WILMINGTON, DE, USA I June 03, 2023 I Positive results from a planned interim analysis of the DUO-O Phase III trial showed that treatment with a combination of LYNPARZA® (olaparib), IMFINZI® (durvalumab), chemotherapy and bevacizumab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) versus chemotherapy plus bevacizumab (control arm) in newly diagnosed patients with advanced high-grade epithelial ovarian cancer without tumor BRCA mutations. Patients were treated with IMFINZI in combination with chemotherapy and bevacizumab followed by IMFINZI, LYNPARZA and bevacizumab as maintenance therapy.
These results will be presented today in an oral presentation at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago (Abstract #LBA5506).
The combination of LYNPARZA, IMFINZI, chemotherapy and bevacizumab reduced the relative risk of disease progression or death by 37% versus chemotherapy and bevacizumab (hazard ratio (HR) 0.63; 95% CI 0.52-0.76; p<0.0001). Median PFS was 24.2 months versus 19.3, respectively. In the homologous recombination deficiency (HRD)-positive subgroup of patients, LYNPARZA, IMFINZI, chemotherapy and bevacizumab reduced the relative risk of disease progression or death by 51% versus chemotherapy and bevacizumab alone (HR 0.49; 95% CI 0.34-0.69; p<0.0001). Median PFS was 37.3 months versus 23.0, respectively.
Professor Philipp Harter, Director, Department of Gynaecology and Gynaecologic Oncology, Evangelische Kliniken Essen-Mitte, Germany, and principal investigator for the trial, said: “The primary aim of first-line treatment of patients with advanced ovarian cancer is long-term control over the disease, but still too many patients progress quickly and face poor clinical outcomes today. Data from the DUO-O trial interim progression-free survival analysis provide evidence for further improvement with olaparib and durvalumab combination versus chemotherapy and bevacizumab alone in patients without tumor BRCA mutations.”
Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “These results are an important milestone in our ongoing journey to address unmet need in ovarian cancer. The DUO-O trial demonstrates the potential of combining PARP inhibition with immunotherapy and we look forward to seeing more mature data and key secondary endpoints results.”
At a pre-planned exploratory analysis of the HRD-negative subgroup of patients, LYNPARZA, IMFINZI, chemotherapy and bevacizumab reduced the relative risk of disease progression or death by 32% versus chemotherapy and bevacizumab (HR 0.68; 95% CI 0.54-0.86). Median PFS was 20.9 months versus 17.4.
At the time of this interim analysis, an additional arm evaluating the combination of IMFINZI, chemotherapy and bevacizumab demonstrated a numerical improvement in PFS which was not statistically significant (HR 0.87; 95% CI 0.73-1.04; p=0.13).
At the time of this planned interim analysis, the overall survival (OS) and other secondary endpoints were immature. OS will be formally assessed at a subsequent analysis.
Summary of results: DUO-O
| Arm 1 chemotherapy and bevacizumab (n=378) |
Arm 2 IMFINZI, chemotherapy and bevacizumab (n=374) |
Arm 3 LYNPARZA, IMFINZI, chemotherapy and bevacizumab (n=378) |
|
| ITT | |||
| Events, n/N (%) | 259 (69) | 226 (60) | 193 (51) |
| Median PFS, months | 19.3 | 20.6 | 24.2 |
| HR (95% CI) vs. arm 1 |
0.87 (0.73-1.04) p=0.13* |
0.63 (0.52-0.76) p<0.0001* |
|
| HRD-positive | |||
| Events, n/N (%) | 86 (60) | 69 (47) | 49 (35) |
| Median PFS, months | 23.0 | 24.4 | 37.3 |
| HR (95% CI) vs. arm 1 |
0.82 (0.60-1.12)
|
0.49** (0.34-0.69) p<0.0001* |
|
| HRD-negative (based on an exploratory analysis) | |||
| Events, n/N (%) | 157 (73) | 142 (71) | 127 (60) |
| Median PFS, months | 17.4 | 15.4 | 20.9 |
| HR (95% CI) vs. arm 1 | 0.94 (0.75-1.18) | 0.68 (0.54-0.86) | |
*Results based on the stratified model
**Results based on the unstratified model: HR 0.51 (95% CI 0.36-0.72)
The safety and tolerability of these combinations was broadly consistent with that observed in prior clinical trials and the known profiles of the individual medicines.
The most common adverse events (AEs) (greater than or equal to 20% of patients) for the combination of LYNPARZA, IMFINZI, chemotherapy and bevacizumab were nausea (57%), anemia (55%), neutropenia (51%), fatigue/asthenia (49%), arthralgia (34%), constipation (30%), diarrhea (30%), thrombocytopenia (28%), hypertension (26%), vomiting (26%), leukopenia (24%), headache (22%), abdominal pain (21%) and hypothyroidism (20%). Grade 3 or higher AEs were neutropenia (31%), anemia (24%), leukopenia (8%), hypertension (7%) and thrombocytopenia (6%).
Approximately 65% of patients treated with the combination of LYNPARZA, IMFINZI, chemotherapy and bevacizumab who experienced AEs during chemotherapy and throughout the maintenance phase remained on treatment at the time of data cut-off, compared to 80% of patients in the control arm (chemotherapy plus bevacizumab).
INDICATIONS
LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:
First-Line Maintenance BRCAm Advanced Ovarian Cancer
For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
First-Line Maintenance HRD-Positive Advanced Ovarian Cancer in Combination with Bevacizumab
In combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either:
- a deleterious or suspected deleterious BRCA mutation, and/or
- genomic instability
Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
Maintenance Recurrent Ovarian Cancer
For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.
Adjuvant Treatment of gBRCAm, HER2-Negative, High-Risk Early Breast Cancer
For the adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative, high-risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
gBRCAm, HER2-Negative Metastatic Breast Cancer
For the treatment of adult patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
First-Line Maintenance gBRCAm Metastatic Pancreatic Cancer
For the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer
For the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
BRCAm Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone
In combination with abiraterone and prednisone or prednisolone (abi/pred) for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
Indications:
IMFINZI is indicated for the treatment of adult patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.
IMFINZI, in combination with IMJUDO and platinum-based chemotherapy, is indicated for the treatment of adult patients with metastatic NSCLC with no sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.
IMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).
IMFINZI, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC).
IMFINZI in combination with IMJUDO is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC).
Please refer to the full Prescribing Information for important dosage modification and management information specific to adverse reactions.
IMPORTANT PRODUCT INFORMATION
IMFINZI is indicated for the treatment of adult patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.
IMFINZI, in combination with IMJUDO and platinum-based chemotherapy, is indicated for the treatment of adult patients with metastatic NSCLC with no sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.
IMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).
IMFINZI, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC).
IMFINZI in combination with IMJUDO is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC).
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, immune-mediated dermatologic reactions, immune-mediated pancreatitis, and solid organ transplant rejection. IMFINZI and IMJUDO can cause severe or life-threatening infusion-related reactions. Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treat with a PD-1/PD-L1 blocking antibody.
Advise women not to become pregnant or breastfeed during treatment with IMFINZI and IMJUDO and for 3 months after the last dose.
The most frequent serious adverse reactions reported in at least 2% of patients with unresectable, Stage III NSCLC were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). The most frequent serious adverse reactions reported in at least 2% of patients with metastatic NSCLC were pneumonia (11%), anemia (5%), diarrhea (2.4%), thrombocytopenia (2.4%), pyrexia (2.4%), and febrile neutropenia (2.1%). The most frequent serious adverse reactions reported in at least 1% of patients with ES-SCLC were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%) and COPD (1.1%). The most frequent serious adverse reactions reported in at least 2% of patients with locally advanced or metastatic BTC were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%), and acute kidney injury (2.4%). Serious adverse reactions in >1% of patients with uHCC included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%).
Most common adverse reactions (≥20% of patients with unresectable, Stage III NSCLC) were cough, fatigue, pneumonitis/radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash. The most common adverse reactions (≥20% of patients with metastatic NSCLC) were nausea (42%), fatigue (36%), musculoskeletal pain (29%), decreased appetite (28%), rash (27%), and diarrhea (22%). Most common adverse reactions (≥20% of patients with ES-SCLC) were nausea, fatigue/asthenia, alopecia. The most common adverse reactions (≥20% of adult patients with locally advanced or metastatic BTC) were fatigue, nausea, constipation, decreased appetite, abdominal pain, rash, and pyrexia. The most common adverse reactions (occurring in ≥20% of patients with uHCC) were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.
The safety and effectiveness of IMFINZI and IMJUDO have not been established in pediatric patients.
Please refer to the full Prescribing Information for important dosage modification and management information specific to adverse reactions.
Notes
Ovarian cancer
Ovarian cancer is one of the most common gynecologic cancers and is the eighth most common cancer in women worldwide with more than 314,000 new patients diagnosed in 2020 and over 207,000 deaths. This number is expected to rise by almost 42% by 2040 to over 445,000 newly diagnosed patients and 314,000 deaths.1,2,3
Over two-thirds of patients are diagnosed with advanced disease, which can progress quickly, often within two years, diminishing their quality of life despite treatment. Unfortunately, 50-70% of patients with advanced disease die within five years.4-7 Outcomes are generally worse in patients with homologous recombination deficiency (HRD)-negative disease, where survival at five years is approximately 30%.5,8
DUO-O
DUO-O is a Phase III randomized, double-blind, placebo-controlled, multi-center trial to evaluate the efficacy and safety of IMFINZI in combination with platinum-based chemotherapy and bevacizumab followed by maintenance treatment with IMFINZI and bevacizumab with or without LYNPARZA in newly diagnosed patients with advanced ovarian cancer without tumor BRCA mutations.
Patients were randomized 1:1:1 to: Arm 1 (control), induction therapy with platinum-based chemotherapy in combination with bevacizumab and placebo followed by maintenance treatment with bevacizumab plus placebo; Arm 2, induction therapy with platinum-based chemotherapy in combination with bevacizumab and IMFINZI followed by maintenance IMFINZI and bevacizumab plus placebo; or Arm 3, induction therapy with platinum-based chemotherapy in combination with bevacizumab and IMFINZI followed by maintenance IMFINZI and bevacizumab plus LYNPARZA. In all arms, platinum-based chemotherapy was administered every 3 weeks (q3w) for up to 6 cycles, bevacizumab was administered q3w for up to 15 months, IMFINZI or placebo was administered q3w for up to 24 months, and LYNPARZA or placebo was administered twice daily for up to 24 months.
The primary endpoint of the trial is progression-free survival (PFS) as assessed by investigator for Arm 3 compared to Arm 1 (control) in the overall trial population which included patients without tumor BRCA mutations and in the subset of these patients with homologous recombination deficiency (HRD)-positive disease. Key secondary endpoints include PFS as assessed by investigator in Arm 2 compared to control, as well as comparisons for overall survival (OS). DUO-O enrolled over 1200 patients across all treatment arms at 179 study locations. For more information about the trial, visit ClinicalTrials.gov.
IMFINZI
IMFINZI (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and releasing the inhibition of immune responses.
IMFINZI is the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiation therapy based on the PACIFIC Phase III trial. IMFINZI is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage small cell lung cancer (SCLC) based on the CASPIAN Phase III trial. Additionally, IMFINZI is approved in combination with a short course of IMJUDO® (tremelimumab-actl) and chemotherapy for the treatment of metastatic NSCLC in the US, EU and Japan based on the POSEIDON Phase III trial.
In addition to its indications in lung cancer, IMFINZI is also approved in combination with chemotherapy in locally advanced or metastatic biliary tract cancer in the US, EU, Japan and several other countries; in combination with IMJUDO in unresectable hepatocellular carcinoma in the US, EU and Japan; and in previously treated patients with advanced bladder cancer in a small number of countries.
Since the first approval in May 2017, more than 200,000 patients have been treated with IMFINZI. As part of a broad development program, IMFINZI is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several gastrointestinal cancers and other solid tumors.
LYNPARZA
LYNPARZA® (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumors harboring a deficiency in homologous recombination repair (HRR), such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as new hormonal agents [NHAs]).
Inhibition of PARP with LYNPARZA leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death.
LYNPARZA is currently approved in a number of countries across multiple tumor types including maintenance treatment of platinum-sensitive relapsed ovarian cancer and as both monotherapy and in combination with bevacizumab for the 1st-line maintenance treatment of BRCA-mutated (BRCAm) and homologous recombination deficiency (HRD)-positive advanced ovarian cancer, respectively; for germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer (in the EU and Japan this includes locally advanced breast cancer); for gBRCAm, HER2-negative high-risk early breast cancer (in Japan this includes all BRCAm HER2-negative high-risk early breast cancer); for gBRCAm metastatic pancreatic cancer; in combination with abiraterone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated (in the EU) and as monotherapy in HRR gene-mutated mCRPC in patients who have progressed on prior NHA treatment (BRCAm only in the EU and Japan). In China, LYNPARZA is approved for the treatment of BRCA-mutated mCRPC, as a 1st-line maintenance therapy in BRCA-mutated advanced ovarian cancer as well as 1st-line maintenance treatment with bevacizumab for HRD-positive advanced ovarian cancer.
LYNPARZA, which is being jointly developed and commercialized by AstraZeneca and Merck & Co., Inc., known as MSD outside the US and Canada, has been used to treat over 75,000 patients worldwide. The companies develop LYNPARZA in combination with their respective PD-L1 and PD-1 medicines independently. LYNPARZA is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.
AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.
The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience.
By harnessing the power of six scientific platforms – Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response, Antibody Drug Conjugates, Epigenetics and Cell Therapies – and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.
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References
- Momenimovahed Z, et al. Ovarian Cancer in the World: Epidemiology and Risk Factors. Int J Womens Health. 2019 Apr 30;11:287-299.
- World Cancer Research Fund International. Ovarian Cancer Statistics. Available at https://www.wcrf.org/cancer-trends/ovarian-cancer-statistics/#:~:text=Latest%20ovarian%20cancer%20data,of%20ovarian%20cancer%20in%202020. Accessed May 2023.
- WOCC. Global Ovarian Cancer Charter Data Briefing. Available at https://worldovariancancercoalition.org/wp-content/uploads/2022/02/Global-Priority_Final.pdf. Accessed May 2023.
- National Cancer Institute. Cancer Stat Facts: Ovarian Cancer. Available at https://seer.cancer.gov/statfacts/html/ovary.html. Accessed May 2023.
- Ray-Coquard, et al. Final Overall Survival (OS) Results From the Phase III PAOLA-1/ENGOT-ov25 Trial Evaluating Maintenance Olaparib (ola) Plus Bevacizumab (bev) in Patients (pts) with Newly Diagnosed Advanced Ovarian Cancer (AOC). Presented at the European Society of Medical Oncology Congress. Paris, France. 09 September 2022.
- Ray-Coquard I, et al. Olaparib Plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N Engl J Med. 2019; 381:2416-2428
- González-Martín A, et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2019; 381:2391-2402
- Medical News Today. What To Know About HRD Testing For Ovarian Cancer. Available at https://www.medicalnewstoday.com/articles/hrd-positive-ovarian-cancer. Accessed May 2023.
SOURCE: AstraZeneca
