The treatment landscape for ovarian cancer has experienced a long period without any new US Food and Drug Administration (FDA)-approved drugs for the treatment of this aggressive disease. Before the 2014 FDA approval of olaparib for the treatment of recurrent ovarian cancer in patients with germline BRCA mutation1 and the 2016 FDA approval of bevacizumab in combination with chemotherapy for platinum-resistant ovarian cancer,2,3 the last FDA approval in ovarian cancer was in the mid-2000s.
However, within the past 2 years, 3 poly (ADP-ribose) polymerase (PARP) inhibitors have been approved in the maintenance setting for patients with recurrent platinum-sensitive ovarian cancer: niraparib (March 2017),4,5 olaparib (August 2017),1,6 and rucaparib (April 2018).7,8 These approvals have reinforced the role of this class of drugs in the maintenance setting of recurrent platinum-sensitive ovarian cancer.
Although there has been recent excitement about PARP inhibitors, they are not actually a novel class of drugs, as preclinical data with these agents dates back to the 1980s. However, the concept of synthetic lethality was introduced with 2 landmark papers published in 2005, which helped make the connection between sensitivity of tumor cells that were deficient in the BRCA1/2 genes and their sensitivity to PARP inhibition and subsequent cell death.9,10 This marked a turning point in the understanding of the possible role of PARP inhibitors in treating cancers that are driven by a mutation in the BRCA1 or BRCA2 genes, which in turn marked a resurgence in the clinical development of this class of agents.
Ovarian cancer is chemosensitive enough that primary treatment with a taxane and platinum-based regimen can achieve a primary remission in a majority of women. Unfortunately, a durable response is lacking, and approximately 70% of patients ultimately relapse.11 For patients with platinum-sensitive disease who achieve at least a partial response to a platinum-based regimen, an oral medication with a reasonable toxicity profile that can help prolong that remission is a very attractive option.
Before the introduction of PARP inhibitors, bevacizumab was evaluated in the maintenance setting for platinum-sensitive recurrent ovarian cancer. The GOG-0213 trial assessed the combination of paclitaxel, carboplatin, and bevacizumab followed by bevacizumab maintenance in patients with platinum-sensitive ovarian cancer.12 Bevacizumab-treated patients had a statistically significant improvement in progression-free survival (PFS)—a secondary end point for the study—which showed a median of 13.8 months with the addition of bevacizumab and 10.4 months with conventional chemotherapy alone. The difference translated into a 39% reduction for disease progression or death. However, the increase in PFS in the bevacizumab arm was accompanied by an increase in toxicity, including serious adverse events (AEs) such as febrile neutropenia, venous thromboembolism, hypertension, and proteinuria; gastrointestinal perforation, fistula, and abscess formation were infrequent and not significantly increased with the addition of bevacizumab. However, 1 patient was diagnosed with grade 4 intracranial hemorrhage after 6 cycles of carboplatin and paclitaxel and 8 cycles of bevacizumab, with the serious AE attributed to bevacizumab.
All 3 PARP inhibitors have shown an impressive increase in PFS in the maintenance setting for patients with platinum-sensitive ovarian cancer. Patients with BRCA mutation or patients deemed homologous recombination deficiency–positive have gained the most benefit, but all study patients have demonstrated a significant reduction in disease progression with the addition of a PARP inhibitor.13-15 The advantages of PARP inhibitors over bevacizumab in the maintenance setting include an increase in clinical benefit (significant increase in PFS), better toxicity profile (manageable toxicities vs potentially life-threatening toxicities), ease of administration (oral medication vs intravenous medication), and cost.12-15
The toxicity profiles of the individual PARP inhibitors should be evaluated in the context in which they are being used. This class of drugs is prescribed for patients who have achieved a complete or partial response in their recurrent cancer and are hoping to maintain this remission for as long as possible. In the maintenance setting, patients will remain on these oral medications until their disease progresses or they are unable to tolerate the toxicities. Thus, the individual toxicity profile of each drug can mean the difference between continuing or discontinuing a life-prolonging medication.
Because of differences in enrolled patient populations, trial design, and clinical end points, comparison of data across clinical trials is not possible. However, it appears that the incidence of grade ≥3 AEs is different with each PARP inhibitor when compared with placebo. The incidence of grade ≥3 AEs for olaparib (SOLO2/ENGOT-Ov21 trial) was 36% versus 18% in the placebo group13; for niraparib it was 74% versus 23% in the placebo group (NOVA trial)14; and for rucaparib it was 56% versus 15% in the placebo group (ARIEL3 trial).15
Hematologic toxicities associated with niraparib are significant when compared with the other 2 PARP inhibitors, particularly in regard to thrombocytopenia. In the NOVA trial, 33.8% of niraparib-treated patients had grade 3/4 thrombocytopenia (including decreased platelet counts).14 This is a significant toxicity for patients who could be on this class of medications for months to years. Other significant hematologic toxicities (grade ≥3 toxicity) related to niraparib use were anemia (25.3%) and neutropenia (19.6%). Results from the SOLO2 trial showed that the highest incidence of grade 3/4 hematologic toxicity related to the use of olaparib was anemia (19%),13 comparable with results seen with the use of rucaparib in the ARIEL3 trial, which also showed that the highest incidence of a grade 3/4 hematologic toxicity was anemia (19%).15 In terms of significant (grade ≥3) nonhematologic toxicities, rucaparib treatment was related to an increase in liver transaminases (10%), although this increase was not associated with abnormal increases in bilirubin or other criteria for drug-induced hepatotoxicity, and generally resolved over time.15
One way to compare the overall effect these toxicities have on patients is to also evaluate the number of patients who actually discontinued the drug because of AEs. All 3 PARP inhibitors had similar discontinuation rates associated with toxicity when compared with placebo: approximately 11% with olaparib in the SOLO2 trial, approximately 13% with niraparib in the NOVA trial, and approximately 13% with rucaparib in the ARIEL3 trial.13-15 Thus, the overall discontinuation rates attributed to AEs were not markedly different among agents.
Another issue worth noting is all 3 PARP inhibitors are associated with low-grade nausea in approximately 70% of patients. Although the discontinuation rates seen in the trials did not point to nausea as a primary reason for discontinuation, it will be interesting to see whether low-grade nausea becomes an issue for patients who may remain on this class of drugs for months or years outside of a clinical trial setting. Pharmacists can recommend supportive care measures and therapeutic options to help manage and control low-grade nausea associated with PARP inhibitors so these drugs can achieve their maximum clinical benefit for patients.
Lastly, the FDA approved each PARP inhibitor with specific recommendations for dose reduction. Because of the available tablet sizes for rucaparib and olaparib, the approved dose reductions for these agents present practical concerns. For example, the available tablet sizes for rucaparib are 200 mg, 250 mg, and 300 mg.7 The starting dose for rucaparib is 600 mg (2 × 300-mg tablets) twice daily; the first dose reduction is 500 mg (two 250-mg tablets) twice daily; the second dose reduction is 400 mg (2 × 200-mg tablets) twice daily; and the third dose reduction is 300 mg (one 300-mg tablet) twice daily.7 For the first dose reduction, a new prescription for 250-mg tablets must be generated, which represents a new copayment for the patient. For the second dose reduction, a new prescription must again be generated, which triggers yet another copayment for the patient.
The situation is similar for olaparib. The available tablet sizes for olaparib are 100 mg and 150 mg. The starting dose of olaparib is 300 mg (two 150-mg tablets) twice daily; the first dose reduction is 250 mg twice daily, and the second dose reduction is 200 mg twice daily.1 For the first dose reduction, the patient must get a prescription for 2 tablet sizes (100 mg and 150 mg), which results in 2 copayments for the patient (1 for each prescription). For the second dose reduction, again the patient must receive a new prescription for 100-mg tablets—which is another copayment for the patient.
In contrast, niraparib dose reductions and available capsule sizes are much more practical. The available capsule size for niraparib is 100 mg. The starting dose is 300 mg (three 100-mg capsules) once daily; the first dose reduction is 200 mg (two 100-mg capsules) once daily; the second dose reduction is 100 mg once daily.4 Each of these dose reductions can be accomplished without generating a new prescription for the patient, therefore eliminating the need for the patient to pay an extra copayment.
Multiple clinical trials have proven the clinical benefit of PARP inhibitors in the maintenance setting for recurrent platinum-sensitive ovarian cancer, and these agents are now being utilized in a more widespread fashion. The demonstrated utility of these medications is based on patient compliance; thus, every effort should be made on the part of healthcare providers to assist patients in maintaining dose consistency. Pharmacists can help navigate practical considerations involving dose reductions for patients as well as help with the management of toxicities and supportive care measures associated with this class of drugs.
- Lynparza® (olaparib) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2017.
- Avastin® (bevacizumab) [prescribing information]. South San Francisco, CA: Genentech, Inc; 2018.
- Hagen T. FDA approves bevacizumab for platinum-sensitive ovarian cancer. OncLive website. www.onclive.com/web-exclusives/fda-approves-bevacizumab-for-platinum-sensitive-ovarian-cancer. Published December 6, 2016. Accessed May 29, 2018.
- Zejula® (niraparib) [prescribing information]. Waltham, MA: Tesaro, Inc; 2017.
- US Food and Drug Administration. Niraparib (Zejula). FDA website. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm548487.htm. Updated May 30, 2017. Accessed May 10, 2018.
- US Food and Drug Administration. FDA approves olaparib tablets for maintenance treatment in ovarian cancer. FDA website. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm572143.htm. Updated August 17, 2017. Accessed May 10, 2018.
- Rubraca® (rucaparib) [prescribing information]. Boulder, CO: Clovis Oncology, Inc; 2018.
- US Food and Drug Administration. FDA approves rucaparib for maintenance treatment of recurrent ovarian, fallopian tube, or primary peritoneal cancer. FDA website. www.fda.gov/drugs/informationondrugs/approveddrugs/ucm603997.htm. Updated April 6, 2018. Accessed May 10, 2018.
- Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase [published correction appears in Nature. 2007;447:346]. Nature. 2005;434:913-917.
- Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917-921.
- Ledermann JA, Raja FA, Fotopoulou C, et al; on behalf of the ESMO Guidelines Working Group. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl 6):vi24-vi32.
- Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel–carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18:779-791.
- Pujade-Lauraine E, Ledermann JA, Selle F, et al; SOLO2/ENGOT-Ov21 Investigators. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1274-1284.
- Mirza MR, Monk BJ, Herrstedt J, et al; for the ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375:2154-2164.
- Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390:1949-1961.