Jessica D'Amico

The introduction of poly ADP-ribose polymerase (PARP) inhibitors to the ovarian cancer treatment landscape represents a rare sprig of hope in nearly a decade-long drought of new treatments. Initially approved for the treatment of women with mutations in the BRCA1 or BRCA2 genes, PARP inhibitors have also garnered FDA approvals for patients with ovarian cancer without the genetic mutations.

PARPs are a group of protein enzymes that recognize and repair single-strand breaks in DNA.

If such breaks go unrepaired until DNA is replicated, double-strand breaks emerge in the replication process.

Homologous recombination (HR) is the most common and precise mechanism for repairing double-strand breaks in DNAa process that is deficient in BRCA-mutated cells.

The inhibition of PARP paired with HR deficiency (HRD) brings about cancer cell death through synthetic lethality, which is the combined use of agents to produce cell death.

PARP INHIBITORS IN PATIENTS WITH WILD-TYPE BRCA

Notably, BRCA is not the only contributor to HRD in cells. Although a majority of germline alterations causing HRD are the result of BRCA1/2 mutations (somatic BRCA1/2 mutations account for 3.5% of cases), HRD can manifest from various etiologies, such as germline mutations in other genes affecting the HR pathway.

Results of the randomized, double-blind phase III ENGOT-OV16/NOVA trial showed efficacy with the PARP inhibitor niraparib (Zejula) in patients with high-grade, serous, platinum-sensitive, recurrent ovarian cancer regardless of BRCA status. Patients with and without BRCA mutations met the primary endpoint of achieving significant increases in median progression-free survival (PFS) with niraparib compared with placebo, at 21.0 versus 5.5 months, respectively, in the BRCA-mutated group (hazard ratio [HR], 0.27; 95% CI, 0.17-0.41; P <.001) and 9.3 months in the niraparib group versus 3.9 months with placebo for patients with BRCA wild-type (HR, 0.45; 95% CI, 0.34-0.61; P <.001). For patients in the nonBRCA-mutated cohort who had tumors with HRD, the median PFS was 12.9 months with niraparib versus 3.8 months with placebo (HR, 0.38; 95% CI, 0.24-0.59; P <.001).

&ldquo;The NOVA trial suggests that there are a lot of patients who benefit from PARP inhibition outside of BRCA1 and BRCA2,&rdquo; said Michael J. Birrer, MD, PhD, director, University of Alabama at Birmingham (UAB) Comprehensive Cancer Center, and professor of medicine, Division of Hematology-Oncology at UAB, in an interview with Targeted Therapies in Oncology&trade;. &ldquo;If you look at that protein complex that repairs double-stranded breaks, it has BRCA1 and BRCA2, but it probably has anywhere from 20 to 25 additional proteins. These proteins are all in the Fanconi [anemia] DNA repair pathway. A mutation in any one of those could contribute to HRD.&rdquo;

The emergence of PARP inhibitors dates back to 2005, when 2 publications discussed their in vitro activity in the destruction of cancer cells with BRCA mutations.

Since then, PARP inhibitors have been investigated extensively, in

mutated and BRCA wild-type cancers, and in both platinum-resistant and platinum-sensitive disease, resulting in FDA approvals for olaparib (Lynparza) in December 2014, rucaparib (Rubraca) in December 2016, and niraparib in March 2017.

&ldquo;I personally believe they&rsquo;re all very active drugs,&rdquo; said Birrer. &ldquo;I don&rsquo;t see major differences from an efficacy standpoint at this point.&rdquo;

Olaparib was the first PARP inhibitor approved by the FDA, and its accelerated approval was accompanied by the BRACAnalysis CDx companion diagnostic test for detecting

Initially indicated in capsule form for patients with germline BRCA-mutated ovarian cancer who have been treated with &ge;3 prior lines of chemotherapy, olaparib is now approved in tablet form for the maintenance treatment of recurrent ovarian, fallopian tube, or primary peritoneal cancer who are experiencing a complete or partial response to platinum-based chemotherapy.

It has been the most widely investigated of the PARP inhibitors thus far.

Olaparib was first examined in a phase I study that showed that the drug elicited the greatest response in patients with BRCA mutations; in particular, patients with germline

Dose-limiting toxicities, including grade 3 somnolence and grade 4 thrombocytopenia, among patients receiving 600-mg olaparib twice daily resulted in the establishment of the maximum-tolerated dose (MTD) as 400 mg twice daily.

The accelerated approval was based in part on a phase II single-arm investigation in which researchers enrolled 137 patients with germline

-mutated ovarian cancer who had received &ge;3 prior lines of chemotherapy and administered 400 mg olaparib twice daily as monotherapy until disease progression or intolerable toxicity.

The objective response rate (ORR) was 34% (46 of 137 patients; 95% CI, 26%-42%), and the median duration of response (DOR) was 7.9 months (95% CI, 5.6-9.6).

Also a factor in olaparib&rsquo;s approval were the results from an international, multicenter, single-arm trial comprising 298 patients, of whom 193 had platinum-resistant ovarian cancer with a germline

regimens. The tumor response rate was 31% (95% CI, 24.6%-38.1%), and 40% of patients had stable disease at 8 weeks (95% CI, 33.4%- 47.7%). The median overall survival (OS) was 16.6 months.

In Study 19an international, multicenter, randomized, double-blind, placebo-controlled phase II study&mdash;maintenance therapy with 400-mg olaparib twice daily showed no OS benefit. However, it did demonstrate significant improvement in PFS versus placebo (median, 8.4 vs 4.8 months, respectively; HR for progression or death, 0.35; 95% CI, 0.25-0.49; P <.001) among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received &ge;2 platinum-based regimens, regardless of BRCA status.

Findings from this study led to the approval of olaparib, from the European Medicines Agency, as maintenance for women with relapsed platinum-sensitive ovarian cancer with a BRCA mutation, following response to platinum-based chemotherapy.

These same results helped secure the recent approval of olaparib tablets in the United States.

The results from a pooled analysis from phase I and II studies of olaparib monotherapy in 300 women with relapsed ovarian, fallopian tube, or peritoneal cancer with germline BRCA mutations who received 400 mg twice daily of olaparib monotherapy showed an ORR of 36% (95% CI, 30%-42%) and a median 7.4- month DOR (95% CI, 5.7-9.1). Among patients who had received &ge;3 prior lines of chemotherapy, the ORR was 31% (95% CI, 25%-38%), with a 7.8-month DOR (95% CI, 5.6-9.5). The ORR was 42% for platinum-sensitive patients versus 26% for platinum-resistant patients among those who had received &ge;3 prior lines of chemotherapy.

The ongoing randomized, double-blind, multicenter phase III SOLO trials have enrolled patients with germline BRCA-mutated ovarian cancer. SOLO1 enrolled patients who received a first-line platinum-based chemotherapy. SOLO2 enrolled patients with platinum-sensitive, relapsed ovarian cancer who are in response after receiving &ge;2 lines of platinum-based therapy. SOLO3 is an open-label study of olaparib versus single-agent chemotherapy in patients with platinum-sensitive, relapsed disease who have received &ge;2 lines of platinum-based therapy. All 3 studies used the tablet form of olaparib.

In SOLO2, maintenance olaparib showed a 70% decrease in the risk for progression or death versus placebo, with an estimated mean PFS of 19.1 months and 5.5 months with olaparib and placebo, respectively.

The study proved pivotal in the approval for maintenance olaparib, providing the confirmatory evidence the FDA required.

Olaparib is generally well-tolerated, with mostly grade 1 and 2 adverse events (AEs) including nausea, vomiting, anemia, and fatigue.

Nevertheless, cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have occurred with olaparib. In Study 19, 2 patients in the olaparib group and 1 patient in the placebo group were diagnosed with AML or MDS. Updated results from the study, however, showed no new cases of AML or MDS.

In the single-arm trial of heavily pretreated patients, researchers identified 2 cases of AML and 1 case of MDS; however, they pointed out the possibility of the diseases stemming from prior therapies.12 With its most recent approval, olaparib comes with a warning about AML or MDS having occurred in less than 1.5% of patients undergoing treatment with the drug, with the majority resulting in a fatal outcome.

Indicated for the treatment of patients with advanced ovarian cancer and BRCA mutations who have been treated with &ge;2 prior chemotherapies,16 rucaparib gained accelerated approval from the FDA and came with a companion diagnostic, the FoundationFocus CDxBRCA, which was the first next-generation-sequencingbased companion diagnostic approved by the FDA.

The approval was based on results from 2 single-arm trials Study 10 and ARIEL2&mdash;comprising 106 patients with BRCA-mutated, advanced ovarian cancer who had received treatment with &ge;2 chemotherapy regimens.

In a pooled analysis of results from the 2 trialsin which all patients received rucaparib 600 mg twice daily&mdash;the ORR was 54% with rucaparib, and the median DOR was 9.2 months.

Due to data from the ARIEL3 trial presented at the 2017 ESMO Congress, rucaparib could also be considered for maintenance therapy for advanced ovarian cancer. The study reached its primary endpoint of improved PFS by 11.2 months among patients with BRCA-mutated disease.

Those with HRD or low to high loss of heterozygosity and BRCA wild-type tumors also achieved a similar PFS benefit. In addition, the trial met the key secondary endpoint of improved PFS in the rucaparib group compared with placebo by blinded independent central review. The drug&rsquo;s manufacturer, Clovis Oncology, has plans to submit a supplemental New Drug Application by October 2017 for a second-line and later indication as maintenance therapy for all patients with platinum-sensitive ovarian cancer who have responded to their most recent platinum therapy.

A phase III confirmatory study of rucaparib versus chemotherapy in patients with relapsed, BRCA-mutated ovarian cancer who have failed 2 prior lines of treatment, ARIEL4, is currently enrolling patients (NCT02855944).

In the pooled analysis of Study 10 and ARIEL2, common treatment-emergent AEs were asthenia/fatigue (78%), with 15% experiencing grade &ge;3; nausea (76%), with 4% grade &ge;3; anemia (51%), with 27% grade &ge;3; vomiting (50%), with 6% grade &ge;3; and transient increased alanine transaminase (ALT) and aspartate transaminase (AST) among 47%, with 13% grade &ge;3.20 Common AEs from rucaparib also include abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea, as well as the potential development of MDS or AML.

Birrer said that rucaparib differs from the other available PARP inhibitors in that it is associated with higher levels of anemia. &ldquo;Between 25% and 30% of patients develop significant anemia, and some of them need to be transfused,&rdquo; he said. &ldquo;I don&rsquo;t consider it a major problem, but it&rsquo;s a little different than other PARP inhibitors.&rdquo;

First examined in a phase I dose-escalation study that determined the MTD to be 300 mg daily,

niraparib&rsquo;s FDA approval was based on positive results from the pivotal NOVA study.

These findings resulted in niraparib&rsquo;s indication as maintenance treatment of adult patients with recurrent epithelial or fallopian tube cancer or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.

The most common AEs among &ge;10% of patients receiving niraparib in the NOVA trial were thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, constipation, vomiting, abdominal pain/distension, mucositis or stomatitis, diarrhea, dyspepsia, dry mouth, fatigue, decreased appetite, urinary tract infection, elevated ALT and AST, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, and hypertension.

Among the 367 patients treated with niraparib in the NOVA trial, 9% experienced grade 3/4 hypertension, compared with 2% in the placebo group. Five (1.4%) developed MDS, compared with 2 of 179 (1.1%) who received placebo.

Niraparib&rsquo;s prescribing information contains a warning of 0.9% of cases of MDS or AML in patients on the trials who received niraparib.

Thrombocytopenia was the most frequent AE with niraparib in the NOVA trial (61.3% vs 5.6% with placebo). &ldquo;Roughly 30% to 35% of patients had grade 3/4 [thrombocytopenia]; some patients had platelet counts down to 2000,&rdquo; Birrer said. &ldquo;That might make a physician think about using 1 agent over the other.&rdquo;

An investigational PARP inhibitor, veliparib was evaluated as a monotherapy in a phase II study that included 50 patients with &le;3 prior chemotherapy regimens, measurable disease, and no previous treatment with a PARP inhibitor. Patients were given oral veliparib 400 mg twice daily in a 28-day cycle. The response rate was 26%, with a median PFS of 8.18 months.

A phase I/II study of veliparib in patients with germline BRCA mutations and platinum-resistant or partially platinum-sensitive relapse of epithelial ovarian cancer determined the MTD to be 300 mg twice daily, and showed a 65% overall response rate. The OS rate in the intent-to-treat population was 13.7 months.

Veliparib has been said to be the most likely of the PARP inhibitors to be combined with chemotherapeutic drugs, because it showed low hematologic toxicity.

Veliparib continues to be studied in ongoing phase III clinical trials, for ovarian cancer and other cancers, but in 2 phase III combination trials, the drug failed to meet its primary endpoints when combined with carboplatin and paclitaxel in nonsmall cell lung cancer and triple-negative breast cancer.

Thus far, veliparib has shown a favorable toxicity profile, with nausea and vomiting, anemia, decreased appetite, abdominal pain, diarrhea, malaise, and fatigue being the most frequent AEs reported.

Talazoparib is an additional PARP inhibitor still in development for patients with advanced or recurrent solid tumors.

Preclinical study results showed that talazoparib exhibits selective antitumor cytotoxicity and elicits DNA repair biomarkers at concentrations much lower than those of olaparib, rucaparib, and veliparib. In vitro experiments, however, showed that talazoparib selectively targeted tumor cells with BRCA or PTEN mutations with greater potency of 20- to 200-fold or more than the other PARP inhibitors.

An open-label, multicenter phase I dose-escalation, first-in-human trial determined an MTD of 1 mg daily, with a 50-hour half-life. Among patients with BRCA-mutated ovarian cancer, 5 of 12 (42%) had confirmed responses and the clinical benefit rate (confirmed responses plus stable disease) was 67%. The median PFS was 36.4 weeks.

Fatigue (37%) and anemia (35%) were the most frequent AEs with talazoparib in the dose-escalation study, with grade 3/4 AEs including anemia (24%) and thrombocytopenia (18%).

As PARP inhibitors continue to take center stage, researchers persist in efforts to develop new agents to add to the armamentarium, as well as to determine potential combinations that show the greatest efficacy with the least toxicity.

Meehan RS, Chen AP. New treatment option for ovarian cancer: PARP inhibitors. Gynecol Oncol Res Pract. 2016;3:3. doi: 10.1186/s40661-016-0024-7.

Dziadkowiec KN, Gasiorowska 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. doi: 10.5114/ pm.2016.65667.

Ledermann JA. PARP inhibitors in ovarian cancer. Ann Oncol. 2016;27(suppl 1):i40-i44. doi: 10.1093/ annonc/mdw094.

Konecny GE, Kristeleit RS. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions. Br J Cancer. 2016;115(10):1157-1173. doi: 10.1038/bjc.2016.311.

Frey MK, Pothuri B. Homologous recombination deficiency (HRD) testing in ovarian cancer clinical practice: a review of the literature. Gynecol Oncol Res Pract. 2017;4:4. doi: 10.1186/s40661-017-0039-8.

Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164. doi: 10.1056/ NEJMoa1611310.

Evans T, Matulonis U. PARP inhibitors in ovarian cancer: evidence, experience and clinical potential. Ther Adv Med Oncol. 2017;9(4):253-267. doi: 10.1177/1758834016687254.

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

U.S. Food & Drug Administration. FDA approves olaparib tablets for maintenance treatment in ovarian cancer. FDA website. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm572143. htm. Published August 17, 2017. Accessed August 17, 2017.

Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123-134. doi: 10.1056/NEJMoa0900212

Domchek SM, Aghajanian C, Shapira-Frommer R, et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol. 2016;140(2):199-203. doi: 10.1016/j.ygyno.2015.12.020.

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. doi: 10.1200/ JCO.2014.56.2728.

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Matulonis UA, Penson RT, Domchek SM, et al. Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. Ann Oncol. 2016;27(6):1013-1019. doi: 10.1093/annonc/mdw133.

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Articles

Michael J. Birrer, MD, PhD, discusses the introduction of poly ADP-ribose polymerase inhibitors to the ovarian cancer treatment landscape.

Jessica D'Amico | Authors

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PARP Inhibitors Offer Hope for Patients With Ovarian Cancer