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LYNPARZA (olaparib) More Than Doubled the Time Without Radiographic Disease Progression in Patients With BRCA1/2- or ATM-Mutated Metastatic Castration-Resistant Prostate Cancer

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AstraZeneca and Merck's LYNPARZA reduced the risk of disease progression or death by 51% in men with homologous recombination repair (HRR) gene mutations

First positive Phase III trial testing a targeted treatment in biomarker-selected prostate cancer patients

AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., US (Merck: known as MSD outside the US and Canada) today presented detailed results from the Phase III PROfound trial in 387 men with metastatic castration-resistant prostate cancer (mCRPC) who have a mutation in their homologous recombination repair (HRRm) genes and whose disease had progressed on prior treatment with new hormonal agent (NHA) treatments (e.g. abiraterone or enzalutamide).

The trial was designed to analyze men with HRRm genes in two cohorts: the primary endpoint was in those with mutations in BRCA1/2 or ATM genes and then, if LYNPARZA® (olaparib) showed clinical benefit, a formal analysis was performed of the overall trial population of men with HRRm genes (BRCA1/2, ATM, CDK12 and 11 other HRRm genes; key secondary endpoint).

Results showed a statistically significant and clinically meaningful improvement with LYNPARZA in the primary endpoint of radiographic progression-free survival (rPFS), improving the time men with BRCA1/2- or ATM-mutated mCRPC lived without disease progression or death to a median of 7.4 months vs. 3.6 months for those treated with abiraterone or enzalutamide. LYNPARZA reduced the risk of disease progression or death by 66% (equal to a hazard ratio of 0.34) for these men.

The trial also met the key secondary endpoint of rPFS in the overall HRRm population, where LYNPARZA reduced the risk of disease progression or death by 51% (equal to a hazard ratio of 0.49) and improved rPFS to a median of 5.8 months vs. 3.5 months for abiraterone or enzalutamide.

The results were presented during the Presidential Symposium at the 2019 European Society of Medical Oncology (ESMO) congress in Barcelona, Spain (Abstract #LBA12_PR).

Results also showed a trend at this interim analysis time point for improvement in overall survival (OS), another key secondary endpoint, in the two groups. LYNPARZA extended OS to 18.5 months vs. 15.1 months for abiraterone or enzalutamide in men with BRCA1/2- or ATM-mutated tumors, despite that at this interim analysis 81% of patients on NHA crossed over to LYNPARZA at progression. A similar trend in OS was observed at this interim analysis in the overall HRRm population with a median of 17.5 months' OS for men treated with LYNPARZA vs. 14.3 months for abiraterone or enzalutamide (analysis at 41% data maturity).

José Baselga, Executive Vice President, Oncology R&D, said: "Results from PROfound demonstrate that, in addition to providing substantial benefit as a precision medicine for men with metastatic castration-resistant prostate cancer with BRCA-mutated tumors, LYNPARZA is effective beyond just BRCA in tumors with mutations in other genes associated with homologous recombination repair. PROfound validates the concept of PARP sensitivity across multiple genes associated with homologous recombination repair in this disease and marks the first positive Phase III trial using a molecular biomarker to identify men for targeted treatment for metastatic castration-resistant prostate cancer. We are working with global health authorities to bring LYNPARZA to these patients as quickly as possible."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories, said: "The results from the Phase III PROfound trial are a testament to Merck and AstraZeneca's lasting commitment to patients with cancer. The trial met the primary endpoint in men with metastatic castration-resistant prostate cancer that progressed on prior hormonal therapy, a notoriously difficult-to-treat disease. The benefit seen in patients beyond just those with BRCA mutations underscores the potential value of genomic testing in prostate cancer."

Maha Hussain, one of the principal investigators of the PROfound trial and Deputy Director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, said: "We have seen advances in the treatment over the last 15 years for men with metastatic castration-resistant prostate cancer. However, to date treatments for this state of disease continue to use ‘one size fits all' approaches overlooking the genomic make-up of the tumor and how it could inform treatment decisions to better personalize care and impact outcomes. I am thrilled by the PROfound results and LYNPARZA's clinically meaningful benefit which offers the potential of a molecularly targeted treatment for this patient population with advanced disease. I am confident we are now entering a new era of personalized care and precision medicine for metastatic castration-resistant prostate cancer."

Summary of resultsi

 

Cohort A

(BRCA1/2 or ATM)

Cohort A+B ii

(Overall HRRm)

 

LYNPARZA

n=162

pcNHA

n=83

LYNPARZA

n=256

pcNHA

n=131

rPFS

Median, months

7.4

3.6

5.8

3.5

% progression-free at 6 months

59.8

22.6

49.7

23.7

% progression-free at 12 months

28.1

9.4

22.1

13.5

Hazard ratio (95% CI)

0.34 (0.25-0.47)

0.49 (0.38-0.63)

p-value

<0.0001

<0.0001

Confirmed ORR

Patients with response (%)

33.3

2.3

21.7

4.5

Odds ratio (95% CI)

20.86 (4.18-379.18)

5.93 (2.01-25.40)

p-value

<0.0001

0.0006 (nominal)

Time to pain progression iii

Median, months

NR

9.92

 

 

Hazard ratio (95% CI)

0.44 (0.22-0.91)

 

p-value

0.0192

 

OS (interim) iv

Median, months

18.5

15.1

17.5

14.3

Hazard ratio (95% CI)

0.64 (0.43-0.97)

0.67 (0.49-0.93)

p-value

0.0173

0.0063 (nominal)

NR, not reached; ORR, objective response rate; pc, physician's choice

i Assessed by blinded independent central review (BICR)

ii Cohort B included patients with any 1 of 12 other HRR mutations

iii Time to pain progression in Cohort A was a key secondary endpoint included in the formal hierarchy

iv Interim analysis was done at 38% (Cohort A) and 41% (Cohort A+B) data maturity; Alpha spend at interim was 0.01; statistical significance not reached

The safety and tolerability profile of LYNPARZA in the PROfound trial was in line with that observed in prior clinical trials. The most common adverse events (AEs) ≥20% were anemia (47%), nausea (41%), fatigue/asthenia (41%), decreased appetite (30%) and diarrhea (21%). Grade 3 or above AEs were anemia (22%), pulmonary embolism (4%), fatigue/asthenia (3%), vomiting (2%), dyspnea (2%), urinary tract infection (2%), decreased appetite (1%), diarrhea (1%) and back pain (1%). 16% of patients on LYNPARZA discontinued treatment due to AEs.

AstraZeneca and Merck are also exploring additional trials in prostate cancer, including the ongoing Phase III PROpel trial, testing LYNPARZA as a 1st-line therapy in mCRPC, in combination with abiraterone.

LYNPARZA is currently approved for the maintenance treatment of platinum-sensitive relapsed ovarian cancer regardless of BRCA status. It is approved as 1st-line maintenance treatment in BRCAm advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved for germline BRCAm HER2-negative metastatic breast cancer previously treated with chemotherapy. For 1st-line maintenance in advanced ovarian cancer and the metastatic breast cancer setting, physicians should select patients for therapy based on an FDA-approved companion diagnostic. LYNPARZA is not approved in metastatic pancreatic cancer, but an application is currently under regulatory review.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

There are no contraindications for LYNPARZA.

WARNINGS AND PRECAUTIONS

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

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 <1% of patients exposed to LYNPARZA, 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.

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—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

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