A Maintenance Study With Niraparib Versus Placebo in Patients With Platinum Sensitive Ovarian Cancer

NCT01847274CompletedPHASE3INTERVENTIONAL

Summary

This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study of niraparib as maintenance in platinum sensitive ovarian cancer patients who have either gBRCAmut or a tumor with high-grade serous histology and who have responded to their most recent chemotherapy containing a platinum agent. Niraparib is an orally active PARP inhibitor. Niraparib or placebo (in a 2:1 ratio) will be administered once daily continuously during a 28-day cycle. Health-related quality of life will be measured by the Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI), European Quality of Life scale, 5-Dimensions (EQ-5D), and a neuropathy questionnaire. Safety and tolerability will be assessed by clinical review of adverse events (AEs), physical examinations, electrocardiograms (ECGs), and safety laboratory values. The primary objective of this study is to evaluate efficacy of niraparib as maintenance therapy in patients who have platinum sensitive ovarian cancer as assessed by the prolongation of progression free survival (PFS).

Key Facts

Lead Sponsor

Tesaro, Inc.

Enrollment

596

Start Date

2013-06-21

Completion Date

2016-04-22

Study Type

INTERVENTIONAL

Official Title

A Phase 3 Randomized Double-blind Trial of Maintenance With Niraparib Versus Placebo in Patients With Platinum Sensitive Ovarian Cancer.

Interventions

Active comparator: Niraparibplacebo

Conditions

Ovarian NeoplasmsPlatinum Sensitive Ovarian Cancer

Eligibility

Age Range

18 Years+

Sex

FEMALE

Inclusion Criteria:

* 18 years of age or older, female, any race
* Histologically diagnosed ovarian cancer, fallopian tube cancer or primary peritoneal cancer
* High grade (or grade 3) serous histology or known to have gBRCAmut
* Has received at least 2 previous courses of platinum-containing therapy, and has disease that was considered platinum sensitive following the penultimate (next to last) platinum course (more than 6 month period between penultimate platinum regimen and progression of disease)
* Has responded to last the platinum regimen, remains in response and is enrolled on study within 8 weeks of completion of the last platinum regimen
* ECOG 0-1
* Adequate bone marrow, kidney and liver function

Exclusion Criteria:

* Known hypersensitivity to the components of niraparib
* Invasive cancer other than ovarian cancer within 2 years (except basal or squamous cell carcinoma of the skin that has been definitely treated)
* Symptomatic uncontrolled brain metastasis
* Is pregnant or breast feeding
* Immunocompromised patients
* Known active hepatic disease
* Prior treatment with a known PARP inhibitor

Outcome Measures

Primary Outcomes

Progression-Free Survival (PFS) in Cohort With Germline BReast CAncer Gene (BRCA) Mutation (gBRCA)

PFS was defined as the time between randomization and disease progression or death from any cause. Computed tomography or magnetic resonance imaging to assess disease progression was performed at baseline, every 8 weeks through cycle 14, and then every 12 weeks until treatment discontinuation. The objective assessment of disease progression was determined by means of central radiologic and clinical review, according to Response Evaluation Criteria in Solid Tumors (RECIST),version 1.1, which was performed in a blinded fashion. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study.

Time frame: From date of randomization to the earliest date of disease progression or death from any cause, up to 7 years 7 months and 4 days

Progression-Free Survival (PFS) in Cohort With No Germline BCRA With Homologous Recombination Deficiency-positive (HRD+) Tumors (Non-gBRCAmut HRD+)

PFS was defined as the time between randomization and disease progression or death from any cause. Computed tomography or magnetic resonance imaging to assess disease progression was performed at baseline, every 8 weeks through cycle 14, and then every 12 weeks until treatment discontinuation. The objective assessment of disease progression was determined by means of central radiologic and clinical review, according to Response Evaluation Criteria in Solid Tumors (RECIST),version 1.1, which was performed in a blinded fashion. PD was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study.

Time frame: From date of randomization to the earliest date of disease progression or death from any cause, up to 7 years, 7 months and 4 days

Progression-Free Survival (PFS) in Cohort With No Germline BRCA Mutation

PFS was defined as the time between randomization and disease progression or death from any cause. Computed tomography or magnetic resonance imaging to assess disease progression was performed at baseline, every 8 weeks through cycle 14, and then every 12 weeks until treatment discontinuation. The objective assessment of disease progression was determined by means of central radiologic and clinical review, according to Response Evaluation Criteria in Solid Tumors (RECIST),version 1.1, which was performed in a blinded fashion.PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study.

Time frame: From date of randomization to the earliest date of disease progression or death from any cause, up to 7 years, 7 months and 4 days

Secondary Outcomes

Time to First Subsequent Therapy in Cohort With Germline BRCA Mutation (gBRCA)

The TFST was defined as the time from the date of randomization to the start date of the first subsequent anti-cancer therapy or death.

Time frame: From date of randomization to the earliest date of first subsequent therapy or death, up to 7 years, 7 months and 4 days

Time to First Subsequent Therapy in Cohort With No Germline BRCA Mutation

The TFST was defined as the time from the date of randomization to the start date of the first subsequent anti-cancer therapy or death

Time frame: From date of randomization to the earliest date of first subsequent therapy or death, up to 7 years, 7 months and 4 days

Chemotherapy-Free Interval in Cohort With Germline BRCA Mutation (gBRCA)

Chemotherapy-Free Interval was defined as the time from the last platinum therapy prior to randomization to the initiation of the next anti-cancer therapy after maintenance treatment

Time frame: From date of last platinum therapy prior to randomization to the initiation of the next anti-cancer therapy after maintenance treatment, up to 7 years, 7 months and 4 days

Chemotherapy-Free Interval in Cohort With No Germline BRCA Mutation

Chemotherapy-Free Interval was defined as the time from the last platinum therapy prior to randomization to the initiation of the next anti-cancer therapy after maintenance treatment

Time frame: From date of last platinum therapy prior to randomization to the initiation of the next anti-cancer therapy after maintenance treatment, up to 7 years, 7 months and 4 days

Progression-Free Survival 2 in Cohort With Germline BRCA Mutation (gBRCA)

Progression-Free Survival 2 was defined as the date of randomization in the current study to the earlier date of assessment of progression on the next anti-cancer therapy following study treatment or death due to any cause. Progression was determined by the investigator via clinical and radiographic assessment using the same criteria as used in the current study.

Time frame: From treatment randomization to the earlier of the date of disease progression on the next anti-cancer therapy following study treatment or death due to any cause, up to 7 years, 7 months and 4 days

Progression-Free Survival 2 in Cohort With No Germline BRCA Mutation

Progression-Free Survival 2 was defined as the date of randomization in the current study to the earlier date of assessment of progression on the next anti-cancer therapy following study treatment or death due to any cause. Progression was determined by the investigator via clinical and radiographic assessment using the same criteria as used in the current study.

Time frame: From treatment randomization to the earlier of the date of disease progression on the next anti-cancer therapy following study treatment or death due to any cause, up to 7 years, 7 months and 4 days

Overall Survival in Cohort With Germline BRCA Mutation (gBRCA)

Overall survival was defined as the date of randomization to the date of death by any cause.

Time frame: From treatment randomization to date of death by any cause, up to 7 years, 7 months and 4 days

Overall Survival in Cohort With No Germline BRCA Mutation

Overall survival was defined as the date of randomization to the date of death by any cause.

Time frame: From treatment randomization to date of death by any cause, up to 7 years, 7 months and 4 days

Time to Second Subsequent Therapy in Cohort With Germline BRCA Mutation (gBRCA)

TSST was defined as the date of randomization to the earlier of the start date of second follow-up anti-cancer treatment or death.

Time frame: From the date of randomization to the start date of the second subsequent anti-cancer therapy, up to 7 years, 7 months and 4 days

Time to Second Subsequent Therapy in Cohort With No Germline BRCA Mutation

TSST was defined as the date of randomization to the earlier of the start date of second follow-up anti-cancer treatment or death.

Time frame: From the date of randomization to the start date of the second subsequent anti-cancer therapy, up to 7 years, 7 months and 4 days

Change From Baseline in Functional Assessment of Cancer Therapy-Ovarian Symptom Index in Cohort With Germline BRCA at Cycle 2

Functional Assessment of Cancer Therapy-Ovarian Symptom Index is a validated, 8-item measure of symptom response to treatment for ovarian cancer. Participants respond to their symptom experience over the past 7 days using a 5-point Likert scale score from "not at all" (0) to "very much" (4). The total score was calculated by multiplying the sum of all items scored by 8 and dividing the result by the number of responses. The total symptom index was calculated as the total of the 8 scores, ranging from 0 ("severely symptomatic") to 32 ("asymptomatic"). A positive change from Baseline indicates improvement. Baseline was latest non-missing pre-dose assessment on or before randomization date. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (pre-dose on Day 1) and at Cycle 2 (Each cycle was of 28 days)

Change From Baseline in Functional Assessment of Cancer Therapy-Ovarian Symptom Index in Cohort With Germline BRCA at Cycle 4

Functional Assessment of Cancer Therapy-Ovarian Symptom Index is a validated, 8-item measure of symptom response to treatment for ovarian cancer. Participants respond to their symptom experience over the past 7 days using a 5-point Likert scale score from "not at all" (0) to "very much" (4). The total score was calculated by multiplying the sum of all items scored by 8 and dividing the result by the number of responses. The total symptom index was calculated as the total of the 8 scores, ranging from 0 ("severely symptomatic") to 32 ("asymptomatic"). A positive change from Baseline indicates improvement. Baseline was latest non-missing pre-dose assessment on or before randomization date. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Pre-dose on Day 1) and at Cycle 4 (Each cycle was of 28 days)

Change From Baseline in Functional Assessment of Cancer Therapy-Ovarian Symptom Index in Cohort With Germline BRCA at Cycle 6

Functional Assessment of Cancer Therapy-Ovarian Symptom Index is a validated, 8-item measure of symptom response to treatment for ovarian cancer. Participants respond to their symptom experience over the past 7 days using a 5-point Likert scale score from "not at all" (0) to "very much" (4). The total score was calculated by multiplying the sum of all items scored by 8 and dividing the result by the number of responses. The total symptom index was calculated as the total of the 8 scores, ranging from 0 ("severely symptomatic") to 32 ("asymptomatic"). A positive change from Baseline indicates improvement. Baseline was latest non-missing pre-dose assessment on or before randomization date. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (pre-dose on Day 1) and at Cycle 6 (Each cycle was of 28 days)

Change From Baseline in Functional Assessment of Cancer Therapy-Ovarian Symptom Index in Cohort With Germline BRCA at Post-progression

Functional Assessment of Cancer Therapy-Ovarian Symptom Index is a validated, 8-item measure of symptom response to treatment for ovarian cancer. Participants respond to their symptom experience over the past 7 days using a 5-point Likert scale score from "not at all" (0) to "very much" (4). The total score was calculated by multiplying the sum of all items scored by 8 and dividing the result by the number of responses. The total symptom index was calculated as the total of the 8 scores, ranging from 0 ("severely symptomatic") to 32 ("asymptomatic"). A positive change from Baseline indicates improvement. Baseline was latest non-missing pre-dose assessment on or before randomization date. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Pre-dose on Cycle 1 Day 1, Each cycle was of 28 days) and up to 7 years, 7 months and 4 days

Change From Baseline in Functional Assessment of Cancer Therapy-Ovarian Symptom Index in Cohort With no Germline BRCA at Cycle 2

Functional Assessment of Cancer Therapy-Ovarian Symptom Index is a validated, 8-item measure of symptom response to treatment for ovarian cancer. Participants respond to their symptom experience over the past 7 days using a 5-point Likert scale score from "not at all" (0) to "very much" (4). The total score was calculated by multiplying the sum of all items scored by 8 and dividing the result by the number of responses. The total symptom index was calculated as the total of the 8 scores, ranging from 0 ("severely symptomatic") to 32 ("asymptomatic"). A positive change from Baseline indicates improvement. Baseline was latest non-missing pre-dose assessment on or before randomization date. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Pre-dose on Day 1) and at Cycle 2 (Each cycle was of 28 days)

Change From Baseline in Functional Assessment of Cancer Therapy-Ovarian Symptom Index in Cohort With no Germline BRCA at Cycle 4

Functional Assessment of Cancer Therapy-Ovarian Symptom Index is a validated, 8-item measure of symptom response to treatment for ovarian cancer. Participants respond to their symptom experience over the past 7 days using a 5-point Likert scale score from "not at all" (0) to "very much" (4). The total score was calculated by multiplying the sum of all items scored by 8 and dividing the result by the number of responses. The total symptom index was calculated as the total of the 8 scores, ranging from 0 ("severely symptomatic") to 32 ("asymptomatic"). A positive change from Baseline indicates improvement. Baseline was latest non-missing pre-dose assessment on or before randomization date. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Pre-dose on Day 1) and at Cycle 4 (Each cycle was of 28 days)

Change From Baseline in Functional Assessment of Cancer Therapy-Ovarian Symptom Index in Cohort With no Germline BRCA at Cycle 6

Functional Assessment of Cancer Therapy-Ovarian Symptom Index is a validated, 8-item measure of symptom response to treatment for ovarian cancer. Participants respond to their symptom experience over the past 7 days using a 5-point Likert scale score from "not at all" (0) to "very much" (4). The total score was calculated by multiplying the sum of all items scored by 8 and dividing the result by the number of responses. The total symptom index was calculated as the total of the 8 scores, ranging from 0 ("severely symptomatic") to 32 ("asymptomatic"). A positive change from Baseline indicates improvement. Baseline was latest non-missing pre-dose assessment on or before randomization date. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Pre-dose on Day 1) and at Cycle 6 (Each cycle was of 28 days)

Change From Baseline in Functional Assessment of Cancer Therapy-Ovarian Symptom Index in Cohort With no Germline BRCA at Post-progression

Functional Assessment of Cancer Therapy-Ovarian Symptom Index is a validated, 8-item measure of symptom response to treatment for ovarian cancer. Participants respond to their symptom experience over the past 7 days using a 5-point Likert scale score from "not at all" (0) to "very much" (4). The total score was calculated by multiplying the sum of all items scored by 8 and dividing the result by the number of responses. The total symptom index was calculated as the total of the 8 scores, ranging from 0 ("severely symptomatic") to 32 ("asymptomatic"). A positive change from Baseline indicates improvement. Baseline was latest non-missing pre-dose assessment on or before randomization date. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Pre-dose on Day 1) and up to 7 years, 7 months and 4 days

Change From Baseline in European Quality of Life Scale, 5-Dimensions (EQ-5D-5L) in Cohort With Germline BRCA at Cycle 2

EQ-5D-5L is a well-validated, general preference-based, health-related Quality of Life (QoL) instrument. The EQ-5D-5L encompasses 5 domains, asking participants to rate their perceived health state today on the following dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each domain has 5 possible levels: "no problems" (Level 1), "slight problems" (Level 2), "moderate problems" (Level 3), "severe problems" (Level 4), and "extreme problems" (Level 5). Responses for 5 dimensions together formed a 5-figure description of health state (e.g.11111 indicates no problems in all 5 dimensions). Baseline was latest non-missing pre-dose assessment on or before randomization date. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Pre-dose on Day 1) and at Cycle 2 (Each cycle was of 28 days)

Change From Baseline in EQ-5D-5L in Cohort With Germline BRCA at Cycle 4

EQ-5D-5L is a well-validated, general preference-based, health-related Quality of Life (QoL) instrument. The EQ-5D-5L encompasses 5 domains, asking participants to rate their perceived health state today on the following dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each domain has 5 possible levels: "no problems" (Level 1), "slight problems" (Level 2), "moderate problems" (Level 3), "severe problems" (Level 4), and "extreme problems" (Level 5). Responses for 5 dimensions together formed a 5-figure description of health state (e.g.11111 indicates no problems in all 5 dimensions). Baseline was latest non-missing pre-dose assessment on or before randomization date. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Pre-dose on Day 1) and at Cycle 4 (Each cycle was of 28 days)

Change From Baseline in EQ-5D-5L in Cohort With Germline BRCA at Cycle 6

EQ-5D-5L is a well-validated, general preference-based, health-related Quality of Life (QoL) instrument. The EQ-5D-5L encompasses 5 domains, asking participants to rate their perceived health state today on the following dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each domain has 5 possible levels: "no problems" (Level 1), "slight problems" (Level 2), "moderate problems" (Level 3), "severe problems" (Level 4), and "extreme problems" (Level 5). Responses for 5 dimensions together formed a 5-figure description of health state (e.g.11111 indicates no problems in all 5 dimensions). Baseline was latest non-missing pre-dose assessment on or before randomization date. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Pre-dose on Day 1) and at Cycle 6 (Each cycle was of 28 days)

Change From Baseline in EQ-5D-5L in Cohort With Germline BRCA at Post-progression

EQ-5D-5L is a well-validated, general preference-based, health-related Quality of Life (QoL) instrument. The EQ-5D-5L encompasses 5 domains, asking participants to rate their perceived health state today on the following dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each domain has 5 possible levels: "no problems" (Level 1), "slight problems" (Level 2), "moderate problems" (Level 3), "severe problems" (Level 4), and "extreme problems" (Level 5). Responses for 5 dimensions together formed a 5-figure description of health state (e.g.11111 indicates no problems in all 5 dimensions). Baseline was latest non-missing pre-dose assessment on or before randomization date. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Pre-dose on Day 1) and up to 7 years, 7 months and 4 days

Change From Baseline in EQ-5D-5L in Cohort With no Germline BRCA at Cycle 2

EQ-5D-5L is a well-validated, general preference-based, health-related Quality of Life (QoL) instrument. The EQ-5D-5L encompasses 5 domains, asking participants to rate their perceived health state today on the following dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each domain has 5 possible levels: "no problems" (Level 1), "slight problems" (Level 2), "moderate problems" (Level 3), "severe problems" (Level 4), and "extreme problems" (Level 5). Responses for 5 dimensions together formed a 5-figure description of health state (e.g.11111 indicates no problems in all 5 dimensions). Baseline was latest non-missing pre-dose assessment on or before randomization date. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Pre-dose on Day 1) and at Cycle 2 (Each cycle was of 28 days)

Change From Baseline in EQ-5D-5L in Cohort With no Germline BRCA at Cycle 4

EQ-5D-5L is a well-validated, general preference-based, health-related Quality of Life (QoL) instrument. The EQ-5D-5L encompasses 5 domains, asking participants to rate their perceived health state today on the following dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each domain has 5 possible levels: "no problems" (Level 1), "slight problems" (Level 2), "moderate problems" (Level 3), "severe problems" (Level 4), and "extreme problems" (Level 5). Responses for 5 dimensions together formed a 5-figure description of health state (e.g.11111 indicates no problems in all 5 dimensions). Baseline was latest non-missing pre-dose assessment on or before randomization date. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Pre-dose on Day 1) and at Cycle 4 (Each cycle was of 28 days)

Change From Baseline in EQ-5D-5L in Cohort With no Germline BRCA at Cycle 6

EQ-5D-5L is a well-validated, general preference-based, health-related Quality of Life (QoL) instrument. The EQ-5D-5L encompasses 5 domains, asking participants to rate their perceived health state today on the following dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each domain has 5 possible levels: "no problems" (Level 1), "slight problems" (Level 2), "moderate problems" (Level 3), "severe problems" (Level 4), and "extreme problems" (Level 5). Responses for 5 dimensions together formed a 5-figure description of health state (e.g.11111 indicates no problems in all 5 dimensions). Baseline was latest non-missing pre-dose assessment on or before randomization date. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Pre-dose on Day 1) and at Cycle 6 (Each cycle was of 28 days)

Change From Baseline in EQ-5D-5L in Cohort With no Germline BRCA at Post-progression

EQ-5D-5L is a well-validated, general preference-based, health-related Quality of Life (QoL) instrument. The EQ-5D-5L encompasses 5 domains, asking participants to rate their perceived health state today on the following dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each domain has 5 possible levels: "no problems" (Level 1), "slight problems" (Level 2), "moderate problems" (Level 3), "severe problems" (Level 4), and "extreme problems" (Level 5). Responses for 5 dimensions together formed a 5-figure description of health state (e.g.11111 indicates no problems in all 5 dimensions). Baseline was latest non-missing pre-dose assessment on or before randomization date. Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value.

Time frame: Baseline (Pre-dose on Day 1) and up to 7 years, 7 months and 4 days

Number of Participants With Response to Neuropathy Questionnaire in Cohort With Germline BRCA at Baseline

A Neuropathy Questionnaire measures the participant's symptom experience over the past 7 days using a 5-point Likert scale of "not at all" (0) to "very much" (4). There are 2 items that ask if the participant's feet (item 1) or hands (item 2) feel numb or have prickling/tingling feelings. The Neuropathy Questionnaire was used to determine the chemotherapy-induced peripheral neuropathy (CIPN) status of each participant as well as provide an anchor for interpreting the impact of CIPN on participant's QoL. Two thresholds were used. For the first, a participant was determined to have CIPN if a score greater than 0 ("not at all") was recorded for either item. For the second, CIPN was assigned if a participant recorded a score greater than 1 ("a little bit"). Baseline was latest non-missing pre-dose assessment on or before randomization date.

Time frame: At Baseline

Number of Participants With Response to Neuropathy Questionnaire in Cohort With Germline BRCA at Cycle 2

A Neuropathy Questionnaire measures the participant's symptom experience over the past 7 days using a 5-point Likert scale of "not at all" (0) to "very much" (4). There are 2 items that ask if the participant's feet (item 1) or hands (item 2) feel numb or have prickling/tingling feelings. The Neuropathy Questionnaire was used to determine the chemotherapy-induced peripheral neuropathy (CIPN) status of each participant as well as provide an anchor for interpreting the impact of CIPN on participant's QoL. Two thresholds were used. For the first, a participant was determined to have CIPN if a score greater than 0 ("not at all") was recorded for either item. For the second, CIPN was assigned if a participant recorded a score greater than 1 ("a little bit").

Time frame: At Cycle 2 (Each cycle was of 28 days)

Number of Participants With Response to Neuropathy Questionnaire in Cohort With Germline BRCA at Cycle 4

A Neuropathy Questionnaire measures the participant's symptom experience over the past 7 days using a 5-point Likert scale of "not at all" (0) to "very much" (4). There are 2 items that ask if the participant's feet (item 1) or hands (item 2) feel numb or have prickling/tingling feelings. The Neuropathy Questionnaire was used to determine the chemotherapy-induced peripheral neuropathy (CIPN) status of each participant as well as provide an anchor for interpreting the impact of CIPN on participant's QoL. Two thresholds were used. For the first, a participant was determined to have CIPN if a score greater than 0 ("not at all") was recorded for either item. For the second, CIPN was assigned if a participant recorded a score greater than 1 ("a little bit").

Time frame: At Cycle 4 (Each cycle was of 28 days)

Number of Participants With Response to Neuropathy Questionnaire in Cohort With Germline BRCA at Cycle 6

A Neuropathy Questionnaire measures the participant's symptom experience over the past 7 days using a 5-point Likert scale of "not at all" (0) to "very much" (4). There are 2 items that ask if the participant's feet (item 1) or hands (item 2) feel numb or have prickling/tingling feelings. The Neuropathy Questionnaire was used to determine the chemotherapy-induced peripheral neuropathy (CIPN) status of each participant as well as provide an anchor for interpreting the impact of CIPN on participant's QoL. Two thresholds were used. For the first, a participant was determined to have CIPN if a score greater than 0 ("not at all") was recorded for either item. For the second, CIPN was assigned if a participant recorded a score greater than 1 ("a little bit").

Time frame: At Cycle 6 (Each cycle was of 28 days)

Number of Participants With Response to Neuropathy Questionnaire in Cohort With Germline BRCA at Post-progression

A Neuropathy Questionnaire measures the participant's symptom experience over the past 7 days using a 5-point Likert scale of "not at all" (0) to "very much" (4). There are 2 items that ask if the participant's feet (item 1) or hands (item 2) feel numb or have prickling/tingling feelings. The Neuropathy Questionnaire was used to determine the chemotherapy-induced peripheral neuropathy (CIPN) status of each participant as well as provide an anchor for interpreting the impact of CIPN on participant's QoL. Two thresholds were used. For the first, a participant was determined to have CIPN if a score greater than 0 ("not at all") was recorded for either item. For the second, CIPN was assigned if a participant recorded a score greater than 1 ("a little bit").

Time frame: Up to 7 years, 7 months and 4 days

Number of Participants With Response to Neuropathy Questionnaire in Cohort With no Germline BRCA at Baseline

A Neuropathy Questionnaire measures the participant's symptom experience over the past 7 days using a 5-point Likert scale of "not at all" (0) to "very much" (4). There are 2 items that ask if the participant's feet (item 1) or hands (item 2) feel numb or have prickling/tingling feelings. The Neuropathy Questionnaire was used to determine the chemotherapy-induced peripheral neuropathy (CIPN) status of each participant as well as provide an anchor for interpreting the impact of CIPN on participant's QoL. Two thresholds were used. For the first, a participant was determined to have CIPN if a score greater than 0 ("not at all") was recorded for either item. For the second, CIPN was assigned if a participant recorded a score greater than 1 ("a little bit"). Baseline was latest non-missing pre-dose assessment on or before randomization date.

Time frame: At Baseline

Number of Participants With Response to Neuropathy Questionnaire in Cohort With no Germline BRCA at Cycle 2

A Neuropathy Questionnaire measures the participant's symptom experience over the past 7 days using a 5-point Likert scale of "not at all" (0) to "very much" (4). There are 2 items that ask if the participant's feet (item 1) or hands (item 2) feel numb or have prickling/tingling feelings. The Neuropathy Questionnaire was used to determine the chemotherapy-induced peripheral neuropathy (CIPN) status of each participant as well as provide an anchor for interpreting the impact of CIPN on participant's QoL. Two thresholds were used. For the first, a participant was determined to have CIPN if a score greater than 0 ("not at all") was recorded for either item. For the second, CIPN was assigned if a participant recorded a score greater than 1 ("a little bit").

Time frame: At Cycle 2 (Each cycle was of 28 days)

Number of Participants With Response to Neuropathy Questionnaire in Cohort With no Germline BRCA at Cycle 4

A Neuropathy Questionnaire measures the participant's symptom experience over the past 7 days using a 5-point Likert scale of "not at all" (0) to "very much" (4). There are 2 items that ask if the participant's feet (item 1) or hands (item 2) feel numb or have prickling/tingling feelings. The Neuropathy Questionnaire was used to determine the chemotherapy-induced peripheral neuropathy (CIPN) status of each participant as well as provide an anchor for interpreting the impact of CIPN on participant's QoL. Two thresholds were used. For the first, a participant was determined to have CIPN if a score greater than 0 ("not at all") was recorded for either item. For the second, CIPN was assigned if a participant recorded a score greater than 1 ("a little bit").

Time frame: At Cycle 4 (Each cycle was of 28 days)

Number of Participants With Response to Neuropathy Questionnaire in Cohort With no Germline BRCA at Cycle 6

A Neuropathy Questionnaire measures the participant's symptom experience over the past 7 days using a 5-point Likert scale of "not at all" (0) to "very much" (4). There are 2 items that ask if the participant's feet (item 1) or hands (item 2) feel numb or have prickling/tingling feelings. The Neuropathy Questionnaire was used to determine the chemotherapy-induced peripheral neuropathy (CIPN) status of each participant as well as provide an anchor for interpreting the impact of CIPN on participant's QoL. Two thresholds were used. For the first, a participant was determined to have CIPN if a score greater than 0 ("not at all") was recorded for either item. For the second, CIPN was assigned if a participant recorded a score greater than 1 ("a little bit").

Time frame: At Cycle 6 (Each cycle was of 28 days)

Number of Participants With Response to Neuropathy Questionnaire in Cohort With no Germline BRCA at Post-progression

A Neuropathy Questionnaire measures the participant's symptom experience over the past 7 days using a 5-point Likert scale of "not at all" (0) to "very much" (4). There are 2 items that ask if the participant's feet (item 1) or hands (item 2) feel numb or have prickling/tingling feelings. The Neuropathy Questionnaire was used to determine the chemotherapy-induced peripheral neuropathy (CIPN) status of each participant as well as provide an anchor for interpreting the impact of CIPN on participant's QoL. Two thresholds were used. For the first, a participant was determined to have CIPN if a score greater than 0 ("not at all") was recorded for either item. For the second, CIPN was assigned if a participant recorded a score greater than 1 ("a little bit").

Time frame: Up to 7 years, 7 months and 4 days

Number of Participants With Concordance of a Candidate Companion BRAC Analysis Diagnostic Test Compared to the Centralized BRCA Mutation Test Used in This Study

This will never be analyzed since the data for the candidate companion BRAC analysis diagnostic test was not collected which was to be compared with centralized BRCA mutation test used in this study.

Time frame: Up to 7 years, 7 months and 4 days

Number of Participants With Concordance of a Candidate Companion HRD Diagnostic Test Compared to the HRD Test Used in This Study

This will never be analyzed since the data for the candidate companion HRD diagnostic test was not collected which was to be compared with HRD test used in this study.

Time frame: Up to 7 years, 7 months and 4 days

Number of Participants With Non-serious Adverse Events (AEs) and Serious AEs (SAEs)

An AE is any untoward medical occurrence that occurs in a participants or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. A SAE is defined as any untoward medical occurrence that at any dose which results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an important medical event(s) as per medical and scientific judgment. Adverse events which were not serious adverse events were considered as non serious adverse events. Data presented for this outcome measure is based on the data cut-off date of 31-March-2021, which aligns with the time of the study unblinding.

Time frame: Up to 7 years, 7 months and 6 days

Number of Participants With Non-serious AEs and SAEs (Post-study Unblinding)

An AE is any untoward medical occurrence that occurs in a participants or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. A SAE is defined as any untoward medical occurrence that at any dose which results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an important medical event(s) as per medical and scientific judgment. Adverse events which were not serious adverse events were considered as non serious adverse events. The data is presented for post-study unblinding duration 01-Apr-2021 to 26-Dec-2021

Time frame: Up to 8 months, 26 days

Number of Participants With Non-serious AEs and SAEs in FE Sub-study

An AE is any untoward medical occurrence that occurs in a participants or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. A SAE is defined as any untoward medical occurrence that at any dose which results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an important medical event(s) as per medical and scientific judgment. Adverse events which were not serious adverse events were considered as non serious adverse events.

Time frame: Up to 2 years, 3 months and 11 days

Number of Participants With Non-serious AEs and SAEs in QTc Sub-study

An AE is any untoward medical occurrence that occurs in a participants or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. A SAE is defined as any untoward medical occurrence that at any dose which results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an important medical event(s) as per medical and scientific judgment. Adverse events which were not serious adverse events were considered as non serious adverse events.

Time frame: Up to 5 years 10 months and 22 days

Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC[0-infinity]) Following Administration of Niraparib (FE Sub-study)

Blood samples were collected at indicated time points to analyze AUC(0-infinity) of niraparib.

Time frame: Pre-dose and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post dose

Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Concentration (AUC[0-last]) Following Administration of Niraparib (FE Sub-study)

Blood samples were collected at indicated time points to analyze the AUC(0-last) of niraparib.

Time frame: Pre-dose (Day -1) and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post dose

Maximum Observed Plasma Concentration (Cmax) Following Administration of Niraparib (FE Sub-study)

Blood samples were collected at indicated time points to analyze the maximum observed plasma concentration of niraparib.

Time frame: Pre-dose (Day -1) and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post dose

Time to Reach Maximum (Tmax) Following Administration of Niraparib (FE Sub-study)

Blood samples were collected at indicated time points to analyze the tmax of niraparib.

Time frame: Pre-dose (Day -1) and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post dose

Terminal Elimination Half-life (t1/2) Following Administration of Niraparib (FE Sub-study)

Blood samples were collected at indicated time points to analyze the t1/2 of niraparib.

Time frame: Pre-dose (Day -1) and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post dose

Number of Participants With Maximum Post-Baseline QT Interval Corrected by Fridericia's Formula (QTcF) Greater Than Pre-specified Thresholds

12-lead electrocardiogram was obtained at indicated time points using an automated electrocardiogram machine that measured QTcF interval. The number of participants with maximum post-Baseline ECG value exceeding the following limits have been reported: QTcF interval \>450 and \<= 480 milliseconds (msec) and \>500 msec.

Time frame: At Baseline (Cycle 1 Day 1, each cycle was of 28 days)

Locations

GSK Investigational Site, Phoenix, United States

GSK Investigational Site, Tucson, United States

GSK Investigational Site, Los Angeles, United States

GSK Investigational Site, Los Angeles, United States

GSK Investigational Site, Palo Alto, United States

GSK Investigational Site, San Francisco, United States

GSK Investigational Site, New Haven, United States

GSK Investigational Site, Sarasota, United States

GSK Investigational Site, Tampa, United States

GSK Investigational Site, Atlanta, United States

GSK Investigational Site, Chicago, United States

GSK Investigational Site, Indianapolis, United States

GSK Investigational Site, Indianapolis, United States

GSK Investigational Site, Boston, United States

GSK Investigational Site, Boston, United States

GSK Investigational Site, Burlington, United States

GSK Investigational Site, Minneapolis, United States

GSK Investigational Site, Minneapolis, United States

GSK Investigational Site, Rochester, United States

GSK Investigational Site, Morristown, United States

GSK Investigational Site, Farmington, United States

GSK Investigational Site, Lake Success, United States

GSK Investigational Site, New York, United States

GSK Investigational Site, New York, United States

GSK Investigational Site, Durham, United States

GSK Investigational Site, Oklahoma City, United States

GSK Investigational Site, Vancouver, United States

GSK Investigational Site, Abington, United States

GSK Investigational Site, Philadelphia, United States

GSK Investigational Site, Providence, United States

GSK Investigational Site, Nashville, United States

GSK Investigational Site, Austin, United States

GSK Investigational Site, Dallas, United States

GSK Investigational Site, Fort Worth, United States

GSK Investigational Site, The Woodlands, United States

GSK Investigational Site, Graz, Austria

GSK Investigational Site, Innsbruck, Austria

GSK Investigational Site, Vienna, Austria

GSK Investigational Site, Edegem, Belgium

GSK Investigational Site, Kortrijk, Belgium

GSK Investigational Site, Leuven, Belgium

GSK Investigational Site, Liège, Belgium

GSK Investigational Site, Calgary, Canada

GSK Investigational Site, Kelowna, Canada

GSK Investigational Site, Vancouver, Canada

GSK Investigational Site, Toronto, Canada

GSK Investigational Site, Montreal, Canada

GSK Investigational Site, Montreal, Canada

GSK Investigational Site, Montreal, Canada

GSK Investigational Site, Sherbrooke, Canada

GSK Investigational Site, Aalborg, Denmark

GSK Investigational Site, Copenhagen, Denmark

GSK Investigational Site, Herlev, Denmark

GSK Investigational Site, Odense, Denmark

GSK Investigational Site, Besançon, France

GSK Investigational Site, Lille, France

GSK Investigational Site, Montpellier, France

GSK Investigational Site, Nice, France

GSK Investigational Site, Saint-Brieuc, France

GSK Investigational Site, Saint-Herblain, France

GSK Investigational Site, Heidelberg, Germany

GSK Investigational Site, Munich, Germany

GSK Investigational Site, Göttingen, Germany

GSK Investigational Site, Hanover, Germany

GSK Investigational Site, Düsseldorf, Germany

GSK Investigational Site, Essen, Germany

GSK Investigational Site, Essen, Germany

GSK Investigational Site, Dresden, Germany

GSK Investigational Site, Kiel, Germany

GSK Investigational Site, Berlin, Germany

GSK Investigational Site, Hamburg, Germany

GSK Investigational Site, Szolnok, Hungary

GSK Investigational Site, Haifa, Israel

GSK Investigational Site, Holon, Israel

GSK Investigational Site, Jerusalem, Israel

GSK Investigational Site, Jerusalem, Israel

GSK Investigational Site, Kfar Saba, Israel

GSK Investigational Site, Rehovot, Israel

GSK Investigational Site, Tel Aviv, Israel

GSK Investigational Site, Tel Litwinsky, Israel

GSK Investigational Site, Rome, Italy

GSK Investigational Site, Brescia, Italy

GSK Investigational Site, Milan, Italy

GSK Investigational Site, Catania, Italy

GSK Investigational Site, Milan, Italy

GSK Investigational Site, Bergen, Norway

GSK Investigational Site, Oslo, Norway

GSK Investigational Site, Bialystok, Poland

GSK Investigational Site, Gdansk, Poland

GSK Investigational Site, Lodz, Poland

GSK Investigational Site, Poznan, Poland

GSK Investigational Site, Oviedo, Spain

GSK Investigational Site, Barcelona, Spain

GSK Investigational Site, Barcelona, Spain

GSK Investigational Site, Madrid, Spain

GSK Investigational Site, Madrid, Spain

GSK Investigational Site, Madrid, Spain

GSK Investigational Site, Palma de Mallorca, Spain

GSK Investigational Site, Linköping, Sweden

GSK Investigational Site, Lund, Sweden

GSK Investigational Site, Stockholm, Sweden

GSK Investigational Site, Nottingham, United Kingdom

GSK Investigational Site, Yeovil, United Kingdom

GSK Investigational Site, Birmingham, United Kingdom

GSK Investigational Site, Bebington, Wirral, United Kingdom

GSK Investigational Site, London, United Kingdom

GSK Investigational Site, London, United Kingdom

GSK Investigational Site, London, United Kingdom

GSK Investigational Site, London, United Kingdom

GSK Investigational Site, Maidstone, United Kingdom

GSK Investigational Site, Rhyl, United Kingdom

GSK Investigational Site, Taunton, United Kingdom

Linked Diseases

Ovarian Neoplasms

Ovarian Neoplasms — a type of gynecological cancer.

Linked Papers

2024-07-16

Niraparib Population Pharmacokinetics and Exposure-Response Relationships in Patients With Newly Diagnosed Advanced Ovarian Cancer

Niraparib is a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor approved for the maintenance treatment of advanced ovarian cancer (OC). Niraparib was originally approved in recurrent OC at a fixed starting dose (FSD) of 300 mg once daily (QD). This analysis characterized the population pharmacokinetics (PK) of niraparib and evaluated the relationships between exposure, efficacy, and safety to support clinical use of an individualized dosing strategy, in which the starting dose of niraparib was adjusted based on patient characteristics to improve the benefit-risk profile. A population PK model was developed by pooling data from four niraparib clinical trials (PN001 [n = 104], QUADRA [n = 455], NOVA [n = 403], and PRIMA [n = 480]) in patients with solid tumors, including OC. Exposure-response analyses were conducted to explore the relationships of niraparib exposure with progression-free survival (PFS) and adverse events in the PRIMA study. A multivariate logistic regression model was also developed to estimate the probability of grade ≥3 thrombocytopenia, using data from patients enrolled in PRIMA and NOVA. The impact of an individualized starting dose (ISD) regimen (200 mg QD in patients with body weight [BW] <77 kg or platelet count [PLT] <150,000/µL, or 300 mg QD in patients with BW ≥77 kg and PLT ≥150,000/µL) on systemic exposure, efficacy, and safety was assessed. Niraparib disposition was best described by a 3-compartment model with linear elimination. Key covariates included baseline creatinine clearance, BW, albumin, and age, all of which had minor effects on niraparib exposure. Comparable model-predicted exposure up to the time of disease progression/death or censoring in the 300-mg FSD and 200-/300-mg ISD groups was consistent with the lower rate of dose reduction in the ISD groups. No consistent niraparib exposure-response relationship was observed for efficacy in all PRIMA patients (first-line OC), and no statistically significant difference was seen in PFS curves for patients receiving a niraparib dose of 200 mg versus 300 mg. In the multivariate regression model, performed using combined data from PRIMA and NOVA, higher niraparib exposure (area under the concentration-time curve at steady-state [AUC Population PK and exposure-response analyses support use of an ISD to improve the safety profile of niraparib, including reducing the rate of grade ≥3 thrombocytopenia, without compromising efficacy. ClinicalTrials.gov, NCT01847274 (NOVA), NCT00749502 (PN001), NCT02655016 (PRIMA), NCT02354586 (QUADRA), www. gov.

2022-02-16

Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer

Ovarian cancer is the sixth most common cancer in women world-wide. Epithelial ovarian cancer (EOC) is the most common; three-quarters of women present when disease has spread outside the pelvis (stage III or IV). Treatment consists of a combination of  surgery and platinum-based chemotherapy. Although initial responses to chemotherapy are good, most women with advanced disease will relapse. PARP (poly (ADP-ribose) polymerase) inhibitors (PARPi), are a type of anticancer treatment that works by preventing cancer cells from repairing DNA damage, especially in those with breast cancer susceptibility gene (BRCA) variants. PARPi offer a different mechanism of anticancer treatment from conventional chemotherapy. To determine the benefits and risks of poly (ADP-ribose) polymerase) inhibitors (PARPi) for the treatment of epithelial ovarian cancer (EOC). We identified randomised controlled trials (RCTs) by searching the Cochrane Central Register of Controlled Trials (Central 2020, Issue 10), Cochrane Gynaecological Cancer Group Trial Register, MEDLINE (1990 to October 2020), Embase (1990 to October 2020), ongoing trials on www.controlled-trials.com/rct, www.clinicaltrials.gov, www.cancer.gov/clinicaltrials, the National Research Register (NRR), FDA database and pharmaceutical industry biomedical literature. We included trials that randomised women with EOC to PARPi with no treatment, or PARPi versus conventional chemotherapy, or PARPi together with conventional chemotherapy versus conventional chemotherapy alone. We used standard Cochrane methodology. Two review authors independently assessed whether studies met the inclusion criteria. We contacted investigators for additional data. Outcomes included overall survival (OS), objective response rate (ORR), quality of life (QoL) and rate of adverse events. We included 15 studies (6109 participants); four (3070 participants) with newly-diagnosed, advanced EOC and 11 (3039 participants) with recurrent EOC. The studies varied in types of comparisons and evaluated PARPi. Eight studies were judged as at low risk of bias in most of the domains. Quality of life data were generally poorly reported. Below we present six key comparisons.  The majority of participants had BRCA mutations, either in their tumour (sBRCAmut) and/or germline (gBRCAmut), or homologous recombination deficiencies (HRD) in their tumours. Newly diagnosed EOC Overall, four studies evaluated the effect of PARPi in newly-diagnosed, advanced EOC. Two compared PARPi with chemotherapy and chemotherapy alone. OS data were not reported. The combination of PARPi with chemotherapy may have little to no difference in progression-free survival (PFS) (two studies, 1564 participants; hazard ratio (HR) 0.82, 95% confidence interval (CI 0).49 to 1.38; very low-certainty evidence)(no evidence of disease progression at 12 months' 63% with PARPi versus 69% for placebo).  PARPi with chemotherapy likely increases any severe adverse event (SevAE) (grade 3 or higher) slightly (45%) compared with chemotherapy alone (51%) (two studies, 1549 participants, risk ratio (RR) 1.13, 95% CI 1.07 to 1.20; high-certainty evidence). PARPi combined with chemotherapy compared with chemotherapy alone likely results in little to no difference in the QoL (one study; 744 participants, MD 1.56 95% CI -0.42 to 3.54; moderate-certainty evidence).  Two studies compared PARPi monotherapy with placebo as maintenance after first-line chemotherapy in newly diagnosed EOC. PARPi probably results in little to no difference in OS (two studies, 1124 participants; HR 0.81, 95%CI 0.59 to 1.13; moderate-certainty evidence) (alive at 12 months 68% with PARPi versus 62% for placebo). However, PARPi may increase PFS (two studies, 1124 participants; HR 0.42, 95% CI 0.19 to 0.92; low-certainty evidence) (no evidence of disease progression at 12 months' 55% with PARPi versus 24% for placebo). There may be an increase in the risk of experiencing any SevAE (grade 3 or higher) with PARPi (54%) compared with placebo (19%)(two studies, 1118 participants, RR 2.87, 95% CI 1.65 to 4.99; very low-certainty evidence), but the evidence is very uncertain. There is probably a slight reduction in QoL with PARPi, although this may not be clinically significant (one study, 362 participants; MD -3.00, 95%CI -4.48 to -1.52; moderate-certainty evidence).  Recurrent, platinum-sensitive EOC Overall, 10 studies evaluated the effect of PARPi in recurrent platinum-sensitive EOC. Three studies compared PARPi monotherapy with chemotherapy alone. PARPi may result in little to no difference in OS (two studies, 331 participants; HR 0.95, 95%CI 0.62 to 1.47; low-certainty evidence) (percentage alive at 36 months 18% with PARPi versus 17% for placebo). Evidence is very uncertain about the effect of PARPi on PFS (three studies, 739 participants; HR 0.88, 95%CI 0.56 to 1.38; very low-certainty evidence)(no evidence of disease progression at 12 months 26% with PARPi versus 22% for placebo). There may be little to no difference in rates of any SevAE (grade 3 or higher) with PARPi (50%) than chemotherapy alone (47%) (one study, 254 participants; RR 1.06, 95%CI 0.80 to 1.39; low-certainty evidence). Four studies compared PARPi monotherapy as maintenance with placebo. PARPi may result in little to no difference in OS (two studies, 560 participants; HR 0.88, 95%CI 0.65 to 1.20; moderate-certainty evidence)(percentage alive at 36 months 21% with PARPi versus 17% for placebo). However, evidence suggests that PARPi as maintenance therapy results in a large PFS (four studies, 1677 participants; HR 0.34, 95% CI 0.28 to 0.42; high-certainty evidence)(no evidence of disease progression at 12 months 37% with PARPi versus 5.5% for placebo). PARPi maintenance therapy may result in a large increase in any SevAE (51%) (grade 3 or higher) than placebo (19%)(four studies, 1665 participants, RR 2.62, 95%CI 1.85 to 3.72; low-certainty evidence). PARPi compared with chemotherapy may result in little or no change in QoL (one study, 229 participants, MD 1.20, 95%CI -1.75 to 4.16; low-certainty evidence). Recurrent, platinum-resistant EOC Two studies compared PARPi with chemotherapy. The certainty of evidence in both studies was graded as very low. Overall, there was minimal information on the QoL and adverse events. PARPi maintenance treatment after chemotherapy may improve PFS in women with newly-diagnosed and recurrent platinum-sensitive EOC; there may be little to no effect on OS, although OS data are immature. Overall, this is likely at the expense of an increase in SevAE. It is  disappointing that data on quality of life outcomes  are relatively sparse. More research is needed to determine whether PARPi have a role to play in platinum-resistant disease.

2020-09-25

Long-term safety in patients with recurrent ovarian cancer treated with niraparib versus placebo: Results from the phase III ENGOT-OV16/NOVA trial

Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in heavily pretreated patients and as maintenance treatment in patients with newly-diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy. We present long-term safety data for niraparib from the ENGOT-OV16/NOVA trial. This multicenter, double-blind, randomized, controlled phase III trial evaluated the efficacy and safety of niraparib for the treatment of recurrent ovarian cancer. Patients were randomly assigned 2:1 to receive either once-daily niraparib 300 mg or placebo. Two independent cohorts were enrolled based on germline BRCA mutation status. The primary endpoint was progression-free survival, reported previously. Long-term safety data were from the most recent data cutoff (September 2017). Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%) and declined every month thereafter. Incidence of any-grade and grade ≥ 3 hematologic and symptomatic TEAEs was also highest in month 1 and subsequently declined. Incidence of grade ≥ 3 thrombocytopenia decreased from 28% (month 1) to 9% and 5% (months 2 and 3, respectively), with protocol-directed dose interruptions and/or reductions. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) were reported in 2 and 6 niraparib-treated patients, respectively, and in 1 placebo patient each. Treatment discontinuations due to TEAEs were <5% in each month and time interval measured. These data demonstrate the importance of appropriate dose reduction according to toxicity criteria and support the safe long-term use of niraparib for maintenance treatment in patients with recurrent ovarian cancer. ClinicalTrials.gov identifier: NCT01847274.