Olaparib: A new option for patients with advanced ovarian cancer
New Drug: Olaparib
Olaparib (Lynparza—AstraZeneca), a new medication to treat women with advanced ovarian cancer associated with mutated BRCA (BReast CAncer) genes, has received accelerated FDA approval. Targeted to patients who have had repeated treatment failures with chemotherapy, olaparib was approved in conjunction with the BRAC Analysis Cdx, a genetic test used to detect mutated BRCA genes.
Pathophysiology and mechanism of action
Epithelial cells form the outer layer of ovary tissue. Patients with ovarian cancer have ovarian epithelial cells replicating uncontrollably, with low DNA damage repair.
BRCA1 and BRCA2 are tumor-suppressor genes that produce DNA enzymes that repair DNA damage during replication. Patients with BRCA gene mutations have decreased DNA repair and thus an increased risk of developing ovarian cancer. During mutations, BRCA1 and BRCA2 have backup enzymes, such as poly-ADP polymerase (PARP), to function. Prior observations have found that in vitro BRCA gene mutations have resulted in increased sensitivity of cancer cells to PARP inhibitors.
PARP is an enzyme involved with normal cellular homeostasis, DNA transcription, and DNA damage repair. Olaparib directly inhibits PARP, allowing rapidly replicating cancer cells to remain damaged. When such cells remain damaged, they are purported to be more susceptible to apoptosis—automatic cell death.
Safety and efficacy
Olaparib’s efficacy was evaluated in a study of 137 patients with advanced ovarian cancer associated with mutated BRCA genes. All patients had undergone at least three chemotherapy treatments.
Researchers evaluated objective response rate (ORR)—the percentage of patients who experienced complete disappearance or partial shrinkage of the tumor—and duration of response (DOR). The study showed that 34% of patients experienced ORR for a median duration of 7.9 months.
The most common adverse effects reported (>20% of patients) included nausea, vomiting, diarrhea, distorted taste, decreased appetite, indigestion, abdominal pain, headache, common coldlike symptoms, cough, joint paint, musculoskeletal pain, muscle pain, back pain, and dermatitis.
Serious adverse effects included developing myelodysplastic syndrome, a condition in which the bone marrow does not produce enough functioning blood cells; acute myeloid leukemia; and lung inflammation.
The most common laboratory abnormalities reported in patients receiving olaparib included an increase in serum creatinine and the mean corpuscular volume and a decrease in hemoglobin, absolute neutrophil count, platelets, and lymphocytes.
Contraindications, warnings, precautions
Olaparib has no contraindications. However, safety and efficacy of olaparib in pediatric patients, nursing mothers, and patients with hepatic impairment have not been studied; thus pharmacists should caution about use in these patient populations.
Give patients the Medication Guide and review it with them carefully. If a patient misses a dose, instruct the patient to wait to take their next normal dose at the designated time. Tell patients to avoid taking olaparib with grapefruit or Seville oranges. Advise patients to their health care provider if they experience symptoms such as weakness, fatigue, fever, weight loss, etc., because these may be signs of myelodysplatic syndrome or acute myeloid leukemia. Advise patients to their health care provider if they experience symptoms such as new or worsening respiratory symptoms because they may be signs of pneumonitis. In addition, advise patients that nausea and vomiting are common and to their health care provider for antiemetic treatments.
Drug class: PARP inhibitor
Indication: Monotherapy for patients with confirmed or suspected mutated BRCA advanced ovarian cancer who have received chemotherapy three or more times
Dosage: 400 mg (eight 50-mg capsules) twice daily (800-mg total daily dose)
- If patients experience adverse reactions, the total daily dose may be reduced to 400 mg (four 50-mg capsules twice daily) or to 200 mg (two 50-mg capsules twice daily)
- A dose recommendation cannot be made for pediatric patients, nursing mothers, and patients with hepatic impairments because of lack of safety and efficacy data.
- The capsule should not be chewed, dissolved, or opened.