AZN AstraZeneca PLC

Combination was well tolerated and allowed patients to maintain their quality of life vs. patients treated with abiraterone alone

PROpel Phase III trial results show clinically meaningful benefit in patients irrespective of homologous recombination repair gene mutations

AstraZeneca and Merck & Co., Inc., known as MSD outside the US and Canada, today announced that positive results from the PROpel Phase III trial showed LYNPARZA® (olaparib) in combination with abiraterone demonstrated a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) versus current standard-of-care abiraterone as a 1st-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) with or without homologous recombination repair (HRR) gene mutations.

These results will be presented on February 17 at the 2022 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium.

Prostate cancer is the second most common cancer in male patients, causing approximately 375,000 deaths in 2020.1 Patients with advanced prostate cancer have a particularly poor prognosis and the five-year survival rate remains low.1,2,3 Approximately half of patients with mCRPC receive only one line of active treatment, with diminishing benefit of subsequent therapies.4,5,6,7 HRR gene mutations occur in approximately 20-30% of patients with mCRPC.8

Fred Saad, Professor and Chairman of Urology and Director of Genitourinary Oncology at the University of Montreal Hospital Center and principal investigator in the trial, said: “It is clear to me that the prognosis for metastatic castration-resistant prostate cancer (mCRPC) is extremely poor, and many patients are only able to receive one line of effective therapy. The results of the PROpel trial, which showed that olaparib in combination with abiraterone significantly delayed disease progression versus abiraterone by more than eight months, demonstrate the potential for this combination to become a new standard of care option in mCRPC if approved.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “This LYNPARZA combination has the potential to afford first-line patients more time without disease progression while also maintaining their quality of life. The PROpel results are impressive because active comparator trials set a high bar and, in this trial, LYNPARZA plus abiraterone showed a significant clinical improvement when compared to an active standard of care in patients with metastatic castration-resistant prostate cancer, regardless of whether they have an HRR gene mutation.”

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories, said: “Results from the PROpel trial showed that LYNPARZA in combination with abiraterone plus prednisone reduced the risk of disease progression or death by a third compared to abiraterone plus prednisone in the first-line setting for patients with metastatic castration-resistant prostate cancer, regardless of their biomarker status. We look forward to discussing these important results with global health authorities as quickly as possible. We thank the patients, caregivers and health care providers for participating in this study.”

In a predefined interim analysis, LYNPARZA in combination with abiraterone reduced the risk of disease progression or death by 34% versus abiraterone alone (based on a hazard ratio [HR] of 0.66; 95% confidence interval [CI] 0.54-0.81; p<0.0001). Median rPFS was 24.8 months for LYNPARZA plus abiraterone versus 16.6 for abiraterone alone.

Results also showed a favorable trend towards improved overall survival (OS) with LYNPARZA plus abiraterone versus abiraterone alone, however the difference did not reach statistical significance at the time of this data cut-off (analysis at 29% data maturity). The trial will continue to assess OS as a key secondary endpoint.

Additional data from efficacy endpoints such as time to first subsequent therapy (TFST), second progression-free survival (PFS2), objective response rate (ORR), as well as prostate-specific antigen levels and circulating-tumor-cell counts further support the treatment benefit of LYNPARZA and abiraterone compared to abiraterone alone in the overall trial population.

The safety and tolerability of LYNPARZA in combination with abiraterone was in line with that observed in prior clinical trials and the known profiles of the individual medicines. There was no increase in the rate of discontinuation of abiraterone in patients treated with LYNPARZA in combination with abiraterone, and no detrimental effect on health-related quality of life versus those treated with abiraterone alone (FACT-P (Functional Assessment of Cancer Therapy-Prostate) questionnaire).

Summary of PROpel results

 

LYNPARZA + abiraterone (n=399)

Placebo + abiraterone (n=397)

rPFS by Investigator 1

 

Number of patients with events (%)

168 (42)

226 (57)

Median PFS (in months)

24.8

16.6

HR (95% CI) p-value

0.66 (0.54, 0.81) <0.0001

rPFS by BICR2

Number of patients with events (%)

157 (39)

218 (55)

Median PFS (in months)

27.6

16.4

HR (95% CI) p-value5

0.61 (0.49, 0.74) <0.0001

OS3

Number of patients with events (%)

107 (27)

121 (30)

Median OS (in months)

NC4

NC

HR (95% CI) p-value

0.86 (0.66, 1.12) 0.2923

PFS2

Number of patients with events (%)

70 (18)

94 (24)

Median (in months)

NC

NC

HR (95% CI) p-value5

0.69 (0.51, 0.94) 0.0184

TFST

Number of patients with events (%)

183 (46)

221 (56)

Median (95% CI) (in months)

25.0 (22.2, NC)

19.9 (17.1, 22.0)

HR (95% CI) p-value5

0.74 (0.61, 0.90) 0.0040

Objective Response Rate

Number of evaluable patients6

161

160

Number of patients with responses (%)

94 (58)

77 (48)

Odds ratio (95% CI)

1.60 (1.02, 2.53)

p-value5

0.0409

rPFS by HRR gene mutation status7

HRRm

Number of patients randomized

111

115

Number of patients with events (%)

43 (39)

73 (63)

Median (in months)

NC

13.9

HR (95% CI)

0.50 (0.34, 0.73)

Non-HRRm

Number of patients randomized

279

273

Number of patients with events (%)

119 (43)

149 (55)

Median (95% CI) (in months)

24.1 (19.6, 27.6)

19.0 (14.3, 21.9)

HR (95% CI)

0.76 (0.60, 0.97)

1. Investigator-assessed PFS data; Interim analysis with 50% maturity (394 events in 796 patients)

2. Assessed by blinded independent central review (BICR)

3. OS analysis was done at 29% maturity (228 events in 796 patients) and boundary for significance 0.001 (2-sided); statistical significance not reached. Survival follow up continues and further analyses were planned.

4. Not calculable

5. Nominal

6. Patients with measurable disease at baseline as per RECIST 1.1 criteria, investigator assessment.

7. Exploratory subgroup analysis by HRR status. The HRRm status of patients in PROpel was determined retrospectively using results from tumor tissue and plasma ctDNA HRRm tests. Patients were classified as HRRm if (one or more) HRR gene mutation was detected by either test; patients were classified as non-HRRm if no HRR gene mutation was detected by either test; 18 patients did not have a valid HRR testing result from either a tumor tissue or ctDNA test and were excluded from this subgroup analysis. The analysis was performed using a Cox proportional hazards model including terms for treatment group, the subgroup factor, and a treatment by subgroup interaction.

The most common adverse events (AEs) (greater than or equal to 20% of patients) were anemia (45%), nausea (28%) and fatigue (28%). Grade 3 or higher AEs were anemia (15%), hypertension (4%), urinary tract infection (2%), fatigue (1%), decreased appetite (1%), vomiting (1%), asthenia (1%), back pain (1%), diarrhea (1%). Approximately 86% of patients treated with LYNPARZA in combination with abiraterone who experienced AEs remained on treatment at the time of data cut-off.

In September 2021 at a planned interim analysis, the Independent Data Monitoring Committee concluded that the PROpel trial met the primary endpoint of rPFS.

LYNPARZA is approved in the US for patients with HRR gene-mutated mCRPC (BRCA-mutated and other HRR gene mutations); and in the EU, Japan and China for patients with BRCA-mutated mCRPC.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

There are no contraindications for LYNPARZA.

WARNINGS AND PRECAUTIONS

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in approximately 1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The median duration of therapy in patients who developed MDS/AML was 2 years (range: <6 months to >10 years). All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.

Pneumonitis: Occurred in 0.8% of patients exposed to LYNPARZA monotherapy, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.

Females Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

Venous Thromboembolic Events: Including pulmonary embolism, occurred in 7% of patients with metastatic castration-resistant prostate cancer who received LYNPARZA plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. Patients receiving LYNPARZA and ADT had a 6% incidence of pulmonary embolism compared to 0.8% of patients treated with ADT plus either enzalutamide or abiraterone. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism, and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated.

ADVERSE REACTIONS—First-Line Maintenance BRCAm Advanced Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection/influenza/nasopharyngitis/bronchitis (28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), UTI (13%), thrombocytopenia (11%), and stomatitis (11%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: decrease in hemoglobin (87%), increase in mean corpuscular volume (87%), decrease in leukocytes (70%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease in platelets (35%), and increase in serum creatinine (34%).

ADVERSE REACTIONS—First-Line Maintenance Advanced Ovarian Cancer in Combination with Bevacizumab

Most common adverse reactions (Grades 1-4) in ≥10% of patients treated with LYNPARZA/bevacizumab compared to a ≥5% frequency for placebo/bevacizumab in the first-line maintenance setting for PAOLA-1 were: nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%) and leukopenia (18%). In addition, the most common adverse reactions (≥10%) for patients receiving LYNPARZA/bevacizumab irrespective of the frequency compared with the placebo/bevacizumab arm were: diarrhea (18%), neutropenia (18%), urinary tract infection (15%) and headache (14%).

In addition, venous thromboembolic events occurred more commonly in patients receiving LYNPARZA/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients for LYNPARZA in combination with bevacizumab in the first-line maintenance setting for PAOLA-1 were: decrease in hemoglobin (79%), decrease in lymphocytes (63%), increase in serum creatinine (61%), decrease in leukocytes (59%), decrease in absolute neutrophil count (35%) and decrease in platelets (35%).

ADVERSE REACTIONS—Maintenance Recurrent Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2 were: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%).

Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), decreased appetite (21%) and dyspepsia (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

ADVERSE REACTIONS—Advanced gBRCAm Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue/asthenia (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), mean corpuscular volume elevation (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

ADVERSE REACTIONS—gBRCAm, HER2-Negative Metastatic Breast Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

ADVERSE REACTIONS—First-Line Maintenance gBRCAm Metastatic Pancreatic Adenocarcinoma

Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for POLO were: fatigue (60%), nausea (45%), abdominal pain (34%), diarrhea (29%), anemia (27%), decreased appetite (25%), constipation (23%), vomiting (20%), back pain (19%), arthralgia (15%), rash (15%), thrombocytopenia (14%), dyspnea (13%), neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and stomatitis (10%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for POLO were: increase in serum creatinine (99%), decrease in hemoglobin (86%), increase in mean corpuscular volume (71%), decrease in lymphocytes (61%), decrease in platelets (56%), decrease in leukocytes (50%), and decrease in absolute neutrophil count (25%).

ADVERSE REACTIONS—HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer

Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA for PROfound were: anemia (46%), fatigue (including asthenia) (41%), nausea (41%), decreased appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia (12%), cough (11%), and dyspnea (10%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for PROfound were: decrease in hemoglobin (98%), decrease in lymphocytes (62%), decrease in leukocytes (53%), and decrease in absolute neutrophil count (34%).

DRUG INTERACTIONS

Anticancer Agents: Clinical studies of LYNPARZA with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

CYP3A Inhibitors: Avoid coadministration of strong or moderate CYP3A inhibitors when using LYNPARZA. If a strong or moderate CYP3A inhibitor must be coadministered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid coadministration of strong or moderate CYP3A inducers when using LYNPARZA.

USE IN SPECIFIC POPULATIONS

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C).

Renal Impairment: No dosage modification is recommended in patients with mild renal impairment (CLcr 51-80 mL/min estimated by Cockcroft-Gault). In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the dose of LYNPARZA to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

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.

Advanced gBRCAm Ovarian Cancer

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of 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.

Please click here for complete Prescribing Information, including Patient Information (Medication Guide).

Notes

Metastatic castration-resistant prostate cancer Metastatic prostate cancer is associated with a significant mortality rate.3 Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.9

In patients with mCRPC, their prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.10 Approximately 10-20% of patients with advanced prostate cancer will develop castration-resistant prostate cancer (CRPC) within five years, and at least 84% of these patients will have metastases at the time of CRPC diagnosis.10

Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.11 Despite the advances in mCRPC treatment in the past decade with taxane and new hormonal agent (NHA) treatment, once patients failed first line therapy, the treatment effect of second line anti-cancer therapy diminished significantly hence there is high unmet medical need in this population.10,12,13,14

PROpel PROpel is a randomized, double-blind, multi-center Phase III trial testing the efficacy, safety, and tolerability of LYNPARZA versus placebo when given in addition to abiraterone in men with mCRPC who had not received prior chemotherapy or NHAs in the 1st-line setting.

Men in both treatment groups will also receive either prednisone or prednisolone twice daily. The primary endpoint is rPFS and secondary endpoints include OS, PFS2, and TFST.

For more information about the trial please visit ClinicalTrials.gov.

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 HRR, such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as NHAs).

Inhibition of PARP proteins 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. In the PROpel Phase III trial, LYNPARZA is combined with abiraterone, an NHA which targets the androgen receptor (AR) pathway.

Androgen receptor signalling engages a transcriptional program that is critical for tumor cell growth & survival in prostate cancer.15,16 Preclinical models have identified interactions between PARP signalling and the AR pathway which support the observation of a combined anti-tumor effect of LYNPARZA and NHAs, like abiraterone, in both HRR deficient and HRR proficient prostate cancer.17,18,19

The PARP1 protein has been reported to be required for the transcriptional activity of androgen receptors; therefore inhibiting PARP with LYNPARZA may impair the expression of androgen receptor target genes and enhance the activity of NHAs.15,18,20 Additionally, it is thought that abiraterone may alter/inhibit the transcription of some HRR genes which may induce HRR deficiency and increase sensitivity to PARP inhibition.17,19,21,22

LYNPARZA is currently approved in a number of countries across PARP-dependent tumor types with defects and dependencies in the DDR pathway. It is approved for the maintenance treatment of platinum-sensitive relapsed ovarian cancer as a 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.

LYNPARZA is also approved for BRCAm, HER2-negative metastatic breast cancer (in the EU this includes locally advanced breast cancer); for germline BRCAm metastatic pancreatic cancer, and for HRR gene-mutated metastatic castration-resistant prostate cancer (BRCAm only in the EU and Japan).

LYNPARZA, which is being jointly developed and commercialized by AstraZeneca and Merck, is the foundation of AstraZeneca's industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

The AstraZeneca and Merck strategic oncology collaboration In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialize LYNPARZA (olaparib), the world’s first PARP inhibitor, and selumetinib, a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types.

Working together, the companies will develop LYNPARZA and selumetinib in combination with other potential new medicines and as monotherapies. Independently, the companies will develop LYNPARZA and selumetinib in combination with their respective PD-L1 and PD-1 medicines.

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.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

About AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

References 1. IARC. Cancer Today – Estimated number of new cases in 2020, worldwide, both sexes, all ages. Available at https://gco.iarc.fr/today/home. Accessed January 2022. 2. Moreira D, et al. Predicting Time From Metastasis to Overall Survival in Castration-Resistant Prostate Cancer: Results From SEARCH. Clin Genitourin Cancer. 2017;15(1):60-66.e2. 3. Chowdhury S, et al. Real-world outcomes in first-line treatment of metastatic castration-resistant prostate cancer: the prostate cancer registry. Target Oncol. 2020;15(3):301-15. 4. George DJ, et al. Treatment Patterns and Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer in a Real-world Clinical Practice Setting in the United States. Clin Genitourin Cancer. 2020; 18(4):284-294. 5. de Bono JS, et al. Subsequent Chemotherapy and Treatment Patterns After Abiraterone Acetate in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302. Eur Urol. 2017;71(4):656-664. 6. Ryan CJ, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152-160. 7. Beer TM, et al. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol. 2017;71(2):151-154 8. Mateo, J, et al (2015). DNA-repair defects and olaparib in metastatic prostate cancer. The New England Journal of Medicine, 373(18), pp.1697 - 1708. 9. Cancer.Net. Treatment of metastatic castration-resistant prostate cancer. Available at www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer. Accessed January 2022. 10. Kirby, M, et al. Characterising the castration-resistant prostate cancer population: a systematic review. International Journal of Clinical Practice, 2021;65(11):1180-1192. 11. Smith MR, et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol. 2005;23(13):2918-25. 12. UroToday. What is Changing in Advanced Prostate Cancer? Available at https://www.urotoday.com/journal/everyday-urology-oncology-insights/articles/122176-what-is-changing-in-advanced-prostate-cancer.html. Accessed January 2022. 13. Liu J, et al. Second-line Hormonal Therapy for the Management of Metastatic Castration-resistant Prostate Cancer: a Real-World Data Study Using a Claims Database. Scientific Report. 2020;10(4240):2020. 14. UroToday. Beyond First-line Treatment of Metastatic Castrate-resistant Prostate Cancer. Available at https://www.urotoday.com/library-resources/mcrpc-treatment/114592-beyond-first-line-treatment-of-metastatic-castrate-resistant-prostate-cancer.html. Accessed January 2022. 15. Schiewer MJ, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2012;2(12):1134-1149. 16. Schiewer MJ & Knudsen KE. AMPed up to treat prostate cancer: novel AMPK activators emerge for cancer therapy. EMBO Mol Med. 2014;6(4):439-441. 17. Li L, et al. Androgen receptor inhibitor–induced “BRCAness” and PARP inhibition are synthetically lethal for castration-resistant prostate cancer. Sci Signal. 2017; 10(480):eaam7479. 18. Polkinghorn WR, et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov. 2013;3(11):1245-1253. 19. Asim M, et al. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat Commun. 2017;374(8). 20. Ju B-G, et al. A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription. Science. 2006;312(5781):1798-1802. 21. Goodwin JF, et al. A hormone-DNA repair circuit governs the response to genotoxic insult. Cancer Discov. 2013;3(11):1254-1271. 22. Tarish FL, et al. Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair. Sci Transl Med. 2015; 7(312):312re11.

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