RUBRACA Film-coated tablet Ref.[7613] Active ingredients: Rucaparib

Pharmacotherapeutic group: Other antineoplastic agents
ATC code: L01XK03

Mechanism of action and pharmacodynamics effects

Rucaparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, including PARP-1, PARP-2, and PARP-3, which play a role in DNA repair. In vitro studies have shown that rucaparib-induced cytotoxicity involves inhibition of PARP enzymatic activity and the trapping of PARP-DNA complexes resulting in increased DNA damage, apoptosis, and cell death.

Rucaparib has been shown to have in vitro and in vivo anti-tumour activity in BRCA mutant cell lines through a mechanism known as synthetic lethality, whereby the loss of two DNA repair pathways is required for cell death. Increased rucaparib-induced cytotoxicity and anti-tumour activity was observed in tumour cell lines with deficiencies in BRCA1/2 and other DNA repair genes. Rucaparib has been shown to decrease tumour growth in mouse xenograft models of human cancer with or without deficiencies in BRCA.

Clinical efficacy

First-Line maintenance treatment of advanced ovarian cancer

The efficacy of rucaparib was evaluated in ATHENA, a Phase 3, double-blind, multicentre trial in which 538 patients with advanced ovarian (EOC), fallopian tube (FTC), or primary peritoneal cancer (PPC) who were in response to first-line platinum-based chemotherapy and surgery were enrolled. Response was defined as no evidence of disease progression radiologically or through rising CA-125 (per Gynecological Cancer Intergroup (GCIG) guidelines) at any time during first-line treatment; and either no evidence of measurable disease by RECIST v1.1, if complete resection after surgery, or a response (complete or partial) if measurable disease was present after surgery and prior to chemotherapy, or a GCIG CA-125 response if non-measurable disease was present in the same situation.

All patients had received between 4 to 8 cycles of platinum-doublet treatment (including ≥4 cycles of platinum/taxane combination). Bevacizumab treatment was allowed during first-line chemotherapy, but not during the maintenance rucaparib treatment. All patients were randomised within 8 weeks of the first day of the last cycle of chemotherapy.

Patients were randomised (4:1) to receive rucaparib tablets 600 mg orally twice daily (n=427) or placebo (n=111). Treatment was continued until disease progression or unacceptable toxicity or for up to 2 years. Randomisation was stratified by disease status post-chemotherapy (residual disease vs. no residual disease), timing of surgery (primary surgery vs. interval debulking), and biomarker status. Biomarker status was determined using the homologous recombination deficiency (HRD) test where biomarker-positive was a tumour with HRD defined by the presence of a deleterious tumour BRCA (tBRCA) mutation or tBCRA wild type (tBRCAwt)/high genomic loss of heterozygosity (LOH^high), and biomarker-negative was a tumour without HRD, defined by tBRCAwt/low genomic LOH (LOH^low).

The major efficacy outcome was investigator-assessed progression-free survival (invPFS) evaluated according to Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1. Key Secondary efficacy endpoints included overall survival (OS) and objective response rate (ORR) according to RECIST version 1.1. invPFS, OS and ORR testing were performed hierarchically: first in the HRD Group, then in the ITT population. Time from randomisation to second progression or death (PFS2), was an additional outcome measure.

The median age of patients treated with rucaparib was 61 years (range: 30 to 83) and 62 years (range: 31 to 80) among patients on placebo. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 69% of patients receiving rucaparib and 68% of patients receiving placebo. Of the 538 patients randomised to rucaparib or placebo, 75% had FIGO Stage III disease and 25% had Stage IV disease, and 16% were in complete response to their most recent platinum-based regimen. Of the 538 patients randomised to rucaparib or placebo 78% had EOC, 13% had FTC and 9% had PPC, most patients (>90%) had tumours with serous histology. In the ITT population, patients received a median of 6 cycles of platinum doublet chemotherapy and 17.8% of patients had received bevacizumab during first-line chemotherapy. Primary debulking surgery had been performed in 48.1% of patients, and 51.9% of patients had undergone neo-adjuvant chemotherapy followed by interval debulking surgery.

Overall, 43% had HRD (21% had a deleterious tBRCA mutation and 22% had tBRCA^wt/LOH^high), 44% were HRD negative (tBRCA^wt/LOH^low), and 12% had an unknown HRD status.

ATHENA demonstrated a statistically significant improvement in invPFS for patients randomised to rucaparib as compared with placebo in the HRD Group and the ITT Population. Results for invPFS with and without censoring for new anti-cancer treatment and missed visits were consistent. Efficacy results are presented in Table 4 and Figures 1 and Figure 2.

Table 4. Efficacy Results – ATHENA (Investigator Assessment):

^a Includes all patients with a deleterious tBRCA mutation (N=115) or tBRCA^wt/LOH^high (N=119).
^b All randomised patients.
^c The median follow up time was 26 months for both the rucaparib and placebo arms.
^d P-value based on the stratified logrank test.
^e At the time of the second interim analysis, the OS data were not mature (35% of patients had died); the median follow up time was 37 months for both the rucaparib and placebo arms.
NR: Not reached.

Figure 1. Kaplan-Meier Curves of Progression-Free Survival in ATHENA as Assessed by Investigator: ITT Population:

Figure 2. Kaplan-Meier Curves of Progression-Free Survival in ATHENA as Assessed by Investigator: HRD Population:

Subgroup analysis (PFS investigator assessment)

Within the HRD Population, a hazard ratio of 0.40 (95% CI [0.21, 0.75]) was observed in the subgroup of patients with a tBRCA mutation (n=115). In the subgroup of non-tBRCA LOH^high (n=119), a hazard ratio of 0.58 (95% CI [0.33, 1.01]). In the HRD-negative subgroup (n=238), a hazard ratio of 0.65 (95% CI [0.45, 0.95]) was observed.

Maintenance treatment of recurrent ovarian cancer

The efficacy of rucaparib was investigated in ARIEL3, a double-blind, multicentre clinical trial in which 564 patients with recurrent EOC, FTC or PPC who were in response to platinum-based chemotherapy were randomised (2:1) to receive Rubraca tablets 600 mg orally twice daily (n=375) or placebo (n=189). Treatment was continued until disease progression or unacceptable toxicity. All patients had achieved a response (complete or partial) to their most recent platinum-based chemotherapy and their cancer antigen 125 (CA-125) was below the upper limit of normal (ULN). Patients were randomised within 8 weeks of completion of platinum chemotherapy and no intervening maintenance treatment was permitted. Patients could not have received prior rucaparib or other PARP inhibitor therapy. Randomisation was stratified by best response to last platinum therapy (complete or partial), time to progression following the penultimate platinum therapy (6 to ≤12 months and >12 months), and tumour biomarker status (tBRCA, non-BRCA homologous recombination deficiency [nbHRD] and biomarker negative).

The primary efficacy outcome was invPFS evaluated according to RECIST, version 1.1 (v1.1). PFS assessed by blinded independent radiology review (IRR) was a key secondary efficacy outcome. Secondary efficacy endpoints included overall survival (OS).

The mean age was 61 years (range: 36 to 85 years); most of the patients were White (80%); and all had an ECOG performance status of 0 or 1. The primary tumour in most patients was ovarian (84%); most patients (95%) had serous histology and 4% of patients reported endometrioid histology. All patients had received at least two prior platinum-based chemotherapies (range: 2 to 6) and 28% of patients had received at least three prior platinum-based chemotherapies. A total of 32% of patients were in complete response (CR) to their most recent therapy. The progression-free interval to penultimate platinum therapy was 6-12 months in 39% of patients and >12 months in 61%. Prior bevacizumab therapy was reported for 22% of patients who received rucaparib and 23% of patients who received placebo. Demographics, baseline disease characteristics, and prior treatment history were generally well balanced between the rucaparib and placebo arms.

None of the patients had received prior treatment with a PARP inhibitor. As such, efficacy of Rubraca in patients who have received prior treatment with a PARP inhibitor in the maintenance setting, has not been investigated and cannot be extrapolated from the available data.

Tumour tissue samples for all of the patients (N=564) were tested centrally to determine HRD positive status (as defined by the presence of a deleterious tumour BRCA [tBRCA] mutation or high genomic loss of heterozygosity). Blood samples for 94% (186/196) of the tBRCA patients were evaluated using a central blood germline BRCA (gBRCA) test. Based on these results, 70% (130/186) of the tBRCA patients had a gBRCA mutation and 30% (56/186) had a somatic BRCA mutation.

The ARIEL3 study met its primary endpoint and demonstrated a statistically significant improvement in invPFS for patients randomised to rucaparib as compared with placebo in the ITT population and in the HRD and tBRCA groups. IRR-assessment for the ITT population supported the primary endpoint. PFS results are summarised in Table 5 and Figure 3.

Table 5. ARIEL3 Efficacy Results (Summary of Primary Objective Outcome: PFS):

^a All randomised patients.
^b Two-sided p-value
^c HRD includes all patients with a deleterious germline or somatic BRCA mutation or non-tBRCA with high genomic loss of heterozygosity, as determined by the clinical trial assay (CTA).
^d tBRCA includes all patients with a deleterious germline or somatic BRCA mutation, as determined by the CTA.
HR: Hazard ratio. A value <1 favours rucaparib.
NA: Not Achieved
CI: Confidence interval

Figure 3. Kaplan-Meier Curves of Progression-Free Survival in ARIEL3 as Assessed by Investigator: ITT population:

At the final OS analysis (70% maturity) the Hazard Ratio (HR) was 1.00 (95% CI: 0.81, 1.22; median 36 months for rucaparib vs 43.2 months for placebo) for the ITT population. For the HRD and tBRCA subgroups the reported HRs were 1.01 (95% CI: 0.77, 1.32; median 40.5 months for rucaparib vs 47.8 months for placebo) and 0.83 (95% CI: 0.58, 1.19; median 45.9 months for rucaparib vs 47.8 months for placebo), respectively. In an exploratory subgroup analyses of patients without a tBRCA mutation (non-nested, non-tBRCA subpopulations [LOH+, LOH-, LOH unknown]), the HR for OS was 1.084 (95% CI: 0.841, 1.396; median 32.2 months for rucaparib vs 38.3 months for placebo). The median survival follow-up for all patients was 77 months (6.4 years) with a range of 2 days to 93 months (7.6 years).

At the time of the final analysis, 89% of patients in the placebo arm had received at least one subsequent treatment, of whom 46% received a PARP inhibitor. In the rucaparib arm, 78% of patients had received at least one subsequent treatment.

Cardiac electrophysiology

Concentration-QTcF prolongation analysis was conducted using data from 54 patients with a solid tumour administered continuous rucaparib at doses ranging from 40 mg once daily to 840 mg twice daily (1.4 times the approved recommended dose). At the predicted median steady-state C_max following 600 mg rucaparib twice daily, the projected QTcF increase from baseline was 11.5 msec (90% CI: 8.77 to 14.2 msec). Thus, the risk for clinically significant QTcF increase from baseline (i.e. >20 msec) is low.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Rubraca in all subsets of the paediatric population in ovarian cancer (see section 4.2 for information on paediatric use).