Olaparib

Olaparib is an oral anticancer medicine belonging to the poly(ADP-ribose) polymerase, or PARP, inhibitor class. It blocks PARP1 and PARP2 enzymes involved in the repair of single-strand DNA damage. Cancer cells with defects in homologous recombination repair, particularly those with harmful BRCA1 or BRCA2 alterations, can become especially dependent on PARP-mediated repair pathways. Inhibition of PARP can therefore lead to accumulation of DNA damage and selective death of susceptible cancer cells, a concept commonly referred to as synthetic lethality. Olaparib is administered orally as tablets and is generally taken twice daily. Its use depends on the cancer type, disease stage, previous treatment, and in several indications the presence of specific genetic or molecular abnormalities. Olaparib has an established role in maintenance treatment of selected ovarian, fallopian tube, and primary peritoneal cancers and is also used in appropriately selected breast, pancreatic, and prostate cancers. Regulatory indications have expanded over time as clinical studies demonstrated benefit in different tumor types and molecular subgroups. Because treatment can affect blood-cell production and carries uncommon but serious risks, regular blood-count monitoring and appropriate patient selection are important during therapy.

Olaparib was developed as a targeted inhibitor of PARP enzymes based on the concept that tumors with impaired homologous recombination DNA repair could be particularly vulnerable to PARP inhibition. The molecule received orphan designation in the European Union for ovarian cancer in December 2007 and was subsequently authorized in the EU as Lynparza on 16 December 2014. In the United States, the FDA granted the first approval for olaparib on 19 December 2014 under the accelerated approval pathway for patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer after three or more prior lines of chemotherapy. Subsequent FDA approvals expanded its use to maintenance treatment in recurrent and first-line ovarian cancer, breast cancer, pancreatic cancer, and metastatic castration-resistant prostate cancer, including selected combination regimens. The EMA has similarly expanded the authorized indications to include selected ovarian, breast, pancreatic, prostate, and endometrial cancers. In India, CDSCO records document regulatory permissions for olaparib tablets and subsequent indication-related updates, including a 2019 marketing permission for first-line maintenance treatment of BRCA-mutated advanced ovarian, fallopian tube, or primary peritoneal cancer. Key clinical programs supporting development include Study 19, SOLO-1, SOLO-2, OlympiAD, POLO, PROfound, PROpel, and PAOLA-1.

Olaparib is used as monotherapy or in combination therapy depending on the indication. In ovarian, fallopian tube, and primary peritoneal cancer, it is used for maintenance treatment in selected patients with BRCA-mutated advanced disease after response to first-line platinum-based chemotherapy, for selected patients with HRD-positive disease in combination with bevacizumab, and for platinum-sensitive recurrent disease following response to platinum chemotherapy. In breast cancer, olaparib is used for selected adults with germline BRCA-mutated, HER2-negative high-risk early breast cancer following neoadjuvant or adjuvant chemotherapy and for selected germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer. In pancreatic cancer, it is used as maintenance therapy for selected patients with germline BRCA-mutated metastatic adenocarcinoma whose disease has not progressed after at least 16 weeks of first-line platinum-based chemotherapy. In prostate cancer, olaparib is used for selected patients with metastatic castration-resistant prostate cancer carrying qualifying homologous recombination repair gene alterations and may also be combined with abiraterone and prednisone or prednisolone in selected BRCA-mutated patients. European authorization additionally includes combination treatment with durvalumab for maintenance of selected mismatch repair-proficient advanced or recurrent endometrial cancer.

Olaparib tablets are administered orally, generally at a recommended dose of 300 mg twice daily, with or without food. Dose selection and modification depend on the indication, adverse effects, concomitant medicines, and renal or hepatic function. Patients receiving olaparib for metastatic castration-resistant prostate cancer should also receive appropriate androgen-deprivation therapy unless they have undergone bilateral orchiectomy. For moderate renal impairment, the FDA prescribing information recommends reducing the dose to 200 mg twice daily. Treatment is generally continued until disease progression or unacceptable toxicity in advanced disease, while specific treatment durations apply in certain settings; for example, adjuvant treatment of high-risk early breast cancer is generally given for up to one year, while first-line ovarian maintenance treatment may be continued for up to two years in patients without evidence of disease at that point. Treatment may be interrupted or dose-reduced for clinically significant toxicity. Olaparib tablets should not be substituted with the historical capsule formulation on a milligram-for-milligram basis because the formulations have different bioavailability and dosing requirements.

Common side effects of olaparib include nausea, fatigue or weakness, anemia, vomiting, diarrhea, decreased appetite, headache, taste disturbance, cough, neutropenia, shortness of breath, dizziness, indigestion, and other changes in blood-cell counts. The frequency of particular adverse effects varies according to whether olaparib is used alone or with other anticancer medicines such as bevacizumab or abiraterone-based therapy. Anemia is particularly important clinically and may require laboratory monitoring, treatment interruption, dose reduction, or supportive management in some patients. Gastrointestinal symptoms such as nausea and diarrhea are also common and can often be managed with supportive treatment and appropriate dose modification when necessary. Individual tolerability varies, and adverse effects should be assessed and managed under medical supervision.

Important serious risks associated with olaparib include myelodysplastic syndrome and acute myeloid leukemia, particularly in patients with extensive previous exposure to chemotherapy or other DNA-damaging treatments. Pneumonitis, including serious or potentially fatal cases, has also been reported and requires evaluation of new or worsening respiratory symptoms. Significant hematologic toxicity, including severe anemia, neutropenia, leukopenia, lymphopenia, and thrombocytopenia, can occur and may require treatment interruption or discontinuation. Thromboembolic events can also occur, particularly in certain combination regimens and patient populations. Olaparib can cause embryo-fetal toxicity, so pregnancy prevention and appropriate counselling are required for patients who could become pregnant and for male patients with partners who could become pregnant. There is no formal contraindication listed in the current U.S. prescribing information, but treatment should be interrupted, dose-reduced, or discontinued when clinically significant toxicity develops according to the applicable prescribing information.

Before treatment, clinicians should review the cancer diagnosis, prior treatment history, relevant BRCA or homologous recombination repair testing where required, complete blood counts, renal and hepatic function, and concomitant medicines. Complete blood counts should be monitored at baseline and periodically during treatment, with closer assessment when abnormalities develop. Strong or moderate CYP3A inhibitors can increase olaparib exposure and should generally be avoided; if unavoidable, dose reduction is required according to the prescribing information. Strong or moderate CYP3A inducers can decrease olaparib exposure and should also be avoided. Patients should be counselled regarding pregnancy prevention and breastfeeding restrictions. Because olaparib can cause hematologic toxicity and rare serious pulmonary complications, unexplained persistent cytopenias, fever, infection, new respiratory symptoms, or unusual fatigue require clinical evaluation. Genetic or companion-diagnostic testing should be performed where required by the specific indication and applicable regulatory labeling.

Prescribers should confirm that the patient's tumor type, disease setting, prior treatment, and molecular profile meet the applicable indication before starting olaparib. Baseline and periodic complete blood counts are essential, with particular attention to hemoglobin and other cell lines because anemia and other cytopenias are common reasons for treatment interruption or dose modification. Renal function should be assessed because moderate renal impairment requires dose adjustment. Medication reconciliation is important because CYP3A inhibitors and inducers can substantially alter olaparib exposure. Pharmacists should ensure that patients understand the twice-daily tablet schedule and should specifically prevent accidental substitution between olaparib tablet and historical capsule dosing. For patients receiving combination therapy, monitoring should also account for toxicities and interactions associated with the partner medicine. Persistent cytopenias after treatment interruption warrant evaluation for underlying bone-marrow disorders, including myelodysplastic syndrome or acute myeloid leukemia, while new respiratory symptoms should prompt assessment for pneumonitis.