Choose a PARPi that has both clinically meaningful PFS and OS in HRD-positive*† aOC after response to 1L platinum-based chemotherapy1
Results for PFS and OS may vary.
Data based upon a prespecified exploratory subgroup analysis and is not controlled for Type I error. See PAOLA-1 study design and efficacy results for additional information.
*
Select patients for this indication based on an FDA-approved companion diagnostic.1
†
Including BRCA mutation (as determined by Myriad MyChoice® CDx) and other causes of HRD. HRD-positive was defined as either a tBRCA mutation and/or an HRD score ≥42 by Myriad MyChoice® CDx.2
INDICATION
LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:
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.
SELECT SAFETY INFORMATION
LYNPARZA is associated with serious and potentially fatal adverse events, including myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), pneumonitis, and venous thromboembolism (VTE). LYNPARZA can cause fetal harm.
Please see full Important Safety Information below.
FDA approval was based on a prespecified exploratory HRD‑positive subgroup
Median PFS1,3
3.1 years (37.2 months) with LYNPARZA + bevacizumab
~1.5 years (17.7 months) with bevacizumab + placebo
The 2-year analysis is based on Kaplan–Meier estimates and is descriptive only; the PAOLA-1 trial was not powered to assess a statistical difference between treatment groups at this time point.1,3
HRD status was not a stratification factor in PAOLA-1 and analysis was not controlled for Type 1 error.
HRD-positive subgroup (n=387)
Events, n (%): 87/255 (34) with LYNPARZA + bevacizumab and 92/132 (70) with bevacizumab + placebo.
HRD status was not a stratification factor in PAOLA-1, and analysis was not controlled for Type 1 error.
ITT population (n=806)
Statistically significant improvement in PFS was observed for LYNPARZA + bevacizumab compared with bevacizumab + placebo.
HRD-negative subgroup (n=277)
Results from an exploratory analysis in this subgroup (HR=1.00 [95% CI: 0.75–1.34]) indicated that the clinical benefit was primarily attributed to the results seen in the HRD‑positive subgroup.
OVERALL SURVIVAL DATA
Prespecified follow-up exploratory analysis in the HRD-positive subgroup
Median OS1,4
~6.3 years (75.2 months) with LYNPARZA + bevacizumab
~4.8 years (57.3 months) with bevacizumab + placebo
Data based upon a prespecified exploratory subgroup analysis of a secondary endpoint, which was not controlled for Type 1 error. HRD status was not a stratification factor in PAOLA-1.
This trial was not designed to assess a statistical difference between treatment groups at 5 years. The analysis is based on Kaplan–Meier estimates and is descriptive only.
HRD-positive subgroup (n=387)1
Events, n (%): 93/255 (36) with LYNPARZA + bevacizumab and 69/132 (52) with bevacizumab + placebo.
ITT population (n=806)4
Statistical significance in OS was not reached for LYNPARZA + bevacizumab compared with bevacizumab + placebo.
HRD-negative subgroup (n=277)1
Results from an exploratory analysis in this subgroup (HR=1.18 [95% CI: 0.87–1.60]) indicated that the clinical benefit was primarily attributed to the results seen in the HRD‑positive subgroup.
See additional PAOLA-1 data, including 5-year follow-up PFS and safety analysis
PAOLA-1 studied the efficacy and safety of LYNPARZA + bevacizumab vs an active comparator (bevacizumab + placebo)
•
Advanced ovarian cancer following response to first-line platinum-based chemotherapy with bevacizumab. Bevacizumab was prescribed for at least 3 cycles in combination with platinum-based chemotherapy
•
Patients were stratified by tumor BRCA mutation status and first-line treatment outcome. HRD status was not a stratification factor
•
The ITT population was randomized 2:1 (N=806) to receive LYNPARZA tablets 300 mg orally BID in combination with bevacizumab 15 mg/kg infusion every 3 weeks (n=537) or placebo orally BID in combination with bevacizumab 15 mg/kg infusion every 3 weeks (n=269)
•
Treatment with LYNPARZA was continued for up to 2 years or until disease progression or unacceptable toxicity. Patients with a partial response could continue treatment beyond 2 years at the physician’s discretion. Bevacizumab was administered every 3 weeks for a total duration of up to 15 months, including the period given with chemotherapy and given as maintenance*
•
The primary endpoint was the investigator-assessed PFS, and a key secondary endpoint was OS
–
FDA approval for LYNPARZA + bevacizumab was based on a prespecified exploratory subgroup of patients with HRD-positive tumors (n=387)
*
Patients continued bevacizumab in the maintenance setting and started treatment with LYNPARZA after ≥3 weeks and ≤9 weeks following completion of their last dose of chemotherapy.
In the PAOLA-1 primary analysis:
ARs occurring in ≥10% of patients treated with LYNPARZA + bevacizumab and at ≥5% frequency compared with bevacizumab + placebo1
*
Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0.
†
Includes asthenia and fatigue.
‡
Includes anemia, anemia macrocytic, erythropenia, hematocrit decreased, hemoglobin decreased, normochromic anemia, normochromic normocytic anemia, normocytic anemia, and red blood cell count decreased.
§
Includes B-lymphocyte count decreased, lymphocyte count decreased, lymphopenia, and T‑lymphocyte count decreased.
||
Includes leukopenia and white blood cell count decreased.
Fatal adverse reactions occurred in 1 patient due to concurrent pneumonia and aplastic anemia. Serious adverse reactions occurred in 31% of patients who received LYNPARZA + bevacizumab. Serious adverse reactions in >5% of patients included hypertension (19%) and anemia (17%).
In addition, venous thromboembolism occurred more commonly
in patients receiving LYNPARZA + bevacizumab (5%) than in those
receiving bevacizumab + placebo (1.9%).
In the PAOLA-1 primary analysis:
Lab abnormalities reported in ≥25% of patients on LYNPARZA + bevacizumab vs bevacizumab + placebo1*
*
Reported within 30 days of the last dose.
†
This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.
‡
Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.
At 5-year follow-up analysis4
No new safety signals were identified, and the safety profile remained generally consistent with the primary analysis
•
The incidence of MDS/AML/AA was 1.7% (9/535) in the LYNPARZA + bevacizumab group and 2.2% (6/267) in the bevacizumab + placebo group
-
In the HRD-positive subgroup, the incidence of MDS/AML was 1.6% (4/255) in patients who received LYNPARZA + bevacizumab and 2.3% (3/131) in patients who received bevacizumab + placebo1
•
22 (4.1%) new primary malignancy events occurred in the LYNPARZA + bevacizumab group, and 8 (3.0%) events occurred in the bevacizumab + placebo group;
•
7 (1.3%) pneumonitis events occurred in the LYNPARZA + bevacizumab group, and 2 (0.7%) events occurred in the bevacizumab + placebo group
Identify the ~50% of women with advanced ovarian cancer who are HRD positive5
Test patients for HRD at diagnosis to help inform eligibility for LYNPARZA + bevacizumab1,6
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
There are no contraindications for LYNPARZA.
WARNINGS AND PRECAUTIONS
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in approximately 1.2% of patients with various BRCAm, gBRCAm, HRR gene-mutated or HRD-positive cancers who received LYNPARZA as a single agent or as part of a combination regimen, consistent with the approved indications, and the majority of events had a fatal outcome. The median duration of therapy in patients who developed MDS/AML was approximately 2 years (range: <6 months to >4 years). All of these patients had previous chemotherapy with platinum agents and/or other
DNA-damaging agents, including radiotherapy.
In SOLO-1, patients with newly diagnosed advanced BRCAm ovarian cancer, the incidence of MDS/AML was 1.9% (5/260) in patients who received LYNPARZA and 0.8% (1/130) in patients who received placebo based on an updated analysis. In PAOLA-1, of patients with newly diagnosed advanced ovarian cancer with HRD-positive status, the incidence of MDS/AML was 1.6% (4/255) in patients who received LYNPARZA and 2.3% (3/131) in the control arm.
In SOLO-2, patients with BRCAm platinum-sensitive relapsed ovarian cancer, the incidence of MDS/AML was 8% (15/195) in patients who received LYNPARZA and 4% (4/99) in patients who received placebo. The duration of LYNPARZA treatment prior to the diagnosis of MDS/AML ranged from 0.6 years to 4.5 years.
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.
Venous Thromboembolism (VTE): Including severe or fatal pulmonary embolism (PE) occurred in patients treated with LYNPARZA. 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.
Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. Verify pregnancy status in 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.
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 and at a ≥5% frequency compared to 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 thromboembolism 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%).
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).
References: 1. LYNPARZA® (olaparib) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2023. 2. Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. PAOLA-1 Protocol. N Engl J Med. 2019;381(25):2416-2428. 3. Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med
. 2019;381(25):2416-2428. 4. Ray-Coquard I, Leary A, Pignata S, et al; PAOLA-1/ENGOT-ov25 investigators. Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial. Ann Oncol. 2023;34(8):681-692. 5. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015;5(11):1137-1154. 6. Myriad MyChoice
® CDx Technical Information. Myriad Genetic Laboratories, Inc. Accessed November 6, 2024. https://s3.amazonaws.com/myriad-library/technical-specifications/myChoice-HRD-Tech-Specs.pdf
This content is sponsored by AstraZeneca, and ION Oncology Practice Network has not independently reviewed or verified the information provided by AstraZeneca.
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