Rucaparib

Rucaparib is an inhibitor of the poly(ADP-ribose) polymerase (PARP) enzymes PARP-1, PARP-2 and PARP-3, which play a role in DNA repair. In the first-line setting the efficacy evidence is ATHENA, a double-blind, multicentre phase 3 trial in 538 patients with advanced ovarian, fallopian tube or primary peritoneal cancer who were in response to first-line platinum-based chemotherapy and surgery.

Mechanism of Action

• PARP inhibition and trapping: in vitro, the cytotoxicity of rucaparib involves both inhibition of the enzymatic activity of PARP and trapping of PARP–DNA complexes, which increases DNA damage, apoptosis and cell death.
• Synthetic lethality: rucaparib showed anti-tumour activity in BRCA-mutant cell lines in vitro and in vivo, through loss of two DNA repair pathways at once. Cytotoxicity and anti-tumour activity were greater in cell lines deficient in BRCA1/2 and other DNA repair genes.
• Wider activity: rucaparib also reduced tumour growth in mouse xenograft models of human cancer with or without BRCA deficiency. DrugBank adds weaker interactions with other PARP family members.

Pharmacokinetics

• Absorption: exposure rises roughly in proportion to dose (40 to 500 mg daily and 240 to 840 mg twice daily). Steady state is reached after 1 week, with AUC accumulation of 3.5 to 6.2 times. At 600 mg twice daily, mean steady-state Cmax is 1,940 ng/mL, AUC0–12h 16,900 h·ng/mL and Tmax 1.9 hours. Mean absolute oral bioavailability was 36% after single doses of 12 to 120 mg. A high-fat meal raised Cmax by 20% and AUC0–24h by 38% and delayed Tmax by 2.5 hours, which is not clinically significant; the tablets are taken with or without food.
• Distribution: in vitro protein binding in human plasma is 70.2%. Rucaparib distributes preferentially to red blood cells (blood-to-plasma ratio 1.83). Steady-state volume of distribution was 113 to 262 L after a single intravenous dose of 12 to 40 mg.
• Metabolism: in vitro, mainly CYP2D6 and, to a lesser extent, CYP1A2 and CYP3A4. A population analysis found no clinically relevant differences between CYP2D6 phenotypes (poor to ultra-rapid metabolisers) or CYP1A2 phenotypes. Unchanged rucaparib was 64.0% of plasma radioactivity after a radiolabelled dose. Oxidation, N-demethylation, N-methylation, glucuronidation and N-formylation are the main pathways. The main metabolite, M324 (18.6% of plasma radioactivity), is at least 30 times less potent than rucaparib against PARP-1, -2 and -3.
• Elimination: DrugBank gives a mean terminal half-life of about 26 hours.
• Special populations: no starting dose adjustment is needed in mild or moderate hepatic or renal impairment (see Administration and Dosage).

• First-line maintenance treatment of advanced ovarian cancer: as monotherapy for adults with advanced (FIGO Stages III and IV) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy.
• Maintenance treatment of platinum-sensitive relapsed ovarian cancer: as monotherapy for adults 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.

• Hypersensitivity to rucaparib or to any of the excipients.
• Breast-feeding, during treatment and for 2 weeks after the last dose.

The safety profile is based on 1,594 patients treated with rucaparib monotherapy for ovarian cancer in clinical trials, with a median exposure of 7.4 months. Reactions in 20% or more of patients were nausea, fatigue/asthenia, vomiting, anaemia, abdominal pain, dysgeusia, raised ALT and AST, decreased appetite, diarrhoea, neutropenia and thrombocytopenia. Most were mild or moderate (Grade 1 or 2). Grade 3 or higher reactions in more than 5% of patients were anaemia (25%), raised ALT (10%), neutropenia (10%), fatigue/asthenia (9%) and thrombocytopenia (7%); the only serious reaction in more than 2% was anaemia (5%). Anaemia (23%), fatigue/asthenia (15%), nausea (14%), thrombocytopenia (14%), neutropenia (10%) and raised AST/ALT (10%) most often led to dose reduction or interruption. Reactions led to permanent discontinuation in 15% of patients, most often thrombocytopenia, nausea, anaemia and fatigue/asthenia.

Very common (≥1/10): anaemia, thrombocytopenia, neutropenia, leukopenia; decreased appetite, increased blood creatinine, hypercholesterolaemia; dysgeusia, dizziness; dyspnoea; nausea, vomiting, diarrhoea, dyspepsia, abdominal pain; increased alanine aminotransferase, increased aspartate aminotransferase; photosensitivity reaction, rash; fatigue (including asthenia and lethargy), pyrexia.

Common (≥1/100 to <1/10): myelodysplastic syndrome/acute myeloid leukaemia; lymphopenia, febrile neutropenia; hypersensitivity (mostly hypersensitivity, drug hypersensitivity and swelling or oedema of the face and eyes); dehydration; intestinal obstruction, stomatitis; increased transaminases; maculopapular rash, palmar-plantar erythrodysaesthesia syndrome, erythema.

The SmPC table lists no further reactions for all grades. Reactions of Grade 3 or higher were very common for anaemia and neutropenia, and common for thrombocytopenia, febrile neutropenia, leukopenia, lymphopenia, myelodysplastic syndrome/acute myeloid leukaemia, decreased appetite, dehydration, hypercholesterolaemia, nausea, vomiting, diarrhoea, abdominal pain, intestinal obstruction, raised ALT and AST, and fatigue.

Important reactions in more detail:

• Haematological toxicity: anaemia, thrombocytopenia and neutropenia of any grade occurred in 46%, 26% and 21% of patients, and of Grade 3 or higher in 25%, 7% and 10%. Anaemia and thrombocytopenia led to discontinuation in 2% and 1%. Severe myelosuppression generally appeared after 2 or more months of treatment.
• Myelodysplastic syndrome/acute myeloid leukaemia: serious reactions seen in 0.5% of patients on treatment and in the 28-day follow-up, and in 1.1% of all patients including long-term follow-up (3,025 patients exposed to oral rucaparib). All affected patients had earlier platinum chemotherapy and/or other DNA-damaging agents.
• Gastrointestinal: nausea in 68% and vomiting in 37%, generally Grade 1 or 2. Abdominal pain occurred in 39% (34% on placebo, probably related to the disease).
• Liver enzymes: raised ALT or AST in 39% (Grade 3 or higher in 10%), within the first weeks, reversible and rarely with raised bilirubin. No event met Hy’s law criteria for drug-induced liver injury.
• Serum creatinine: raised in 17%, mostly Grade 1 or 2 and without symptoms, possibly through inhibition of the renal transporters MATE1 and MATE2-K.
• Photosensitivity: 10% of patients, mostly low grade (0.2% Grade 3 or higher).
• Older patients and renal impairment: in patients aged 75 or over, raised creatinine (33%), dizziness (19%), pruritus (16%) and memory impairment (4%) were more frequent than in younger patients. In moderate renal impairment (creatinine clearance 30–59 mL/min), Grade 3 or higher anaemia (34%), neutropenia (13%), thrombocytopenia (12%), fatigue/asthenia (12%) and raised AST/ALT (12%) were more frequent than with normal renal function.

• Strong CYP3A4 inhibitors or inducers: rucaparib is mainly metabolised in vitro by CYP2D6, with smaller contributions from CYP1A2 and CYP3A4, but a significant role for CYP3A4 in vivo cannot be excluded. Use caution with strong CYP3A4 inhibitors or inducers. DrugBank advises caution with grapefruit products (which may raise levels) and St John’s wort (which may lower them).
• P-gp and BCRP: rucaparib is a substrate of both in vitro. Use caution with strong P-gp inhibitors.
• CYP1A2 substrates (rucaparib is a moderate inhibitor): caffeine exposure rose 2.55-fold. For substrates with a narrow therapeutic index (for example tizanidine, theophylline), dose adjustment may be considered with clinical monitoring.
• CYP2C9 substrates (mild inhibitor): S-warfarin exposure rose 1.49-fold. For narrow-index substrates (for example warfarin, phenytoin), dose adjustment may be considered; extra INR monitoring for warfarin and drug-level monitoring for phenytoin should be considered.
• CYP2C19 substrates (mild inhibitor): omeprazole exposure rose 1.55-fold; the effect of proton pump inhibitors is likely small and no dose adjustment is considered necessary.
• CYP3A substrates (mild inhibitor): a sensitive CYP3A probe rose 1.38-fold. Caution with narrow-index substrates such as alfentanil, astemizole, cisapride, ciclosporin, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus and terfenadine; dose adjustment may be considered according to observed reactions.
• Oral contraceptives: ethinylestradiol exposure rose 1.43-fold and levonorgestrel 1.56-fold; no dose adjustment is recommended.
• BCRP and P-gp substrates: rosuvastatin exposure rose 1.35-fold and digoxin 1.20-fold; no dose adjustment is recommended.
• Metformin: rucaparib strongly inhibits the transporters MATE1 and MATE2-K, moderately OCT1 and weakly OCT2 (in vitro), which could lower metformin renal elimination and liver uptake. Caution is advised.
• UGT1A1 substrates: rucaparib weakly inhibits UGT1A1. Caution with irinotecan in patients with the UGT1A1*28 variant (poor metabolisers), because exposure to its active metabolite SN-38 and related toxicity may increase.
• Other enzymes: in vitro, rucaparib is a weak inhibitor of CYP2C8 and CYP2D6 and down-regulates CYP2B6.

Treatment should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. The tablets are taken by mouth, with or without food, about 12 hours apart. Maintenance treatment should start no later than 8 weeks after the final dose of the platinum-containing regimen.

Recommended Dose

• 600 mg twice daily (total daily dose 1,200 mg), that is two 300 mg tablets twice daily.
• First-line maintenance of advanced ovarian cancer: until disease progression, unacceptable toxicity or completion of 2 years of treatment.
• Maintenance of platinum-sensitive relapsed ovarian cancer: until disease progression or unacceptable toxicity.

Dose Adjustments for Side Effects

• Moderate to severe reactions (CTCAE Grade 3 or 4) such as neutropenia, anaemia and thrombocytopenia are managed by interrupting and/or reducing the dose. Other moderate to severe non-haematological reactions, such as nausea and vomiting, can be managed the same way if symptomatic treatment does not control them.
• Dose steps: starting dose 600 mg twice daily (two 300 mg tablets); first reduction 500 mg twice daily (two 250 mg tablets); second reduction 400 mg twice daily (two 200 mg tablets); third reduction 300 mg twice daily (one 300 mg tablet).
• Raised AST/ALT occurs early and is generally transient. Grade 1 to 3 rises can be managed without a dose change or with interruption and/or reduction. For Grade 3 without other signs of liver dysfunction, check liver function tests weekly until Grade 2 or lower and continue rucaparib provided bilirubin is below the upper limit of normal and alkaline phosphatase is below 3 times the upper limit; interrupt if AST/ALT have not fallen to Grade 2 or lower within 2 weeks, then resume at the same or a reduced dose. For Grade 4, interrupt until Grade 2 or lower, then resume at a reduced dose and check liver function tests weekly for 3 weeks.

Special Populations

• Elderly: no adjustment of the starting dose at 65 years or over. Greater sensitivity of some elderly patients cannot be ruled out, and clinical data are limited at 75 years or over.
• Hepatic impairment: no starting dose adjustment in mild or moderate impairment, but patients with moderate impairment are monitored carefully for hepatic function and reactions. There are no clinical data in severe impairment (total bilirubin above 3 times the upper limit of normal), so rucaparib is not recommended.
• Renal impairment: no starting dose adjustment in mild or moderate impairment. There are no clinical data in severe impairment (creatinine clearance below 30 mL/min), so it is not recommended and may be used only if the potential benefit outweighs the risk. Renal function and reactions are monitored carefully in moderate or severe impairment.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Missed or Vomited Dose

If a dose is missed, resume with the next scheduled dose. If vomiting follows a dose, do not retake it; take the next scheduled dose.

Haematological Toxicity

Myelosuppression (anaemia, neutropenia, thrombocytopenia) typically first appears after 8 to 10 weeks of treatment and is manageable with routine medical care and/or dose adjustment in more severe cases. A complete blood count is advised before starting and monthly afterwards. Treatment should not start until the patient has recovered from haematological toxicity of previous chemotherapy (Grade 1 or lower). Supportive care and institutional guidelines apply to low blood counts. Rubraca is interrupted or the dose reduced, and blood counts are checked weekly until recovery; if counts have not returned to Grade 1 or better after 4 weeks, the patient is referred to a haematologist.

Myelodysplastic Syndrome and Acute Myeloid Leukaemia

Myelodysplastic syndrome or acute myeloid leukaemia, including fatal cases, has been reported; treatment had lasted from under 2 months to about 6 years in those patients. If it is suspected, the patient is referred to a haematologist for investigation, including bone marrow analysis and blood sampling for cytogenetics. If it is confirmed after investigation of prolonged haematological toxicity, Rubraca is stopped.

Photosensitivity

Patients may burn more easily. They should avoid direct sunlight and, outdoors, wear a hat and protective clothing and use sunscreen and lip balm with a sun protection factor of 50 or greater.

Nausea and Vomiting

These are frequent, generally low grade and can be managed by dose reduction or interruption. Antiemetics such as 5-HT3 antagonists, dexamethasone, aprepitant and fosaprepitant can be used, and may be considered preventively before starting. Proactive management helps to avoid prolonged or severe nausea and vomiting and complications such as dehydration or hospitalisation.

Intestinal Obstruction

In clinical trials in ovarian cancer, 3.5% of patients treated with rucaparib had a serious event of intestinal obstruction, fatal in 1 patient (less than 0.1%); the underlying disease may play a role. If obstruction is suspected, a prompt diagnostic evaluation and appropriate treatment are needed.

Pregnancy, Breastfeeding and Fertility

• Contraception and pregnancy testing: women of childbearing potential should avoid becoming pregnant and use effective contraception during treatment and for 6 months after the last dose. A pregnancy test before starting is recommended in women of reproductive potential.
• Pregnancy: there are no or limited data. Animal studies showed reproductive toxicity, including embryo-foetal toxicity in rats at exposures below those in patients on 600 mg twice daily. Rucaparib may cause foetal harm and should not be used in pregnancy unless the woman’s clinical condition requires it. Pregnant women should be told of the potential risk to the foetus.
• Breastfeeding: it is unknown whether rucaparib or its metabolites pass into human milk, and a risk to the infant cannot be excluded. Breast-feeding is contraindicated during treatment and for 2 weeks after the last dose.
• Fertility: there are no human data. An effect on fertility cannot be ruled out from animal studies, and the mechanism of action suggests rucaparib may affect human fertility.

Sodium

Each tablet contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

Rubraca has a minor influence on the ability to drive and use machines. Patients who report fatigue, nausea or dizziness should take care.

Rubraca tablets do not require any special storage conditions. They are supplied in HDPE bottles with a polypropylene induction seal closure, each holding 60 tablets, in cartons of 1 or 2 bottles; not all pack sizes may be marketed.

5 years.

Prescription only (Rx), with treatment started and supervised by a physician experienced in the use of anticancer medicinal products. Rucaparib is a tablet taken at home, so it is supplied to the patient or to the treating clinic on prescription.