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PARP Inhibitors: Current Approvals and Future Directions

Renee K. McAlister, PharmD
Genitourinary/Melanoma Clinical Pharmacist
Vanderbilt-Ingram Cancer Center/Vanderbilt University Medical Center
Nashville, TN


Overview of PARP Inhibitors 
The poly ADP-ribose polymerase (PARP) enzymes are a family of 18 proteins that repair single-stranded deoxyribonucleic acid (DNA) damage via base-excision repair and via inhibition of the nonhomologous end-joining DNA repair pathway, a method of double-strand break repair.1,2 Inhibition of the PARP1 and PARP2 enzymes results in the accumulation of double-stranded breaks, which are normally repaired by the homologous recombination double-stranded DNA repair pathway. The BRCA1 and BRCA2 enzymes function to repair double-stranded DNA breaks via homologous recombination. A germline or somatic mutation in one BRCA1/2 allele is compensated for by the wild-type allele, and double-stranded break repair function is maintained. However, subsequent loss of the wild-type allele, known as loss of heterozygosity (LOH), renders the homologous recombination pathway ineffective. Tumor cells that have LOH are therefore most susceptible to PARP inhibition because they have essentially no way to fix double-stranded breaks. Ovarian and breast cancers are the most common malignancies associated with BRCA1/2 mutations; however, prostate and pancreatic cancers have been associated with BRCA1/2 mutations as well.3 PARP inhibition represents a new class of chemotherapeutic agents, and three PARP inhibitors have been approved by the Food and Drug Administration (FDA). All approvals to date have been for treatment of ovarian cancer, though several other PARP inhibitors are currently in development.

Currently Approved PARP Inhibitors

Olaparib
Olaparib (Lynparza), the first PARP inhibitor on the market, was granted accelerated approval on December 19, 2014, as monotherapy in patients with deleterious or suspected deleterious germline BRCA (gBRCA) mutated advanced ovarian cancer who had been previously treated with three or more lines of chemotherapy.4 BRACAnalysis CDx, a diagnostic test that detects BRCA mutations, was included in this approval. Accelerated approval was based on a multicenter single-arm phase 2 study that enrolled patients with a gBRCA1/2 mutation and recurrent ovarian, breast, pancreatic, or prostate cancer.3 Patients received olaparib 400 mg (supplied as 50-mg capsules) twice daily until the disease progressed or an unacceptable level of toxicity was reached. Of the 298 patients enrolled, 193 patients had a diagnosis of ovarian cancer resistant to prior platinum-based therapy, defined as relapse within 6 months of platinum therapy, or were unsuitable candidates for further platinum chemotherapy. Tumor response rate was 26.2% overall (95% confidence interval [CI], 21.3–31.6) and 31.1% in patients with ovarian cancer (95% CI, 24.6–38.1) and did not differ according to BRCA1 versus BRCA2 mutation. Median progression-free survival (PFS) was 7 months, and median overall survival (OS) was 16.6 months for patients with ovarian cancer. The most common adverse event (AE) greater than grade 3 was anemia (18.7% in the ovarian cancer group).

Recent data from the SOLO2 study have led to granting of FDA priority review status for use of olaparib in the maintenance setting for ovarian cancer.5 SOLO2 was a randomized double-blind phase 3 study that evaluated maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer with a BRCA1/2 mutation who were in response to the most recent platinum-based chemotherapy after at least two lines of treatment.6 A total of 295 patients were randomized in a 2:1 ratio to receive olaparib 300 mg (supplied as a 150-mg tablet) twice daily or placebo. Pharmacokinetics of the new tablet dosage form were also studied in this trial, and the 300-mg dose was found to provide similar concentrations to the 400-mg dose administered as 50-mg capsules. This tablet dosage form has not yet been approved by the FDA. Median PFS in the olaparib group was 19.1 months versus 5.5 months in the placebo group (p < .0001). OS data have not yet been published. Grade 3 or greater anemia was observed in 19.5% of patients.

Rucaparib
Rucaparib (Rubraca) was granted accelerated FDA approval on December 19, 2016, for the treatment of patients with deleterious BRCA mutation (germline or somatic) associated advanced ovarian cancer who had been treated with two or more chemotherapies. The FoundationFocus CDxBRCA, a next-generation sequencing diagnostic that detects alterations in the BRCA1/2 genes, was approved by the FDA at the same time.7 Approval was based on the results of two multicenter single-arm open-label clinical trials that included a total of 106 patients at the time of approval. The first trial was a phase 1/2 study of rucaparib for relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer with gBRCA mutations.8 This study enrolled 41 patients who had received 2−4 prior chemotherapy regimens and had a progression-free interval 6 months after administration of their last platinum agent. Patients received rucaparib 600 mg twice daily in 21-day cycles until disease progression. The overall objective response rate (ORR) was 67%, with 15 of 22 responses ongoing at time of publication. The ORR was 65% for patients with a BRCA1 mutation and 70% for patients with a BRCA2 mutation. Grade 3–4 AEs included asthenia or fatigue (16%), anemia (22%), and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations (11%).

The second trial was ARIEL2, from which the final results of part 1 were just recently published. ARIEL2 was a two-part phase 2 open-label study that enrolled patients with recurrent platinum-sensitive high-grade ovarian carcinoma on the basis of the presence or absence of BRCA mutation (deleterious germline or somatic BRCA mutant, BRCA wild-type and high loss of heterozygosity [LOH], or BRCA wild-type and low LOH).1 Two hundred six patients were enrolled and received oral rucaparib 600 mg twice daily for continuous 28-day cycles. Median PFS was 12.8 months in the BRCA mutant group (95% CI, 9–14.7, p < .0001, compared to low LOH), 5.7 months in the high LOH group (95% CI, 5.3–7.6, p = .011, compared to low LOH), and 5.2 months (95% CI, 3.6–5.5) in the low LOH group. The most common grade 3 or greater AEs were anemia (22%) and AST/ALT elevations (12%).

Niraparib
Niraparib (Zejula), the third FDA-approved PARP inhibitor, was approved on March 27, 2017, for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who had had a complete or partial response to platinum-based chemotherapy.9 Niraparib approval was based on the ENGOT-OV16/NOVA trial, a randomized double-blind phase 3 trial that included 553 patients with platinum-sensitive, recurrent ovarian cancer.10 Patients who had had a complete or partial response following platinum-based therapy were enrolled into cohorts on the basis of the presence or absence of a gBRCA mutation as well as the type of non-BRCA mutation (homologous recombination deficiency [HRD] vs. non-HRD), and were randomized in a 2:1 ratio to receive niraparib 300 mg or placebo once daily. The primary end point, PFS, was longer in the niraparib group versus the placebo group in all cohorts (21.0 vs. 5.5 months in the gBRCA cohort [p < .001], 12.9 vs. 3.8 months in the non-gBRCA with HRD cohort [p < .001], and 9.3 vs. 3.9 months in the overall non-gBRCA cohort [p < .001]). Grade 3-4 AEs were reported in 74.1% of patients receiving niraparib versus 22.9% receiving placebo. The most common grade 3-4 AEs were hematologic: thrombocytopenia (33.8%), anemia (25.3%), and neutropenia (19.6%).

Currently Approved PARP Inhibitors: A Summary
All three FDA-approved PARP inhibitors are approved in the setting of recurrent disease, though they are approved at different stages of therapy. As noted, niraparib is approved for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have had a complete or partial response to the most recent platinum-based chemotherapy. The National Comprehensive Cancer Network (NCCN) guidelines recommend the use of niraparib for patients in this setting.11 Rucaparib is approved for patients with deleterious gBRCA- or somatic BRCA-mutated advanced ovarian cancer who have progressed after two or more lines of therapy. The NCCN guidelines include rucaparib as an acceptable agent for treatment of recurrent disease.11 Olaparib is approved for patients with deleterious gBRCA-mutated advanced ovarian cancer who have progressed after three or more lines of therapy, but it has also received priority review for use in the maintenance setting. The NCCN guidelines also include olaparib as an acceptable targeted therapy for treatment of recurrent disease.11 

Future Directions for FDA-Approved PARP Inhibitors
As noted above, PARP inhibitors are also being studied in several other oncologic diagnoses, particularly those with BRCA1/2 mutations. Results of the OlympiAD study were presented at the American Society for Clinical Oncology (ASCO) Annual Meeting in June 2017. OlympiAD was a randomized open-label phase 3 trial studying olaparib versus chemotherapy (capecitabine, vinorelbine, or eribulin) in 302 patients with HER2-negative (50% of whom had triple-negative breast cancer [TNBC]) gBRCA-positive metastatic breast cancer (MBC).12 PFS was significantly longer in the olaparib group versus the chemotherapy group (7 vs. 4.2 months, respectively, p = .0009). ORRs were 59.9% and 28.8% for the olaparib and chemotherapy arms, respectively. Olaparib is also being studied for use in non–small cell lung cancer (NSCLC), small cell lung cancer (SCLC), head and neck cancer, sarcomas, and other malignancies.13

Ongoing studies for rucaparib use in ovarian cancer include ARIEL3, which is studying the use of rucaparib as maintenance therapy for platinum-sensitive high-grade serous or endometrioid epithelial ovarian, primary peritoneal or fallopian tube cancer, and ARIEL4, a confirmatory phase 3 randomized study of rucaparib versus chemotherapy for patients with relapsed BRCA mutant high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer.14,15 Rucaparib is also being studied for use in metastatic castrate-resistant prostate cancer (mCRPC), pancreatic cancer, ovarian cancer in combination with atezolizumab, and MBC.16

Niraparib is currently being studied for use in mantle cell lymphoma, endometrial cancer, TNBC or ovarian cancer in combination with pembrolizumab, recurrent ovarian cancer, and mCRPC.17

Additional studies have shown that the presence of a mutation in the isocitrate dehydrogenase (IDH) 1 or IDH2 genes may increase susceptibility to PARP inhibitors, as mutations in IDH1/2 render the homologous recombination DNA damage repair pathway ineffective in a manner similar to mutations in BRCA1/2.18 IDH1 and IDH2 mutations are common in malignancies such as gliomas, acute myeloid leukemia, and cholangiocarcinoma.19 Olaparib is currently being studied in IDH1 and IDH2 mutant solid tumors, and niraparib is being studied in DNA double-strand break repair deficient malignancies.20

New PARP Inhibitors on the Horizon
Two PARP inhibitors that have yet to gain FDA approval, talazoparib and veliparib, are currently being studied in clinical trials as well. Results of the ABRAZO trial, a two-stage, phase 2 study of talazoparib in 84 patients with locally advanced breast cancer or MBC and a gBRCA1/2 mutation previously exposed to platinum-based chemotherapy (cohort 1) or at least three prior non-platinum-based cytotoxic regimens (cohort 2), were presented at the 2017 ASCO Annual Meeting. The primary end point, ORR, was 24% for patients with a BRCA1 mutation and 34% for patients with a BRCA2 mutation.21 The ORR was 26% for patients with TNBC and 29% for patients with hormone receptor–positive disease. Grade 3 or greater AEs were anemia (35%), thrombocytopenia (19%), and neutropenia (15%). EMBRACA, a phase 3 study to evaluate talazoparib versus physician’s choice of treatment in gBRCA1/2-mutated MBC, is currently under way.22

The results of several trials that evaluated the use of veliparib were also presented at the 2017 ASCO Annual Meeting. Studies evaluated veliparib for disease states such as SCLC (in combination with cisplatin and etoposide), NSCLC (in combination with carboplatin and paclitaxel-based chemoradiation), pancreatic cancer (in combination with modified FOLFIRI [folinic acid, fluorouracil, irinotecan], prostate cancer (in combination with abiraterone and prednisone), and TNBC (in combination with carboplatin).23

Conclusion
In summary, three PARP inhibitors are currently approved by the FDA for the treatment of ovarian cancer. The currently approved PARP inhibitors are also being studied in other disease states, particularly in the setting of BRCA1/2 and IDH1/2 mutations. Several additional PARP inhibitors are being studied in clinical trials in a variety of settings. It remains to be seen whether the use of PARP inhibitors will result in favorable response rates and survival data in malignancies other than breast or ovarian cancer. 

References

1.  Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18(1):75-87.

2.  Dziadkowiec KN, Gąsiorowska E, Nowak-Markwitz E, Jankowska A. PARP inhibitors: review of mechanisms of action and BRCA1/2 mutation targeting. Prz Menopauzalny. 2016;15(4):215-219.

3.  Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244-250.

4.  Lynparza (olaparib) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; January 2017.

5.  AstraZeneca shares progress on LYNPARZA™ (olaparib) tablets in the US [press release]. AstraZeneca; March 28, 2017. https://www.astrazeneca-us.com/media/press-releases/2017/astrazeneca-shares-progress-on-lynparza-olaparib-tablets-in-the-us-03282017.html. Accessed August 7, 2017.

6.  Pujade-Lauraine E, Ledermann JA, Penson RT, et al. Treatment with olaparib monotherapy in the maintenance setting significantly improves progression-free survival in patients with platinum-sensitive relapsed ovarian cancer: results from the phase III SOLO2 study [abstract LBA2]. Gynecol Oncol. 2017;145(suppl 1):219-220.

7.  Rucaparib. US Food and Drug Administration Web site. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm533891.htm. Updated May 18, 2017. Accessed August 7, 2017.

8.  Shapira-Frommer R, Oza AM, Domchek SM, et al. A phase 2 open-label, multicenter study of single-agent rucaparib in the treatment of patients with relapsed ovarian cancer and a deleterious BRCA mutation [abstract 2746]. Eur J Cancer. 2015;51(suppl 3):S545.

9.  Niraparib (Zejula). US Food and Drug Administration Web site. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm548487.htm. Updated May 30, 2017. Accessed August 7, 2017.

10. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.

11.  National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines): ovarian cancer including fallopian tube cancer and primary peritoneal cancer [version 2.2017]. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Published June 27, 2017. Accessed August 7, 2017.

12.  Robson ME, Im SA, Senkus E, et al. OlympiAD: phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm) [abstract LBA4; published online ahead of print June 2017]. J Clin Oncol. 2017; 35(18)(suppl). doi: 10.1200/JCO.2017.35.18_suppl.LBA4.

13.  ClinicalTrials.gov [database online]. Bethesda, MD: US National Institutes of Health; https://clinicaltrials.gov/ct2/results?cond=&term=olaparib&cntry1=&state1=&Search=Search. Accessed August 7, 2017.

14.  Clovis Oncology, Inc. A study of rucaparib as switch maintenance following platinum-based chemotherapy in patients with platinum-sensitive, high-grade serous or endometrioid epithelial ovarian, primary peritoneal or fallopian tube cancer (ARIEL3). https://clinicaltrials.gov/ct2/show/NCT01968213. NLM Identifier: NCT01968213. Accessed August 7, 2017.

15.  Clovis Oncology, Inc. ARIEL4: a study of rucaparib versus chemotherapy BRCA mutant ovarian, fallopian tube, or primary peritoneal cancer patients. https://clinicaltrials.gov/ct2/show/NCT02855944 NLM Identifier: NCT02855944. Accessed August 7, 2017.

16.  ClinicalTrials.gov [database online]. Bethesda, MD: National Institutes of Health. https://clinicaltrials.gov/ct2/results?cond=&term=rucaparib&cntry1=&state1=&Search=Search. Accessed August 7, 2017.

17.  ClinicalTrials.gov [database online]. Bethesda, MD: National Institutes of Health. https://clinicaltrials.gov/ct2/results?cond=&term=niraparib&cntry1=&state1=&Search=Search. Accessed July 11, 2017.

18.  Sulkowski PL, Corso CD, Robinson ND, et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med. 2017;9(375): eaal2463.

19.  IDH-mutant tumors vulnerable to PARP inhibition. Cancer Discov. 2017;7(4):OF4.

20.  ClinicalTrials.gov [database online]. Bethesda, MD: National Institutes of Health. https://clinicaltrials.gov/ct2/results?cond=&term=PARP%2C+IDH&cntry1=&state1=&Search=Search. Accessed August 7, 2017.

21.  Turner NC, Telli ML, Rugo HS, et al. Final results of a phase 2 study of talazoparib (TALA) following platinum or multiple cytotoxic regimens in advanced breast cancer patients (pts) with germline BRCA1/2 mutations (ABRAZO) [abstract 1007]. J Clin Oncol. 2017;35(15)(suppl):1007.

22.  Pfizer. A study evaluating talazoparib (BMN 673), a PARP inhibitor, in advanced and/or metastatic breast cancer patients with BRCA mutation (EMBRACA Study) (EMBRACA). https://clinicaltrials.gov/ct2/show/NCT01945775?term=NCT01945775&rank=1. NLM Identifier: NCT01945775. Accessed August 7, 2017.

23.  American Society of Clinical Oncology. 2017 ASCO annual meeting abstracts. http://abstracts.asco.org/199/IndexView_199.html. Published May 17, 2017. Accessed August 7, 2017.

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