LYNPARZA + bevacizumab: NOW APPROVED in patients with HRD-positive* advanced ovarian cancer, following complete or partial response to first-line platinum-based chemotherapy1

LYNPARZA is the only PARPi combination regimen investigated against an active and established maintenance therapy: bevacizumab1-4

For the potential
of more time
progression free1

*Select patients for this indication based on an
FDA-approved companion diagnostic.1

LYNPARZA is not indicated in patients under 18.1

In women with HRD-positive* advanced ovarian cancer in response to first-line platinum-based chemotherapy with bevacizumab, LYNPARZA + bevacizumab demonstrated a clinically significant median PFS benefit of 3.1 years (37.2 months) vs ~1.5 years (17.7 months) with bevacizumab + placebo. HR=0.33 (95% CI: 0.25–0.45)1†

PFS in the HRD population was a prespecified exploratory analysis in the PAOLA-1 trial.5

CI=confidence interval; HR=hazard ratio; HRD=homologous recombination deficiency; PARPi=poly (ADP-ribose) polymerase inhibitor; PFS=progression-free survival.

PAOLA-1 is the first and only phase 3 trial to investigate a PARP inhibitor combination regimen against an active and established maintenance therapy: bevacizumab1-5

PAOLA-1 icon

PAOLA-1 studied LYNPARZA + bevacizumab vs an active comparator (bevacizumab + placebo)1,5,6

PAOLA-1 studied LYNPARZA + bevacizumab vs. an active comparator (bevacizumab + placebo)

*LYNPARZA or placebo was administered for up to 24 months or until disease progression or unacceptable toxicity. This study did not implement a prespecified crossover study design.

PAOLA-1 primary endpoint1:

Investigator-assessed PFS

Select secondary endpoints5,7‡:

  • Safety
  • Time from randomization until second disease progression or death
  • Time until first subsequent therapy or death
  • Overall survival

PRESPECIFIED EXPLORATORY ANALYSES1,5‡:

PFS in predefined subgroups, including HRD status and BRCA mutation status

PFS within HRD-positive patients served as the basis of the FDA-approved indication.

More endpoints than those noted here were studied in PAOLA-1. Not all results from these endpoints are detailed on this site.7

BID=twice daily; BRCAm=BRCA-mutated; Q3W=every 3 weeks.

Approximately half of the patients in the PAOLA-1 trial were HRD positive5

All trial participants were retrospectively evaluated for HRD using the Myriad myChoice® CDx1*

HRD-positive patients were defined as BRCAm or non-BRCAm with other biomarkers of HRD. In the PAOLA-1 trial, 48% of patients were HRD positive.5,7

*HRD positive is defined as either a tBRCA mutation and/or an HRD score ≥42 by myChoice® CDx; HRD negative is defined as either non-tBRCA and/or an HRD score <42 by Myriad myChoice® CDx.7 4.2% of the test results were missing, 2.1% failed, and 11.3% were inconclusive, yielding approximately 18% of the total PAOLA-1 population with an unknown HRD status.8

Approximately half of the patients in the PAOLA-1 trial were HRD positive

All women with a BRCA mutation are HRD positive, but not all women who are HRD positive have a BRCA mutation9†

Key genotypic biomarkers of HRD in tumor cells beyond BRCA mutations include mutations in other specific HRR genes or other causes of altered gene expression (eg, epigenetic alterations).10,11

In a prespecified exploratory analysis of HRD-negative and HRD-unknown patients, there was insufficient evidence to suggest differential efficacy between the combination of LYNPARZA + bevacizumab and bevacizumab + placebo.

tBRCA=tumor BRCA.

In women with HRD-positive* advanced ovarian cancer, following complete or partial response to first-line platinum-based chemotherapy + bevacizumab1

LYNPARZA + bevacizumab demonstrated a clinically significant median PFS benefit of 3.1 years vs ~1.5 years with bevacizumab + placebo in HRD-positive patients1†

HRD positive – prespecified exploratory analysis

LYNPARZA + bevacizumab demonstrated a clinically significant PFS benefit vs bevacizumab + placebo in HRD-positive patients1

HR=0.59;
95% CI: 0.49–0.72;
P<0.0001

Data based upon a prespecified exploratory subgroup analysis, which was not controlled for Type 1 error. HRD status was not a stratification factor for PAOLA-1.5,6

Additional subgroup analyses:

  • In HRD-positive, non-BRCAm patients, median PFS in the LYNPARZA + bevacizumab arm was 28.1 months and median PFS in the bevacizumab + placebo arm was 16.6 months. HR=0.43; 95% CI: 0.28–0.66 (prespecified exploratory analysis)5
  • In BRCAm patients, median PFS in the LYNPARZA + bevacizumab arm was 37.2 months and median PFS in the bevacizumab + placebo arm was 21.7 months. HR=0.31; 95% CI: 0.20–0.47 (stratified subgroup)1,5

There was insufficient evidence to suggest differential efficacy between the 2 groups.

ESTIMATED PROPORTION OF PATIENTS FREE FROM PROGRESSION OR DEATH AT 2 YEARS1,5

LYNPARZA + bevacizumab (n=255)

66%

bevacizumab + placebo (n=132)

29%

The 2-year analysis is descriptive only; the PAOLA-1 trial was not powered to assess a statistical difference between treatment groups at these time points.

*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 is defined as either a tBRCA mutation and/or an HRD score ≥42 by Myriad myChoice® CDx.7

The 2-year analysis is descriptive only; the PAOLA-1 trial was not powered to assess a statistical difference between treatment groups at these time points.

In PAOLA-1

ARs occurring in ≥10% of patients treated with LYNPARZA + bevacizumab and at ≥5% frequency compared with placebo + bevacizumab1

Common ARs with LYNPARZA were generally consistent with the known safety profile of LYNPARZA monotherapy1

Adverse reactions reported in PAOLA-1 phase 3 trial
Adverse reactions reported in PAOLA-1 phase 3 trial

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*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%).1

  • In addition, venous thromboembolic events occurred more commonly in patients receiving LYNPARZA + bevacizumab (5%) than in those receiving placebo + bevacizumab (1.9%)1

AR=adverse reaction.

In PAOLA-1

Lab abnormalities reported in ≥25% of women on LYNPARZA + bevacizumab vs
bevacizumab + placebo1*

Lab abnormalities reported in PAOLA-1 phase 3 trial
Lab abnormalities reported in PAOLA-1 phase 3 trial

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*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.

Laboratory abnormalities in PAOLA-1 were mostly
Grades 1 and 21

LYNPARZA dose modifications due to ARs in PAOLA-11,5

  • Anemia (4%) and nausea (3%) were reported to cause discontinuation rates >2%; all other ARs leading to discontinuation occurred with a frequency of 1% or below1,6
  • Recorded ARs occurred during study treatment or up to 30 days after discontinuation of the intervention6

Please refer to the Prescribing Information for bevacizumab when used in combination with LYNPARZA for recommended dosing information.

8 out of 10 women remained on LYNPARZA as prescribed in combination with bevacizumab without discontinuing due to ARs1

TUMOR TEST for HRD with Myriad myChoice® CDx AT DIAGNOSIS1,12

Start with tumor testing at diagnosis to help inform first-line maintenance treatment eligibility for LYNPARZA + bevacizumab1,12

WHY TUMOR TEST FOR HRD AT DIAGNOSIS

Test for HRD genomic instability at diagnosis

BRCA results are part of the HRD assay.12 Test cannot distinguish between germline and somatic mutations.12 If found to have a BRCA mutation, consult with a genetic counselor for germline testing to identify familial risk.

WHEN TO TUMOR TEST

Presents to her doctor icon

Presents
to her doctor16

Collect tissue sample icon

Collect tissue
sample at biopsy or
surgical cytoreduction16

Promptly send tumor tissue to lab icon

Promptly
send tumor
tissue to CDx
lab16

Receive results icon

Receive
results within
2 weeks17

  • Tumor tests cannot distinguish between germline and somatic BRCA mutations12
  • If found to have a BRCA mutation, consult with genetic counselor for germline testing to identify familial risk

HOW TO TEST

At first tissue collection, order Myriad myChoice® CDx* to determine patient’s HRD status1,12

  • Visit MyriadmyChoice.com for more information about ordering the Myriad myChoice® CDx
  • Partner with your pathologist for specimen handling and shipment

*HRD positive is defined as either a tBRCA mutation and/or an HRD score ≥42 by Myriad myChoice® CDx; HRD negative is defined as either non–tBRCA-mutated and/or an HRD score <42 by Myriad myChoice® CDx. HRD unknown is defined in accordance with a test that fails, is inconclusive, or is missing.7,8 Test determines HRD status by detecting BRCA1 and BRCA2 variants and assessing genomic instability.12

Test for HRD at diagnosis to identify patients that may be eligible for LYNPARZA + bevacizumab1,12†

LYNPARZA monotherapy is a first-line maintenance therapy option for women with a BRCAm detected by an FDA-approved test who did not receive bevacizumab at induction.1

HRRm=homologous recombination repair gene mutation.

An integrated regimen

Consider LYNPARZA + bevacizumab as part of your integrated first-line maintenance treatment in advanced ovarian cancer1,5,12

*When used with LYNPARZA, the recommended dose of bevacizumab is 15 mg/kg every 3 weeks. Refer to the Prescribing Information for bevacizumab when used in combination with LYNPARZA for more information.1

Per PAOLA-1 protocol:

  • Bevacizumab prescribed for at least the last 3 cycles in combination with platinum-based chemotherapy7
  • Bevacizumab used for a total of 15 months, including the period given with chemotherapy and given as maintenance1,7

IMPORTANT SAFETY INFORMATION

See Important Safety Information, including Warnings and Precautions for MDS/AML, Pneumonitis and Embryo-Fetal Toxicity, below.

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.

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.

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%).

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).

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

You may report side effects related to AstraZeneca products by clicking here.

References: 1. LYNPARZA® (olaparib) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020. 2. Zejula® (niraparib) [prescribing information]. Waltham, MA: TESARO, Inc.; 2020. 3. Rubraca® (rucaparib) [prescribing information]. Boulder, CO: Clovis Oncology, Inc.; 2018. 4. Talzenna® (talazoparib) [prescribing information]. New York, NY: Pfizer, Inc.; 2020. 5. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428. 6. Ray-Coquard I, Pautier P, Pignata S. et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. Supplementary Appendix. N Engl J Med. 2019;381(25):2416-2428. 7. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. PAOLA-1 Protocol. N Engl J Med. 2019;381(25):2416-2428. 8. Ray-Coquard I, Pautier P, Pignata S, et al. Phase III PAOLA-1/ ENGOT-ov25: maintenance olaparib with bevacizumab in patients with newly diagnosed, advanced ovarian cancer treated with platinum-based chemotherapy and bevacizumab as standard of care. Poster presented at: ESMO 2019; September 27-October 1, 2019; Barcelona, Spain. 9. 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. 10. Frey MK, Pothuri B. Homologous recombination deficiency (HRD) testing in ovarian cancer clinical practice: a review of the literature. Gynecol Oncol Res Pract. 2017;4:4. 11. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. 12. Myriad myChoice® CDx. Technical Information. Myriad Genetic Laboratories, Inc. Accessed April 12, 2020. https://bit.ly/myChoiceCDxSpecs 13. Pennington KP, Walsh T, Harrell MI, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014;20(3):764-775. 14. Pal T, Permuth-Wey J, Betts JA, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816. 15. FoundationOne® CDx. Technical Information. Foundation Medicine, Inc. Accessed April 12, 2020. https://assets.ctfassets.net/ 16. Capoluongo E, Ellison G, López-Guerrero JA, et al. Guidance statement on BRCA1/2 tumor testing in ovarian cancer patients. Semin Oncol. 2017;44(3):187-197. 17. Myriad Genetics. About genetic testing. Accessed April 12, 2020. https://myriad.com/healthcare-professionals/about-genetic-testing/overview