim 62. The method according to any one of claims 54-61, wherein the anti-VEGF antibody or antigen-binding fragment thereof is administered at a dose of from 5 mg / kg to 20 mg / kg. Claim 63. The method according to claim 62, wherein the anti-VEGF antibody or antigen- binding fragment thereof is administered at a dose of 15 mg / kg. 81   AZ Ref.: B7H1-620-WO-PCT   Claim 64. The method according to any one of claims 54-63, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of from 800 mg to 1500 mg. Claim 65. The method according to claim 64, wherein the anti-PD-L1 antibody or antigen- binding fragment thereof is administered at a dose of 1120 mg. Claim 66. The method according to any one of claims 54-63, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of from 10 mg / kg to 20 mg / kg. Claim 67. The method according to claim 66, wherein the anti-PD-L1 antibody or antigen- binding fragment thereof is administered at a dose of 15 mg / kg. Claim 68. The method according to any one of claims 54-67, wherein the PARP inhibitor is administered at a dose of between 100 mg and 300 mg. Claim 69. The method according to claim 68, wherein the PARP inhibitor is administered at a dose of 300 mg. Claim 70. The method according to any one of claims 54-69, wherein the one or more chemotherapy agents is paclitaxel and / or carboplatin. Claim 71. The method according to any one of claims 54-70, wherein paclitaxel is administered at a dose of 175 mg / m2. Claim 72. The method according to either claim 69 or claim 71, wherein carboplatin is administered at a dose that produces an Area Under of Curve (AUC) of AUC5 or AUC6. Claim 73. The method according to any one of claims 54-72, wherein step (a) comprises administration of the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 82   AZ Ref.: B7H1-620-WO-PCT   antibody or antigen-binding fragment thereof, and the one or more chemotherapy agents every two to four weeks. Claim 74. The method according to claim 73, wherein step (a) comprises administration of: a dose of the anti-VEGF antibody or antigen-binding fragment thereof; a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof; and a cycle of the one or more chemotherapy agents every two to four weeks for nine to eighteen weeks. Claim 75. The method according to any one of claims 54-72, wherein step (a) comprises administration of: a dose of the anti-VEGF antibody or antigen-binding fragment thereof; a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof; and a cycle of the one or more chemotherapy agents every three weeks. Claim 76. The method according to claim 75, wherein step (a) comprises administration of: a dose of the anti-VEGF antibody or antigen-binding fragment thereof; a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof; and a cycle of the one or more chemotherapy agents every three weeks for nine to fifteen weeks. Claim 77. The method according to any one of claims 54-76, wherein step (a) comprises administration of: three to five doses of the anti-VEGF antibody or antigen-binding fragment thereof; three to five doses of the anti-PD-L1 antibody or antigen-binding fragment thereof; and three to five cycles of the one or more chemotherapy agents. Claim 78. The method according to any one of claims 54-77, wherein step (a) comprises administration of: 15 mg / kg of the anti-VEGF antibody or antigen-binding fragment thereof; and83   AZ Ref.: B7H1-620-WO-PCT   Claim 79. The method according to claim 78, wherein step (a) comprises administration of: 15 mg / kg of bevacizumab; and 1120 mg of durvalumab. Claim 80. The method according to claim 79, wherein step (a) comprises administration of: 15 mg / kg of bevacizumab every 3 weeks; and 1120 mg of durvalumab every 3 weeks. Claim 81. The method according to any one of claims 78-80, wherein step (a) further comprises administration of: 175 mg / m2of paclitaxel; and / or 25 mg / m2of cisplatin. Claim 82. The method according to any one of claims 54-81, wherein step (b) comprises administration of a dose of the anti-VEGF antibody or antigen-binding fragment thereof and a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every two to four weeks. Claim 83. The method according to any one of claims 54-82, wherein step (b) comprises administration of a dose of the anti-VEGF antibody or antigen-binding fragment thereof and a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every three weeks. Claim 84. The method according to any one of claims 54-81, wherein step (b) comprises administration of: a dose of the anti-VEGF antibody or antigen-binding fragment thereof and a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every two to four weeks; and a dose of the PARP inhibitor twice daily. Claim 85. The method according to any one of claims 54-82, wherein step (b) comprises administration of: 84   AZ Ref.: B7H1-620-WO-PCT   a dose of the anti-VEGF antibody or antigen-binding fragment thereof and a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every three weeks; and a dose of the PARP inhibitor twice daily. Claim 86. The method according to claim 75, wherein step (b) comprises administration of: a dose of the anti-VEGF antibody or antigen-binding fragment thereof every three weeks for up to 15 months; and a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every three weeks for up to 24 months. Claim 87. The method according to claim 75, wherein step (b) comprises administration of: a dose of the anti-VEGF antibody or antigen-binding fragment thereof every three weeks for up to 15 months; a dose of the anti-PD-L1 antibody or antigen-binding fragment thereof every three weeks for up to 24 months; and twice daily doses of the PARP inhibitor for up to 24 months. Claim 88. The method according to any one of claims 54-83 or 86, wherein step (b) comprises administration of: 15 mg / kg of the anti-VEGF antibody or antigen-binding fragment thereof; and 1120 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof. Claim 89. The method according to claim 88, wherein step (b) comprises administration of: 15 mg / kg of bevacizumab every 3 weeks; and 1120 mg of durvalumab every 3 weeks; Claim 90. The method according to any one of claims 54-81, 84, 85, or 87, wherein step (b) comprises administration of: 15 mg / kg of the anti-VEGF antibody or antigen-binding fragment thereof; 1120 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof; and 300 mg of the PARP inhibitor. 85   AZ Ref.: B7H1-620-WO-PCT   Claim 91. The method according to claim 90, wherein step (b) comprises administration of: 15 mg / kg of bevacizumab; 1120 mg of durvalumab; and 300 mg olaparib. Claim 92. The method according to claim 91, wherein step (b) comprises administration of: 15 mg / kg of bevacizumab every 3 weeks; 1120 mg of durvalumab every 3 weeks; and 300 mg olaparib twice a day. Claim 93. The method according to any one of claims 54-92, wherein the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the one or more chemotherapy agents are administered intravenously. Claim 94. The method according to any one of claims 54-93, wherein the PARP inhibitor is administered orally. Claim 95. The method according to any one of claims 54-94, wherein the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the one or more chemotherapy agents of step (a) are administered to the subject simultaneously, separately, and / or sequentially. Claim 96. The method according to any one of claims 54-95, wherein the anti-VEGF antibody or antigen-binding fragment thereof and the anti-PD-L1 antibody or antigen-binding fragment thereof of step (b) are administered to the subject simultaneously, separately, and / or sequentially. Claim 97. The method according to any one of claims 54-95, wherein the anti-VEGF antibody or antigen-binding fragment thereof, the anti-PD-L1 antibody or antigen-binding 86   AZ Ref.: B7H1-620-WO-PCT   fragment thereof, and the PARP inhibitor of step (b) are administered to the subject simultaneously, separately, and / or sequentially. Claim 98. The method according to any one of claims 54-97, wherein the ovarian cancer is advanced ovarian cancer. Claim 99. The method according to any one of claims 54-98, wherein the ovarian cancer is high-grade epithelial ovarian cancer. Claim 100. The method according to any one of claims 54-99, wherein the ovarian cancer is an ovarian cancer tumor lacking a BRCA1 / BRCA2 mutation (non-tBRCAm). Claim 101. The method according to any one of claims 54-100, wherein the ovarian cancer is an ovarian cancer tumor that is a homologous recombination deficiency (HRD) positive tumor. Claim 102. The method according to any one of claims 54-100 wherein the ovarian cancer is an ovarian cancer tumor that is a homologous recombination deficiency (HRD) negative tumor. Claim 103. The method according to any one of claims 54-102, wherein the treatment produces an increase in progression free survival in the subject compared to a patient who has only received bevacizumab and chemotherapy. Claim 104. The method according to claim 103, wherein the treatment produces an increase in progression free survival for at least 4 months. Claim 105. The method according to any one of claims 54-103, wherein the treatment produces an increase in overall survival in the subject compared to a patient who has only received bevacizumab and chemotherapy. Claim 106. The method according to claim 105, wherein the treatment produces an increase in overall survival for at least 4 months. 87   AZ Ref.: B7H1-620-WO-PCT   Claim 107. Use of a combination in the manufacture of a medicament for the treatment of ovarian cancer in a subject in need thereof, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, a therapeutically effective amount of an anti-VEGF antibody or antigen- binding fragment thereof, and a therapeutically effective amount of a PARP inhibitor. Claim 108. Use of a combination in the manufacture of a medicament for the treatment of ovarian cancer in a subject in need thereof, wherein the combination comprises: (a) a therapeutically effective amount of one or more chemotherapy agents, a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a therapeutically effective amount of an anti-VEGF antibody or antigen-binding fragment thereof; and (b) a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding fragment thereof and a therapeutically effective amount of an anti-VEGF antibody or antigen- binding fragment thereof. 88

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