EFFICACY: SOLO-1

SOLO-1: a landmark phase 3 trial in first-line maintenance of advanced ovarian cancer1,2

In women with sBRCA- and gBRCA-mutated advanced ovarian cancer following response to first-line platinum-based chemotherapy

At median follow-up of 41 months, median PFS not reached in LYNPARZA arm1,2

Explore the study design
SOLO-1 Results of LYNPARZA® (olaparib) vs. placebo

*HR from a Cox proportional hazards model including response to previous platinum chemotherapy (CR vs PR) as a covariate.
The P -value is derived from a stratified log-rank test.

SOLO-1: First-line MTX sBRCAm or gBRCAm1-3

391 patients enrolled

Diagnosis

  • Advanced ovarian, primary peritoneal, and/or fallopian tube cancer

BRCA mutation

  • Germline BRCAm determined by an FDA-approved companion diagnostic
  • OR
  • Somatic BRCAm determined by an investigational FoundationOne® tissue assay
Response to platinum-based chemotherapy Response to platinum-based chemotherapy

Response to platinum-based chemotherapy

In complete or partial response (LYNPARZA and placebo arms: CR=82%; PR=18%)

ECOG performance score ECOG performance score

ECOG performance score

77% of patients receiving LYNPARZA had a score of 0, as did 80% of patients receiving placebo

Median age for patients treated with LYNPARZA Median age for patients treated with LYNPARZA

Age

Median age of 53 years for patients treated with LYNPARZA (range: 29 to 82) and 53 years for patients on placebo (range: 31 to 84)

Included patients regardless of outcome Included patients regardless of outcome

Included patients regardless of surgical outcome

  • Stage III patients must have had 1 attempt at optimal debulking surgery
  • Stage IV patients must have had either a biopsy and/or upfront or interval debulking surgery

Randomized 2:1

LYNPARZA tablets
300 mg BID (n=260)

PLACEBO
BID (n=131)

Primary endpoint: Investigator-assessed PFS

Treatment with LYNPARZA was continued for up to 2 years or until disease progression Treatment with LYNPARZA was continued for up to 2 years or until disease progression

Treatment with LYNPARZA was continued for up to 2 years or until disease progression or unacceptable toxicity. Patients who remained in CR received a maximum treatment duration of 2 years; patients whose disease remained stable could continue to receive LYNPARZA beyond 2 years.

Blinded independent central review (BICR)1-3

Sensitivity analysis of PFS by BICR was consistent with the investigator-assessed PFS and confirmed the robustness of the data (HR=0.28 [95% CI: 0.20–0.39])

BICR does not form part of the multiplicity strategy in SOLO-1.

Median PFS:

LYNPARZA (n=260)
NR

PLACEBO (n=131)
14.1 months

PFS across prognostic-factor subgroups2

Progression-free survival across prognostic-factor subgroups
Progression-free survival across prognostic-factor subgroups

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SOLO-1 was not powered to detect differences in the treatment effect between these subgroups; therefore, results from these exploratory analyses should be interpreted with caution because of the modest patient numbers and baseline imbalances.2

In SOLO-1, in patients with residual disease after platinum-based therapy

Objective response rate (ORR) for LYNPARZA and placebo4

LYNPARZA (n=54) | Placebo (n=26)

Objective response rate for LYNPARZA
Objective response rate for LYNPARZA

Over 1 in 4 patients

with residual disease experienced a conversion to a complete response with LYNPARZA

Over 1 in 7 patients

with residual disease experienced a conversion to a partial response with LYNPARZA

Objective response rates for placebo
Objective response rates for placebo

These post hoc analyses should be interpreted with caution because of the modest patient numbers and baseline imbalances. Patients were prospectively classified as responders if the RECIST criteria for a CR or PR were satisfied at any time, up to and including the defined analysis cutoff point. For each treatment group, the ORR was the number of CRs and PRs divided by the number of patients in the group in the full analysis set with measurable disease at baseline. Only patients with PR and measurable disease at enrollment could achieve an objective response of CR or PR. Although this analysis is defined as post hoc in the poster, the descriptive presentation of this data is described in version 1 of the protocol. Trial was not powered to assess statistical difference between treatment groups.4,5

BICR=blinded independent central review; BID=twice daily; BRCAm=BRCA mutation; CA-125=cancer antigen 125; CI=confidence interval; CR=complete response; ECOG=Eastern Cooperative Oncology Group; FIGO=International Federation of Gynecology and Obstetrics; gBRCAm=germline BRCA-mutated; HR=hazard ratio; MTX=maintenance; NC=not calculated; NR=not reached; ORR=objective response rate; PFS=progression-free survival; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors; sBRCAm=somatic BRCA-mutated; ULN=upper limit of normal.

IMPORTANT SAFETY INFORMATION

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.

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

In 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.

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.

FemalesAdvise 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 (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%).

DRUG INTERACTIONS

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

CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using LYNPARZA. If a moderate inducer cannot be avoided, there is a potential for decreased efficacy of 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).

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