RUBRACA 300 MG FILM-COATED TABLETS - summary of medicine characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

Rubraca 300 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Rubraca 300 mg film-coated tablets

Each tablet contains rucaparib camsylate corresponding to 300 mg rucaparib.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Rubraca 300 mg film-coated tablet

Yellow, 8 × 16 mm, oval film-coated tablet, debossed with “C3”.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Rubraca is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.

Rubraca is indicated as monotherapy treatment of adult patients with platinum sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), highgrade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with two or more prior lines of platinum based chemotherapy, and who are unable to tolerate further platinum based chemotherapy.

4.2 Posology and method of administration

Treatment with rucaparib should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Detection of BRCA mutation

There is no requirement for BRCA testing prior to using Rubraca for the maintenance treatment of adult patients with relapsed high-grade epithelial ovarian cancer (EOC), fallopian tube cancer (FTC), or primary peritoneal cancer (PPC) who are in a complete or partial response to platinum-based chemotherapy.

Before taking Rubraca as treatment for relapsed or progressive EOC, FTC, or PPC, patients must have confirmation of deleterious germline or somatic mutations in the breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2) gene using a validated test.

Posology

The recommended dose is 600 mg rucaparib taken twice daily, equivalent to a total daily dose of 1,200 mg, until disease progression or unacceptable toxicity.

For the maintenance treatment, patients should start the maintenance treatment with Rubraca no later than 8 weeks after completion of their final dose of the platinum containing regimen.

If a patient vomits after taking Rubraca, the patient should not retake the dose and should take the next scheduled dose.

Missed doses

If a dose is missed, the patient should resume taking Rubraca with the next scheduled dose.

Dose adjustments for adverse reactions

Adverse reactions may be managed through dose interruptions and/or dose reductions for moderate to severe reactions (i.e. CTCAE Grade 3 or 4) such as neutropenia, anaemia and thrombocytopenia.

Liver transaminase elevations (aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)) occur early in treatment and are generally transient. Grade 1–3 elevations in AST/ALT can be managed without change to the rucaparib dose, or with treatment modification (interruption and/or dose reduction). Grade 4 reactions require treatment modification (see Table 2).

Other moderate to severe non-haematological adverse reactions such as nausea and vomiting, can be managed through dose interruption and/or reductions, if not adequately controlled by appropriate symptomatic management.

Table 1. Recommended dose adjustments

Table 2. Management of Treatment-emergent AST/ ALT Elevations

Special populations

Elderly

No adjustment is recommended to the starting dose for elderly patients (> 65 years of age) (see sections 4.8 and 5.2). Greater sensitivity of some elderly patients (> 65 years of age) to adverse events cannot be ruled out. There are limited clinical data in patients aged 75 or over.

Hepatic impairment

No starting dose adjustment is required in patients with mild or moderate hepatic impairment (see section 5.2). Patients with moderate hepatic impairment should be carefully monitored for hepatic function and adverse reactions. There are no clinical data in patients with severe hepatic impairment (ie, total bilirubin > 3 times ULN), therefore rucaparib is not recommended for use in patients with severe hepatic impairment.

Renal impairment

No starting dose adjustment is required in patients with mild or moderate renal impairment (see section 5.2). There are no clinical data in patients with severe renal impairment (CLcr less than 30 mL/min), therefore rucaparib is not recommended for use in patients with severe renal impairment. Rucaparib may only be used in patients with severe renal impairment if the potential benefit outweighs the risk. Patients with moderate or severe renal impairment should be carefully monitored for renal function and adverse reactions.

Paediatric population

The safety and efficacy of Rubraca in children or adolescents aged less than 18 years have not been established. No data are available.

Method of administration

Rubraca is for oral use and can be taken with or without food. The doses should be taken approximately 12 hours apart. See section 5.2.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Breast-feeding (see section 4.6).

4.4 Special warnings and precautions for use

Efficacy of Rubraca as treatment for relapsed or progressive EOC, FTC, or PPC has not been investigated in patients who have received prior treatment with a PARP inhibitor. Therefore, use in this patient population is not recommended.

Haematological toxicity

During treatment with rucaparib, events of myelosuppression (anaemia, neutropenia, thrombocytopenia) may be observed and are typically first observed after 8–10 weeks of treatment with rucaparib. These reactions are manageable with routine medical treatment and/or dose adjustment for more severe cases. Complete blood count testing prior to starting treatment with Rubraca, and monthly thereafter, is advised. Patients should not start Rubraca treatment until they have recovered from haematological toxicities caused by previous chemotherapy (< CTCAE Grade 1).

Supportive care and institutional guidelines should be implemented for the management of low blood counts for the treatment of anaemia and neutropenia. Rubraca should be interrupted or dose reduced according to Table 1 (see section 4.2) and blood counts monitored weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or better after 4 weeks, the patient should be referred to a haematologist for further investigations.

Myelodysplastic syndrome/acute myeloid leukaemia

Myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), including cases with fatal outcome, have been reported in patients who received rucaparib. The duration of therapy with rucaparib in patients who developed MDS/AML varied from less than 1 month to approximately 28 months.

If MDS/AML is suspected, the patient should be referred to a haematologist for further investigations, including bone marrow analysis and blood sampling for cytogenetics. If, following investigation for prolonged haematological toxicity, MDS/AML is confirmed, Rubraca should be discontinued.

Photosensitivity

Photosensitivity has been observed in patients treated with rucaparib. Patients should avoid spending time in direct sunlight because they may burn more easily during rucaparib treatment; when outdoors, patients should wear a hat and protective clothing, and use sunscreen and lip balm with sun protection factor (SPF) of 50 or greater.

Gastrointestinal toxicities

Gastrointestinal toxicities (nausea and vomiting) are frequently reported with rucaparib, are generally low grade (CTCAE Grade 1 or 2), and may be managed with dose reduction (refer to Table 1) or interruption. Antiemetics, such as 5-HT3 antagonists, dexamethasone, aprepitant and fosaprepitant, can be used as treatment for nausea/vomiting and may also be considered for prophylactic (i.e., preventative) use prior to starting Rubraca. It is important to proactively manage these events to avoid prolonged or more severe events of nausea/vomiting which have the potential to lead to complications such as dehydration or hospitalisation.

Embryofetal toxicity

Rubraca can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings from animal studies. In an animal reproduction study, administration of rucaparib to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 600 mg twice daily (see section 5.3).

Pregnancy/con­traception

Pregnant women should be informed of the potential risk to a foetus. Women of reproductive potential should be advised to use effective contraception during treatment and for 6 months following the last dose of Rubraca (see section 4.6). A pregnancy test before initiating treatment is recommended in women of reproductive potential.

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on rucaparib

Enzymes responsible for rucaparib metabolism have not been identified. Based on in vitro data, CYP2D6, and to a lesser extent CYP1A2 and CYP3A4, were able to metabolize rucaparib.

Although in vitro rucaparib metabolism mediated by CYP3A4 was slow, a significant contribution of CYP3A4 in vivo cannot be excluded. Caution should be used for concomitant use of strong CYP3A4 inhibitors or inducers.

In vitro, rucaparib was shown to be a substrate of P-gp and BCRP. Effect of Pgp and BCRP inhibitors on rucaparib PK cannot be ruled out. Caution is recommended when rucaparib is co-administered with medicinal products that are strong inhibitors of P-gp.

Effects of rucaparib on other medicinal products

In medicinal product interaction studies in cancer patients, the effects of steady-state rucaparib at 600 mg twice daily on CYP1A2, CYP2C9, CYP2C19, CYP3A, BCRP and P-gp were evaluated with single oral doses of sensitive probes (caffeine, S-warfarin, omeprazole, midazolam, rosuvastatin, and digoxin, respectively). The effect of rucaparib on the pharmacokinetics of the combined oral contraceptive (ethinylestradiol and levonorgestrel) was also evaluated. Data suggest that rucaparib is a moderate inhibitor of CYP1A2, and a mild inhibitor of CYP2C9, CYP2C19, and CYP3A. Rucaparib also marginally inhibits P-gp and weakly inhibits BCRP in the gut.

CYP1A2 substrates

Rucaparib showed no effect on Cmax of caffeine while moderately increasing AUCinf of caffeine by 2.55 fold (90% CI: 2.12, 3.08). When co-administering medicinal products metabolized by CYP1A2, particularly medicines which have a narrow therapeutic index (e.g., tizanidine, theophylline), dose adjustments may be considered based on appropriate clinical monitoring.

CYP2C9 substrates

Rucaparib increased S-warfarin Cmax by 1.05 fold (90% CI: 0.99 to 1.12) and AUC0–

96h by 1.49 fold (90% CI: 1.40 to 1.58), respectively. When co-administering medicinal products that are CYP2C9 substrates with a narrow therapeutic index (e.g., warfarin, phenytoin), dose adjustments may be considered, if clinically indicated. Caution should be exercised and additional International Normalised Ratio (INR) monitoring with co-administration of warfarin and therapeutic drug level monitoring of phenytoin should be considered, if used concomitantly with rucaparib.

CYP2C19 substrates

Rucaparib increased omeprazole Cmax by 1.09 fold (90% CI: 0.93 to 1.27) and AUCinf by 1.55 fold (90% CI: 1.32 to 1.83). The risk for a clinically relevant effect of concomitant administration of proton pump inhibitors (PPIs) is likely small (see section 5.2). No dose adjustment is considered necessary for co-administered medicinal products that are CYP2C19 substrates.

CYP3A substrates

Rucaparib increased midazolam Cmax by 1.13 fold (90% CI: 0.95 to 1.36) and AUCinf by 1.38 fold (90% CI: 1.13 to 1.69). Caution is advised when co-administering medicinal products that are CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, terfenadine). Dose adjustments may be considered, if clinically indicated based on observed adverse reactions.

Oral contraceptives

Rucaparib increased ethinylestradiol Cmax by 1.09 fold (90% CI: 0.94 to 1.27) and AUClast by 1.43 fold (90% CI: 1.15 to 1.77). Rucaparib increased levonorgestrel Cmax by 1.19 fold (90% CI: 1.00 to 1.42) and AUClast by 1.56 fold (90% CI: 1.33 to 1.83). No dose adjustment is recommended for co-administered oral contraceptives.

BCRP substrates

Rucaparib increased rosuvastatin Cmax by 1.29 fold (90% CI: 1.07 to 1.55) and AUCinf by 1.35 fold (90% CI: 1.17 to 1.57). No dose adjustment is recommended for coadministered medicinal products that are BCRP substrates.

P-gp substrates

Rucaparib showed no effect on Cmax of digoxin while marginally increasing AUC0–72h by 1.20 fold (90% CI: 1.12 to 1.29). No dose adjustment is recommended for coadministered medicinal products that are P-gp substrates.

Interaction of rucaparib with other enzymes and transporter was evaluated in vitro. Rucaparib is a weak inhibitor of CYP2C8, CYP2D6, and UGT1A1. Rucaparib down regulated CYP2B6 in human hepatocytes at clinically relevant exposures. Rucaparib is a potent inhibitor of MATE1 and MATE2-K, a moderate inhibitor of OCT1, and a weak inhibitor of OCT2. As inhibition of these transporters could decrease metformin renal elimination and decrease liver uptake of metformin, caution is advised when metformin is co-administered with rucaparib. The clinical relevance of UGT1A1 inhibition by rucaparib is not clear. Caution should be used when rucaparib is coadministered with UGT1A1 substrates (i.e. irinotecan) to patients with UGT1A1*28 (poor metabolizer) due to a possible increase in the exposure of SN-38 (the active metabolite of irinotecan) and associated toxicities.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/con­traception in females

Women of childbearing potential should be advised to avoid becoming pregnant while receiving rucaparib. Patients should be advised to use effective contraception during treatment and for 6 months following the last dose of rucaparib (see section 4.5).

Pregnancy

There are no or limited data from the use of rucaparib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Based on its mechanism of action and preclinical data, rucaparib may cause fetal harm when administered to a pregnant woman. Rubraca should not be used during pregnancy unless the clinical condition of the woman requires treatment with rucaparib. A pregnancy test before initiating treatment is recommended in women of reproductive potential.

Breast-feeding

There are no animal studies on the excretion of rucaparib in breast milk. It is unknown whether rucaparib/or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Rubraca must not be used during breast-feeding.

Because of the potential for serious adverse reactions in breast-fed infants from rucaparib, breast-feeding is contraindicated during treatment with Rubraca and for 2 weeks after the final dose (see section 4.3).

Fertility

There are no data on the effect of rucaparib on human fertility. Based on the animal studies, impact on fertility associated with the use of rucaparib cannot be ruled out (see section 5.3). Moreover, according to its mechanism of action, rucaparib may impact human fertility.

4.7 Effects on ability to drive and use machines

Rubraca has minor influence on the ability to drive and use machines. Caution when driving or using machines is advised for patients who report fatigue, nausea, or dizziness during treatment with Rubraca (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

The overall safety profile of rucaparib is based on data from 937 patients in clinical trials in ovarian cancer treated with rucaparib monotherapy.

Adverse reactions occurring in > 20% of patients receiving rucaparib were nausea, fatigue/asthenia, vomiting, anaemia, abdominal pain, dysgeusia, ALT elevations, AST elevations, decreased appetite, diarrhoea, thrombocytopenia and creatinine elevations. The majority of adverse reactions were mild to moderate (Grade 1 or 2).

The > Grade 3 adverse reactions occurring in > 5% of patients were anaemia (23%), ALT elevations (10%), fatigue/asthenia (10%), neutropenia (8%), thrombocytopenia (6%), and nausea (5%). The only serious adverse reaction occurring in > 2% of patients was anaemia (5%).

Adverse reactions that most commonly led to dose reduction or interruption were anaemia (20%), fatigue/asthenia (18%), nausea (16%), thrombocytopenia (15%), and AST/ALT elevations (10%). Adverse reactions leading to permanent discontinuation occurred in 10% of patients, with thrombocytopenia, nausea, anaemia, and fatigue/asthenia being the most frequent adverse reactions leading to permanent discontinuation.

Tabulated list of adverse reactions

The adverse reaction frequency is listed by MedDRA System Organ Class (SOC) at the preferred term level. Frequencies of occurrence of adverse reactions are defined as: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

Table 3. Tabulated list of adverse reactions by MedDRA system organ class

a MDS/AML rate is based on overall total patient population of 1321 who have received one dose of oral rucaparib.

b Includes laboratory findings

c Includes fatigue, asthenia and lethargy

Description of selected adverse reactions

Haematological toxicity

Haematological adverse reactions of all CTCAE Grades of anaemia, thrombocytopenia and neutropenia were reported in 42%, 26% and 16% of patients respectively. Thrombocytopenia and anaemia led to discontinuation in 1.8% and 2.1% of patients. Adverse reactions CTCAE Grade 3 or higher occurred in 23% (anaemia), 8% (neutropenia) and 6% (thrombocytopenia) of patients. The time of onset for adverse reactions of myelosuppression Grade 3 or higher was generally later in treatment (after 2 or more months). For risk mitigation and management, see section 4.4.

Myelodysplastic syndrome/Acute myeloid leukaemia

MDS/AML are serious adverse reactions that occur uncommonly (0.5%) in patients on treatment and during the 28 day safety follow up, and commonly (1.3%) for all patients including during the long term safety follow up (rate is calculated based on overall safety population of 1321 patients exposed to at least one dose of oral rucaparib in all clinical studies). In the pivotal Phase 3 study (ARIEL3), the incidence of MDS/AML during therapy in patients who received rucaparib was 0.8%. Although no cases were reported during therapy in patients who received placebo, one case has been reported in a placebo -treated patient during the long term safety follow up. All patients had potential contributing factors for the development of MDS/AML; in all cases, patients had received previous platinum-containing chemotherapy regimens and/or other DNA damaging agents. For risk mitigation and management, see section 4.4.

Gastrointestinal toxicities

Vomiting and nausea were reported in 42% and 77% of patients, respectively and were generally low grade (CTCAE Grade 1 to 3). Abdominal pain (combined terms abdominal pain, abdominal pain lower, abdominal pain upper) was reported in 40.1% of rucaparib treated patients, but was also very common (33%) in placebo patients, most likely associated with underlying disease. For risk mitigation and management, see section 4.4.

Photosensitivity

Photosensitivity was reported in 13% of patients as low grade skin reactions (CTCAE Grade 1 or 2), and by 2 (0.2%) patients as > CTCAE Grade 3 reaction. For risk mitigation and management, see section 4.4.

Increases in serum aminotransferases (AST/ALT)

Events related to increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed in 38% (all grades) and 11% (> CTCAE Grade 3) of patients. These events occurred within the first few weeks of treatment with rucaparib, were reversible, and were rarely associated with increases in bilirubin. Increased ALT was observed in 34.8% (all grades) and 9.9% (> CTCAE Grade 3) of patients, increased AST in 31.4% (all grades) and 2.8% (> CTCAE Grade 3) of patients and increased ALT and AST in 28.6% (all grades) and 2.1% (> CTCAE Grade 3) of patients. No events met Hy’s Law criteria for drug-induced liver injury. AST/ALT elevations may need to be managed with treatment interruption and/or dose reduction as described in Table 2 (see section 4.2). Most patients could continue rucaparib with or without treatment modification without recurrence of Grade > 3 LFT abnormalities.

Elevations in serum creatinine

Increases in serum creatinine, predominantly mild to moderate (CTCAE Grade 1 or 2), were observed in 20% of patients within the first few weeks of treatment with rucaparib. Four (0.4%) patients reported a CTCAE Grade 3 reaction. Elevations in creatinine with rucaparib treatment may be due to inhibition of the renal transporters MATE1 and MATE2-K (see section 4.5). These increases in serum creatinine were clinically asymptomatic.

Elderly

In patients > 75 years old, frequencies of some adverse reactions increased: increased blood creatinine (32%), dizziness (20%), pruritus (15%), and memory impairment (4%) were higher than in patients < 75 years old (18%, 15%, 9% and 1% respectively).

Patients with Renal Impairment

In patients with moderate renal impairment (CLcr of 30–59 mL/min), frequencies of some adverse reactions increased: Grade 3 or 4 anaemia (31%), Grade 3 or 4 thrombocytopenia (12%), and Grade 3 fatigue/asthenia (15%) were higher than in patients with mild renal impairment (CLcr

> 59–80 mL/min) or normal renal function (CLcr > 80 mL/min) (21%, 5%, and 8%).

Paediatric population

No studies have been conducted to investigate the pharmacokinetics of rucaparib in paediatric patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or by searching for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

There is no specific treatment in the event of Rubraca overdose, and symptoms of overdose are not established. In the event of suspected overdose, physicians should follow general supportive measures and should treat symptomatically.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

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 randomized (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 investigator-assessed progression-free survival (invPFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (v1.1). PFS assessed by blinded independent radiology review (BIR) was a key secondary efficacy outcome.

The mean age was 61 years (range: 36 to 85); most of the patients were white (80%); and all had an Eastern Cooperative Oncology Group (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 platinumbased 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.

ARIEL3 demonstrated a statistically significant improvement in PFS for patients randomised to rucaparib as compared with placebo in the ITT population and in the HRD and tBRCA subgroups. IRR- assessment for the ITT population supported the primary endpoint. At the time of the analysis of PFS, OS data were not mature (with 22% of events). Efficacy results are summarised in Table 4 and Figure 1.

Table 4. ARIEL3 Efficacy Results

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.

Figure 1. Kaplan-Meier Curves of Progression-Free Survival in ARIEL3 as

Assessed by Investigator: ITT population

In the ITT population, 38% of patients (141/375) in the rucaparib group and 35% of patients (66/189) in the placebo group had measurable disease at baseline. In an exploratory analysis in this subgroup, a response was noted in 18% (95% CI 12% – 26%) of patients (n=26) on rucaparib compared to 8% (95% CI 3% – 17%) of patients (n=5) on placebo (2-sided p-value = 0.0069), including 10 patients (7%) in the rucaparib group who achieved a complete remission.

In the tBRCA population, 31% of patients (40/130) in the rucaparib group and 35% of patients (23/66) in the placebo group had measurable disease at baseline. In an exploratory analysis, a response was noted in 38% (95% CI 23% – 54%) of patients (n=15) on rucaparib compared to 9% (95% CI 1% –28%) of patients (n=2) on placebo (2-sided p-value = 0.0055), including 7 (18%) patients in the rucaparib group who achieved a complete remission.

Treatment of BRCA-mutated ovarian cancer after 2 or more chemotherapies The efficacy of rucaparib was investigated in 106 patients in 2 multicentre, single-arm, open-label clinical studies, Study 10 and ARIEL2, in patients with advanced BRCA-mutant epithelial ovarian, fallopian tube or primary peritoneal cancer who had progressed after 2 or more prior chemotherapies (the primary efficacy population). The tumour histology was high grade serous in 91.5% of patients, endometrioid in 2.8% and mixed histology in 4.7%. None of the patients had received prior treatment with a PARP inhibitor. BRCA status based on a local test was known for some patients at the time of enrollment. Central BRCA testing was performed retrospectively after patients were enrolled. All 106 patients received rucaparib 600 mg twice daily. Patients

who had been hospitalised for bowel obstruction in the last 3 months were excluded.

The primary efficacy outcome measure of both studies was objective response rate (ORR) as assessed by the investigator according to RECIST version 1.1. An analysis of progression-free survival (PFS) was also performed.

Study 10 population characteristics in 42 patients were: median age 57 years (range 42 to 84), white (83%), ECOG performance status 0 (62%) or 1 (38%), high grade ovarian cancer (100%), 3 or more prior lines of chemotherapy (36%), median time since ovarian cancer diagnosis 43 months [range: 6 – 178], median progression-free interval from the last platinum treatment 8.0 months [range: 6.0 – 116.4].

ARIEL2 population characteristics in 64 patients were: median age 60 years (range 33 to 80), white (75%), ECOG performance status 0 (61%) or 1 (39%), high grade ovarian cancer (100%), 3 or more prior lines of chemotherapy (78%), median time since ovarian cancer diagnosis 53 months [range: 22–197], median progression-free interval from the last platinum treatment 7.6 months [range: 0.7–26.5].

Most of the primary efficacy population were platinum-sensitive (n=79, 74.5%); the remaining patients were platinum-resistant (n=20, 18.9%) or platinum-refractory (n=7, 6.6%). Patients with germline (g)BRCA (n=88, 83.0%) or somatic (s)BRCA (n=18, 17.0%) mutations were included.

In the subset of 79 platinum-sensitive patients, progression free interval after last platinum dose was > 6 – 12 months for 55 (69.6%) patients and

> 12 months for 24 (30.4%) patients. Platinum-sensitive patients had received 2 (n=47, 59.5%), 3 (n=28, 35.4%), or > 3 (n=4, 5.1%) prior lines of platinumbased chemotherapy. The proportion of platinum-sensitive patients with gBRCA and sBRCA mutations was comparable to the primary efficacy population at n=66 (83.5%) and n=13 (16.5%) respectively.

Efficacy results from all patients treated are summarized in Table 5.

Table 5. Summary of primary efficacy findings for patients with BRCA-mutant ovarian cancer who received rucaparib 600 mg twice daily and two or more prior chemotherapy regimens based on investigator assessment of response

a The median duration of response is determined from the patients who had an objective tumour response according to RECIST guidelines, following treatment with rucaparib. NA: Not Achieved

CI: Confidence interval

Four (5.1%) of 79 platinum sensitive patients overall had progressive disease as best response. ORR was similar for patients with germline BRCA-mutant ovarian cancer or somatic BRCA-mutant ovarian cancer and for patients with a BRCA1 gene mutation or BRCA2 gene mutation.

The ORR, by independent radiology review for the platinum-sensitive population, was 42/79, 53.2% (95% CI [41.6–64.5]).

For the platinum-resistant population (N=20), ORR by investigator review was 35.0% (95% CI [15.4, 59.2], with a complete response rate of 5.0%, and a partial response rate of 30.0%. The median duration of response was 196 days (95% CI [113 – NA]). The median progression-free survival was 282 days (95% CI [218–335]), and the median overall survival was 18.8 months (95% CI [12.9-NA]).

For the platinum-refractory population (N=7), there were no responders. The median progression-free survival was 162 days (95% CI [51–223]). Median overall survival was not achieved in this population.

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 Cmax 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 MHRA 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).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The MHRA will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

Plasma exposures of rucaparib, as measured by Cmax and AUC, were approximately dose proportional at evaluated doses (40 to 500 mg daily, 240 to 840 mg twice a day). Steady state was achieved after 1 week of dosing. Following repeated twice daily dosing, the accumulation based on AUC ranged from 3.5 to 6.2 fold.

Absorption

In patients with cancer following rucaparib 600 mg taken twice daily, the mean steady-state Cmax was 1940 ng/mL and AUC0-i2h was 16900 h-ng/mL with Tmax of 1.9 hours. The mean absolute oral bioavailability following a single oral dose of 12 to 120 mg rucaparib was 36%. The absolute oral bioavailability at 600 mg has not been determined. In patients with cancer following a high-fat meal, the Cmax increased by 20%, the AUC0–24h increased by 38%, and the Tmax was delayed by 2.5 hours, as compared with dosing under fasted conditions. The food effect on PK was not considered clinically significant. Rubraca can be administered with or without food.

Distribution

The in vitro protein binding of rucaparib is 70.2% in human plasma at therapeutic concentration levels. Rucaparib preferentially distributed to red blood cells with a blood-to-plasma concentration ratio of 1.83. In patients with cancer, rucaparib had a steady-state volume of distribution of 113 L to 262 L following a single intravenous dose of 12 mg to 40 mg rucaparib.

Biotransformation

In vitro, rucaparib is metabolised primarily by CYP2D6, and to a lesser extent by CYP1A2, and CYP3A4. In a population PK analysis, no clinically relevant PK differences were observed among patients with different CYP2D6 phenotypes (including poor metabolizers, n=9; intermediate metabolizers, n=71; normal metabolizers, n=76; and ultra-rapid metabolizers, n=4) or patients with different CYP1A2 phenotypes (including normal metabolizers, n=28; hyperinducers, n=136). The results should be interpreted with caution due to the limited representation of some subgroup phenotypes.

Following administration of a single oral dose of [14C]-rucaparib to patients with solid tumours, unchanged rucaparib accounted for 64.0% of the radioactivity in plasma. Oxidation, N-demethylation, N-methylation, glucuronidation, and N-formylation were the major metabolic pathways for rucaparib. The most abundant metabolite was M324, an oxidative deamination product of rucaparib, accounting for 18.6% of the radioactivity in plasma. In vitro, M324 was at least 30 fold less potent than rucaparib against PARP-1, PARP-2, and PARP-3. Other minor metabolites accounted for 13.8% of the radioactivity in plasma. Rucaparib accounted for 44.9% and 94.9% of radioactivity in urine and faeces, respectively; while M324 accounted for 50.0% and 5.1% of radioactivity in urine and faeces, respectively.

Elimination

The clearance ranged from 13.9 to 18.4 L/hour, following a single intravenous dose of rucaparib 12 mg to 40 mg. Following administration of a single oral dose of [14C]-rucaparib 600 mg to patients, the overall mean recovery of radioactivity was 89.3%, with a mean recovery of 71.9% in faeces and 17.4% in urine by 288 hours post dose. Ninety percent of the observed faecal recovery was achieved within 168 hours postdose. The mean half-life (t1/2) of rucaparib was 25.9 hours.

Medicinal product interactions

In vitro, rucaparib was shown to be a substrate of P-gp and BCRP, but not a substrate of renal uptake transporters OAT1, OAT3, and OCT2, or hepatic transporters OAPT1B1 and OATP1B3. Effect of P-gp and BCRP inhibitors on rucaparib PK cannot be ruled out.

In vitro, rucaparib reversibly inhibited CYP1A2, CYP2C19, CYP2C9, and CYP3A, and to a lesser extent CYP2C8, CYP2D6, and UGT1A1. Rucaparib induced CYP1A2, and down regulated CYP2B6 and CYP3A4 in human hepatocytes at clinically relevant exposures.

In vitro, rucaparib is a potent inhibitor of MATE1 and MATE2-K, a moderate inhibitor of OCT1, and a weak inhibitor of OCT2. At clinical exposures, rucaparib did not inhibit bile salt export pump (BSEP), OATP1B1, OATP1B3, OAT1 and OAT3. Inhibition of MRP4 by rucaparib cannot be fully ruled out at clinical exposures. No interaction with MRP2 or MRP3 was observed in vitro at the clinical exposure of rucaparib, however, mild bi-phasic activation and inhibition of MRP2 and concentration dependent inhibition of MRP3 were observed at concentrations higher than the observed plasma Cmax of rucaparib. The clinical relevance of MRP2 and MRP3 interaction in the gut is not known. In vitro, rucaparib is an inhibitor of the BCRP and P-gp efflux transporters. No significant P-gp inhibition was observed in vivo (section 4.5).

Population PK analysis suggested that concomitant use of PPIs is unlikely to have clinically meaningful impact on rucaparib PK. A firm conclusion cannot be made regarding the effect of co-administration of rucaparib and PPIs because dose level and time of administration have not been documented in detail for the PPIs.

Pharmacokinetics in specific populations

Age, race, and body weight

Based on population PK analysis, no clinically significant relationships were identified between predicted steady-state exposure and patient’s age, race, and body weight. Patients included in the population PK study were aged 21 to 86 years (58% < 65 years, 31% 65–74 years, and 11% > 75 years), 82% were Caucasian, and had body weights between 41 and 171 kg (73% had body weight > 60 kg).

Hepatic impairment

A population PK analysis was performed to evaluate the effect of hepatic impairment on the clearance of rucaparib in patients receiving rucaparib 600 mg twice daily. No clinically important differences were observed between 34 patients with mild hepatic impairment (total bilirubin < ULN and AST > ULN or total bilirubin > 1.0 to 1.5 times ULN and any AST) and 337 patients with normal hepatic function. In a study evaluating the pharmacokinetics of rucaparib in patients with hepatic impairment, patients with moderate hepatic impairment (N=8, National Cancer Institute – Organ Dysfunction Working Group criteria; total bilirubin > 1.5 – < 3 times ULN) had a 45% higher AUC of rucaparib following a single dose of 600 mg compared to patients with normal hepatic function (N=8). Cmax or Tmax were similar between the groups. No data are available for patients with severe hepatic impairment (see section 4.2).

Renal impairment

No formal studies of rucaparib in patients with renal impairment have been conducted. A population PK analysis was performed to evaluate the effect of renal impairment on the clearance of rucaparib in patients receiving rucaparib 600 mg twice daily. Patients with mild renal impairment (N=149; CLcr between 60 and 89 mL/min, as estimated by the Cockcroft-Gault method) and those with moderate renal impairment (N=76; CLcr between 30 and 59 mL/min) showed approximately 15% and 33% higher steady-state AUC, respectively, compared to patients with normal renal function (N=147; CLcr greater than or equal to 90 mL/min). The pharmacokinetic characteristics of rucaparib in patients with CLcr less than 30 mL/min or patients on dialysis are unknown (see section 4.2).

5.3 Preclinical safety data

General toxicology

The findings in non-clinical toxicology studies performed with oral rucaparib were generally consistent with the adverse events observed in clinical studies. In repeat-dose toxicity studies of up to 3 months duration in rats and dogs, the target organs were the gastrointestinal, haematopoietic, and lymphopoietic systems. These findings occurred at exposures below those observed in patients treated at the recommended dose, and were largely reversible within 4 weeks of cessation of dosing. In vitro, the IC50 of rucaparib against the human ether-á-go-go related gene (hERG) was 22.6 UM, which is approximately 13fold higher than the Cmax in patients at the recommended dose.

Intravenous administration of rucaparib in the rat and dog induced cardiac effects at a high Cmax (5.4 to 7.3-fold higher than patients), but not at a lower Cmax (1.3 to 3.8-fold higher than patients). No cardiac effects were observed with oral dosing of rucaparib in repeat-dose toxicology studies at a rucaparib Cmax comparable to that observed in patients. Although no cardiac effects were observed following oral dosing, based on the findings in the intravenous studies and safety margins, cardiac effects in patients cannot be excluded when rucaparib is given orally.

Carcinogenicity

Carcinogenicity studies have not been performed with rucaparib.

Genotoxicity

Rucaparib was not mutagenic in a bacterial reverse mutation (Ames) assay. Rucaparib induced structural chromosomal aberrations in the in vitro human lymphocyte chromosomal aberration assay.

Reproductive toxicology

In an embryo-foetal development study in rats, rucaparib was associated with post-implantation loss at exposures of approximately 0.04 times the human AUC at the recommended dose.

Fertility studies have not been conducted with rucaparib. No effects on male and female fertility were observed in 3-month general toxicology studies in rats and dogs at exposures of 0.09 to 0.3 times the human AUC at the recommended dose. A potential risk cannot be ruled out based on the safety margin observed. In addition, according to its mechanism of action rucaparib may have the potential to impair fertility in humans.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Microcrystalline cellulose

Sodium starch glycolate (Type A)

Colloidal anhydrous silica Magnesium stearate

Rubraca 300 mg film-coated tablets

Tablet coating

Polyvinyl alcohol (E1203)

Titanium dioxide (E171)

Macrogol 4000 (E1521)

Talc (E553b)

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

HDPE bottle, with a polypropylene (PP) induction seal closure, containing 60 tablets. Each carton contains one bottle.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Clovis Oncology Ireland Ltd.

Regus Dublin Airport

Skybridge House – Dublin Airport

Swords

County Dublin

K67 P6K2

Ireland

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 50731/0003

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/01/2021