Rucaparib

Rucaparib is an antineoplastic agent belonging to the pharmacological class of Poly(ADP-Ribose) Polymerase (PARP) inhibitors.

The FDA approves Rucaparib for treating advanced ovarian cancer and prostate cancer in adults.

When rucaparib is taken orally, its absolute bioavailability is 36%, mainly distributed to red blood cells, and binds 70% to plasma proteins. CYP2D6 primarily metabolizes it. Urine and faeces are the processes of elimination.

The most common side effects of Rucaparib include increased liver enzymes, decreased appetite, anaemia, weakness, gastrointestinal disturbance, acute myeloid leukaemia (blood cancer), and nasopharyngitis (inflammation of the throat and nasal passages).

Rucaparib is available as an oral tablet.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Rucaparib is an antineoplastic agent belonging to the pharmacological class of Poly(ADP-Ribose) Polymerase (PARP) inhibitors.

Rucaparib inhibits the poly (ADP-ribose) polymerase (PARP) enzymes, which are involved in DNA repair and include PARP-1, PARP-2, and PARP-3. According to in vitro research, rucaparib-induced cytotoxicity may be caused by enhanced PARP-DNA complex formation and suppression of PARP enzymatic activity, leading to DNA damage, apoptosis, and cancer cell death. Tumour cell lines lacking BRCA1/2 and other DNA repair genes showed increased rucaparib-induced cytotoxicity and anti-tumour activity. It has been demonstrated that rucaparib inhibits the formation of tumours in mice xenograft models of human cancer, whether or not BRCA defects are present.

Rucaparib reaches peak plasma time approximately 1.9 hours after administration.

At steady state, the peak plasma concentration of Rucaparib is 1940 ng/mL, achieved after continuous administration.

The area under the curve (AUC) of Rucaparib is 16,900 hr⋅ng/mL.

Rucaparib is available as an oral tablet.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

The physician recommends taking this medication orally twice daily, with or without meals.

• Prostate cancer
• Ovarian cancer

• Prostate cancer: Male prostate glands are tiny, walnut-sized glands that secrete seminal fluid, which feeds and moves sperm. Urinary difficulties are the most prevalent sign of prostate cancer, while at other times, there are none at all. Rucaparib inhibits poly ADP-ribose polymerase (PARP), which hinders the development of cancer cells and reduces urination difficulties. Rucaparib also helps take advantage of DNA repair deficits in tumour cells, which results in anti-cancer actions.
• Ovarian cancer: Cancer that develops in the female reproductive system (ovaries) is known as ovarian cancer. This type of cancer can also be lethal and is typically diagnosed much later. Usually, it extends to the stomach and pelvis. Rucaparib targets DNA repair pathways in cancer cells with homologous recombination defects, boosting its therapeutic benefits. It also kills the cancer cells and inhibits poly ADP-ribose polymerase (PARP), which prevents damaged cancer cells from being repaired.

• As a maintenance dose in adult patients with fallopian tubes, primary peritoneal, or recurrent epithelial ovarian cancer who are responding entirely or partially to platinum-based chemotherapy may benefit from rucaparib.
• Rucaparib may also be indicated in adult patients with metastatic castration-resistant prostate cancer (mCRPC) linked with a deleterious BRCA mutation (germline and/or somatic) who have had androgen receptor-focused therapy and taxane-based chemotherapy.

Orally: Administer Rucaparib tablets orally twice daily with water, which can be taken with or without meals. Unless a healthcare professional advises, tablets should not be crushed, chewed, or broken. Broken or damaged tablets should not be ingested. If a dose is missed or vomited, no additional dose should be taken on that day, and the next dose should be taken at the regular scheduled time.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Rucaparib is available as an oral tablet.

Dose Adjustment in Adult Patients:

Ovarian Cancer

600 milligrams BID PO

Continue till the disease worsens or the toxicity becomes unacceptable.

Prostate Cancer

600 mg BID PO

Continue the drug until the disease worsens or the toxicity becomes intolerable.

Avoid consuming grapefruit or its juice while taking Rucaparib to avoid possible issues with drug metabolism. To control weight, eat a balanced diet and get regular exercise. Avoid drinking and smoking. Include leafy greens, citrus fruits, fatty fish, berries, yoghurt, apples, peaches, broccoli, cauliflower, cabbage, beans, herbs, and spices. Avoid processed meats, fast food, fried foods, refined carbohydrates, and added sugar.

The dietary restriction should be individualized as per patient requirements.

• Rucaparib has been associated with rare instances of acute myeloid leukaemia and myelodysplastic syndrome. Assess complete blood counts (CBC) at baseline and monthly. Treatment should not begin until the patient has recovered from grade ≤1 haematological toxicity from prior chemotherapy.
• When a patient's neutrophil count is less than 1000 cells/mm3, do not use rucaparib; instead, think about other treatments for patients who have neutropenia and acute bacterial infections of the skin and skin structure.
• Rucaparib causes individuals to be more vulnerable to sunburn. Advise patients to use the proper sun protection measures while undergoing treatment.
• Rucaparib has the potential to damage fetuses because of its mode of action. Information on the hazards and the necessity of effective contraception both during and after treatment should be given to women who are or may become pregnant.

Avoid grapefruit, have a balanced diet, hydrate, and quit smoking.

The adverse reactions related to Rucaparib can be categorized as:

• Common Adverse Effects(Incidence ≥ 20%): Nausea, fatigue, vomiting, anemia, constipation, abdominal pain, dysgeusia (altered taste), and increased liver enzyme levels, photosensitivity.
• Less Common Adverse Effects (Incidence 5-20%): Diarrhea, decreased appetite, headache, insomnia, and hypertension (high blood pressure).
• Rare Adverse Effects: Elevated creatinine levels, myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) and severe hypersensitivity reactions.

The clinically relevant drug interactions of Rucaparib are briefly summarized here.

• Interactions between Drugs: If taking any of the following medications: warfarin, phenytoin, immunosuppressants (ciclosporin, sirolimus, tacrolimus), antacids (cisapride, omeprazole), anticoagulants (warfarin), antipsychotics (pimozide), antidiabetic (metformin), benzodiazepines (midazolam), muscle relaxants (tizanidine), anti-asthma (theophylline).
• Interactions with Food: Grapefruit should not be taken concurrently because grapefruit inhibits CYP3A4 metabolism; serum levels of rucaparib may rise. Exercise caution with St. John's Wort. Rucaparib serum levels may be lowered by St. John's Wort, which stimulates CYP3A4 metabolism.

• Pregnancy

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

According to research on animals and their mode of action, pregnant women who take it may experience damage to the fetus.

Pregnant women's data are not available to determine the risk related to drugs.

It is advised that women who are capable of reproducing undergo pregnancy tests before beginning.

Contraception

Use effective contraception during therapy and for six months after the last dosage if you are a female of reproductive potential.

Males who have female partners who are capable of having children should use effective contraception during therapy and for three months after the last dosage.

Donating sperm: Avoid donating sperm throughout therapy and for three months after the last dosage.

Animal Data

Research on animals When 600 mg BID was administered to pregnant rats during organogenesis, the embryofetal mortality during maternal exposure was 0.04 times higher than the AUC.

• Nursing Mothers

Information about rucaparib's presence in human milk, its impact on milk supply, or its effects on a breastfed kid needs to be included. For two weeks after the final dosage of rucaparib, lactating mothers are advised not to breastfeed due to the possibility of significant adverse effects in breastfed infants.

• Pediatric Use

The safety and effectiveness of Rucaparib in pediatric patients have not been established.

Dose Adjustment in Kidney Impairment Patients:

Moderate to mild (CrCl 30-89): No dosage modification is necessary

Patients with severe (CrCl <30 mL/min) or dialysis patients: Lack of information; not recommended.

Dose Adjustment in Hepatic Impairment Patients:

For mild to moderate cases (total bilirubin <3 times the upper limit of normal [ULN] or AST > ULN), there is no need to change the dose.

Severe: Unstudied (total bilirubin > 3 times ULN and any AST)

• Kristeleit RS, Drew Y, Oza AM, Domchek SM, Banerjee S, Glasspool RM, Balmaña J, Chen LM, Patel MR, Burris HA, Safra T, Borrow J, Lin KK, Goble S, Maloney L, Shapira-Frommer R. Efficacy and safety of rucaparib treatment in patients with BRCA-mutated, relapsed ovarian cancer: final results from Study 10. Br J Cancer. 2023 Jan;128(2):255-265. doi: 10.1038/s41416-022-02022-y. Epub 2022 Dec 8. PMID: 36482193; PMCID: PMC9902459.
• Monk BJ, Parkinson C, Lim MC, O'Malley DM, Oaknin A, Wilson MK, Coleman RL, Lorusso D, Bessette P, Ghamande S, Christopoulou A, Provencher D, Prendergast E, Demirkiran F, Mikheeva O, Yeku O, Chudecka-Glaz A, Schenker M, Littell RD, Safra T, Chou HH, Morgan MA, Drochýtek V, Barlin JN, Van Gorp T, Ueland F, Lindahl G, Anderson C, Collins DC, Moore K, Marme F, Westin SN, McNeish IA, Shih D, Lin KK, Goble S, Hume S, Fujiwara K, Kristeleit RS. A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol. 2022 Dec 1;40(34):3952-3964. doi: 10.1200/JCO.22.01003. Epub 2022 Jun 6. PMID: 35658487; PMCID: PMC9746782.
• Kristeleit R, Shapiro GI, Burris HA, Oza AM, LoRusso P, Patel MR, Domchek SM, Balmaña J, Drew Y, Chen LM, Safra T, Montes A, Giordano H, Maloney L, Goble S, Isaacson J, Xiao J, Borrow J, Rolfe L, Shapira-Frommer R. A Phase I-II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors. Clin Cancer Res. 2017 Aug 1;23(15):4095-4106. doi: 10.1158/1078-0432.CCR-16-2796. Epub 2017 Mar 6. PMID: 28264872.
• Swisher EM, Kristeleit RS, Oza AM, Tinker AV, Ray-Coquard I, Oaknin A, Coleman RL, Burris HA, Aghajanian C, O'Malley DM, Leary A, Welch S, Provencher D, Shapiro GI, Chen LM, Shapira-Frommer R, Kaufmann SH, Goble S, Maloney L, Kwan T, Lin KK, McNeish IA. Characterization of patients with long-term responses to rucaparib treatment in recurrent ovarian cancer. Gynecol Oncol. 2021 Dec;163(3):490-497. doi: 10.1016/j.ygyno.2021.08.030. Epub 2021 Sep 30. PMID: 34602290.

• US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Rubraca® (rucaparib)
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/209115s011lbl.pdf
• April Hazard Vallerand, Cynthia A. Sanoski. [link]. Sixteenth Edition. Philadelphia, China: F. A. Davis Company; 2019: Page No 1116-1117
• https://www.ema.europa.eu/en/documents/product-information/rubraca-epar-product-information_en.pdf