On May 19, 2020, olaparib was approved for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer who experienced disease progression after treatment with enzalutamide or abiraterone.1,2
The U.S. Food and Drug Administration (FDA) simultaneously approved the FoundationOne CDx assay for selection of patients with metastatic castration-resistant prostate cancer carrying HRR gene alterations and the BRACAnalysis CDx test for selection of patients with metastatic castration-resistant prostate cancer carrying germline BRCA1/2 alterations as companion diagnostic devices for treatment with olaparib in this setting.
Supporting Efficacy Data
Approval was based on findings from the multicenter, open-label, phase III PROfound trial (ClinicalTrials.gov identifier NCT02987543).2,3 In the trial, 387 patients were randomly assigned 2:1 to receive oral olaparib at 300 mg twice daily (n = 256) or the investigator’s choice of enzalutamide at 160 mg once daily or abiraterone at 1,000 mg once daily (n = 131) until disease progression or unacceptable toxicity. The investigators noted: “The physician’s choice of either enzalutamide or abiraterone was selected as the comparator because switching between these agents does occur in practice, despite the lack of randomized evidence to support this approach.”
Olaparib has warnings/precautions for myelodysplastic syndrome/acute myeloid leukemia, pneumonitis, venous thromboembolic events, and embryofetal toxicity.
All patients received a gonadotropin-releasing hormone (GnRH) analog or had undergone bilateral orchiectomy. Patients were randomly assigned to either of two cohorts based on HRR gene mutation status. Those with mutations in BRCA1, BRCA2, or ATM were assigned to cohort A (n = 245; 162 in the olaparib group and 83 in the hormone-therapy group). Patients with mutations among 12 other genes involved in the HRR pathway (BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L) were assigned to cohort B (n = 142; 94 in the olaparib group and 48 in the hormone-therapy group). Those with both cohort A and cohort B gene mutations were assigned to cohort A.
The major efficacy outcome was radiologic progression-free survival in cohort A on blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECISTv1.1). Additional efficacy outcomes included confirmed objective response rate in patients with measurable disease in cohort A, radiologic progression-free survival in combined cohorts A and B, and overall survival in cohort A.
Median patient age was 69 years (range = 47–91 years). Overall, 69% were white, 29% were Asian, and 95% had an Eastern Cooperative Oncology Group performance status of 0 or 1. Of those receiving olaparib, 58% had RECISTv1.1 measurable disease, including 17% with lung and 10% with liver metastases, 66% of patients had received prior taxane therapy, 40% had received enzalutamide, 38% had received abiraterone, and 20% had received both enzalutamide and abiraterone.
In cohort A, median radiologic progression-free survival was 7.4 months (95% confidence interval [CI] = 6.2–9.3 months) with olaparib vs 3.6 months (95% CI = 1.9–3.7 months) with hormone therapy (hazard ratio [HR] = 0.34, 95% CI = 0.25–0.47, P < .0001). Median overall survival in cohort A was 19.1 months (95% CI = 17.4–23.4 months) with olaparib vs 14.7 months (95% CI = 11.9–18.8 months) with hormone therapy (HR = 0.69, 95% CI = 0.50–0.97, P = .0175). Overall response rates among 84 vs 43 patients with measurable disease in cohort A were 33% vs 2% (P < .0001). In the combined cohorts, median radiologic progression-free survival was 5.8 months (95% CI = 5.5–7.4 months) with olaparib vs 3.5 months (95% CI = 2.2–3.7 months) with hormone therapy (HR = 0.49, 95% CI = 0.38–0.63, P < .0001).
How It Works
Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular functions, including DNA transcription and DNA repair. Olaparib inhibits the growth of select tumor cell lines in vitro and decreases tumor growth in mouse xenograft models of human cancer both as monotherapy and after platinum-based chemotherapy. Increased cytotoxicity and antitumor activity following treatment with olaparib were observed in cell lines and mouse tumor models with deficiencies in BRCA1/2, ATM, or other genes involved in the HRR of DNA damage and correlated with platinum response. Studies in vitro have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.
How It Is Used
In the current indication, the recommended dosage of olaparib is 300 mg twice daily, with treatment continuing until disease progression or unacceptable toxicity. Patients must be selected for treatment based on testing with an FDA-approved companion diagnostic for olaparib. Patients receiving olaparib for metastatic castration-resistant prostate cancer should also receive a GnRH analog or should have received bilateral orchiectomy. The recommended starting dose is 200 mg twice daily in patients with moderate renal impairment.
For management of adverse reactions, interruption of treatment or dose reduction should be considered. The recommended dose reductions are first to 250 mg twice daily and then to 200 mg twice daily if required. Concomitant use of olaparib with strong or moderate CYP3A inhibitors should be avoided. If concomitant use cannot be avoided, the olaparib dose should be reduced to 100 mg twice daily when used with a strong inhibitor and to 150 mg twice daily when used with a moderate inhibitor. Concomitant use with strong or moderate CYP3A inducers should be avoided.
The most common adverse events of any grade (in at least 10% of patients) with the use of olaparib as a single agent in clinical trials have been nausea, fatigue/asthenia, anemia, vomiting, diarrhea, decreased appetite, headache, neutropenia, dysgeusia, cough, dyspnea, dizziness, dyspepsia, and leukopenia.
Safety data in the current indication are from 256 patients receiving olaparib and 130 patients receiving enzalutamide or abiraterone in the PROfound trial. Among patients receiving olaparib, 62% were exposed for at least 6 months and 20% for more than 1 year.
The most common adverse events of any grade (in at least 10% of patients) in the olaparib group were anemia (46% vs 15% with hormone therapy), nausea (41% vs 19%), fatigue/asthenia (41% vs 32%), decreased appetite (30% vs 18%), diarrhea (21% vs 7%), vomiting (18% vs 12%), thrombocytopenia (12% vs 3%), cough (11% vs 2%), and dyspnea (10% vs 3%). The most common grade 3 or 4 adverse events included anemia (21% vs 5%), thrombocytopenia (4% vs 0%), and fatigue/asthenia (3% vs 5%). Venous thromboembolic events, including pulmonary embolism, occurred in 7% vs 3%. The most common grade 3 or 4 laboratory abnormalities included decreased lymphocytes (23% vs 13%) and decreased hemoglobin (13% vs 4%).
Serious adverse events occurred in 36% of patients receiving olaparib, with the most common being anemia (9%), pneumonia (4%), pulmonary embolism (2%), fatigue/asthenia (2%), and urinary tract infection (2%). Adverse events led to dose interruption in 45% of patients (most commonly, anemia in 25% and thrombocytopenia in 6%) and to dose reduction in 22% (most commonly, anemia in 16%). Treatment discontinuation due to adverse events occurred in 18% of patients, with the most common cause being anemia (7%). Adverse events led to death in 4% of patients, with causes including pneumonia (1.2%), cardiopulmonary failure (0.4%), aspiration pneumonia (0.4%), intestinal diverticulum (0.4%), septic shock (0.4%), Budd-Chiari syndrome (0.4%), sudden death (0.4%), and acute cardiac failure (0.4%).
Olaparib has warnings/precautions for myelodysplastic syndrome/acute myeloid leukemia, pneumonitis, venous thromboembolic events, and embryofetal toxicity. Myelodysplastic syndrome/acute myeloid leukemia has occurred in fewer than 1.5% of patients receiving olaparib monotherapy, with the majority of events leading to a fatal outcome. Patients should be monitored for hematologic toxicity at baseline and monthly thereafter, and treatment should be discontinued if myelodysplastic syndrome/acute myeloid leukemia is confirmed. Pneumonitis has occurred in fewer than 1% of patients receiving olaparib and was fatal in some cases. Treatment should be interrupted if pneumonitis is suspected and discontinued if confirmed. Venous thromboembolic events, including pulmonary embolism, occurred in 7% of patients with metastatic castration-resistant prostate cancer. Patients should be monitored for signs and symptoms of venous thrombosis and pulmonary embolism, which should be treated appropriately.
1. U.S. Food and Drug Administration: FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer. Accessed June 2, 2020.
2. U.S. Food and Drug Administration: Highlight of prescribing information for Lynparza (olaparib) tablets. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208558s014lbl.pdf. Accessed June 2, 2020.
3. de Bono J, Mateo J, Fizazi K, et al: Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med 382:2091-2102, 2020.