Role of PARP Inhibitors in BRCA-Related Malignancies

Sana Iqbal, PharmD; Mohammad A. Rattu, PharmD, BCOP, BCPS, BCGP; Neal Shah, PharmD

Disclosures

US Pharmacist. 2018;43(9):HS10-HS17. 

In This Article

Available Parp Inhibitors

As mentioned previously, PARP enzymes utilize NAD+.[1] From a biochemical perspective, currently approved PARP inhibitors contain a nicotinamide moiety (i.e., aromatic ring, carboxamide) to mimic the substrate-protein interaction of NAD+ with PARP (Figure 2).[1,19,20]

Figure 2.

Chemical structures of nicotinamide, olaparib, rucaparib, and niraparib
Currently approved PARP inhibitors contain a nicotinamide moiety (i.e., aromatic ring, carboxamide) to mimic the substrate-protein interaction of NAD+ with PARP.
PARP: Poly (ADP-ribose) polymerase; Source: References 19, 20.

Olaparib (Lynparza)

In 2014, the FDA approved olaparib for maintenance therapy for recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer if patients had a complete or partial response to platinum-based chemotherapy (i.e., platinum-sensitive disease).[4,21] Study 19 (cited in the package insert) evaluated 265 adult patients (ages 21 to 89 years, median age 58 years, in the olaparib group) with platinum-sensitive ovarian cancer who had received ≥2 prior platinum-containing regimens.[4] Patients were randomized to receive either olaparib capsules 400 mg twice daily or placebo until there was unacceptable toxicity or progressive disease.[4] In the olaparib group, 36% of patients had gBRCAm, 13% had prior bevacizumab use, and 81% had an Eastern Cooperative Oncology Group Scale (ECOG) performance status (PS) of 0.[4] Of all patients, 45% were in complete response (CR) and 40% had a progression-free interval (PFI) of 6 to 12 months since their prior platinum dose.[4] The median progression-free survival (PFS) of olaparib compared with placebo was 8.4 versus 4.8 months, with a hazard ratio (HR) of 0.35; 95% confidence interval (CI), 0.24–0.49; P <.0001; the overall survival (OS) was similar between olaparib and placebo (29.8 vs. 27.8 months).[4] Grade 3 reactions in the olaparib group included neutropenia, anemia, thrombocytopenia, nausea, vomiting, diarrhea, constipation, fatigue/asthenia, and respiratory tract infections.[4] The investigators concluded that there was a statistically significant improvement in PFS in patients treated with olaparib.[4]

In 2017, the FDA approved olaparib for suspected/deleterious gBRCAm advanced ovarian cancer if patients received ≥3 prior chemotherapies.[4,21] The SOLO-2 study evaluated 295 patients (aged 28 to 83 years, median age 5 to 6 years, in the olaparib group) with gBRCAm platinum-sensitive ovarian/fallopian tube/primary peritoneal cancers who had received ≥ 2 prior platinum-containing regimens.[4] Patients received olaparib tablets 300 mg twice daily or placebo until unacceptable toxicity or progressive disease.[4] In the olaparib group, 17% had prior bevacizumab use, 83% of patients had an ECOG PS of 0, and 44% had received ≥3 platinum-containing regimens.[4] Of all patients, 47% were in CR and 40% had a PFI of 6 to 12 months since their prior platinum dose.[4] The median PFS of olaparib compared with placebo was 19.1 versus 5.5 months (HR, 0.3 [95% CI, 0.22–0.41], P <.0001), but complete OS data have yet to be published from this study.[4] Grade 3 reactions in the olaparib group included neutropenia, anemia, thrombocytopenia, nausea, vomiting, diarrhea, stomatitis, fatigue/asthenia, and headache.[4] The investigators concluded that there was a statistically significant improvement in PFS in patients treated with olaparib.[4]

Earlier this year, the FDA approved olaparib for suspected/deleterious gBRCAm, HER2-negative metastatic breast cancer for patients who have received chemotherapy in neoadjuvant/adjuvant/metastatic settings.[4,22] According to the package insert, patients with ER/PR-positive breast cancer should either have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy.[4] The OlympiAD study evaluated 302 patients (aged 22 to 76 years, median age 44 years, in the olaparib group) with gBRCAm HER2-negative metastatic breast cancer who had received an anthracycline (unless contraindicated) or taxane in the neoadjuvant/adjuvant/metastatic settings, ≥1 endocrine therapies in the adjuvant/metastatic settings (or have been deemed inappropriate for endocrine therapy), and have no evidence of disease progression during platinum treatment (if treated with a prior platinum-containing regimen).[4] Patients received olaparib tablets 300 mg twice daily or chemotherapy (e.g., capecitabine, eribulin, vinorelbine) until progression or unacceptable toxicity.[4] All patients had an ECOG PS of either 0 or 1, and 50% had triple-negative disease, while 50% had ER/PR-positive with HER2 negative disease.[4] In the olaparib group, 7% and 21% had received prior platinum-based regimens for localized and metastatic disease, respectively.[4] The median PFS of olaparib compared with placebo was 7 versus 4.2 months (HR, 0.58 [95% CI, 0.43–0.8]; P = .0009), but complete OS data have yet to be published from this study.[4] Grade 3 reactions in the olaparib group included neutropenia, anemia, thrombocytopenia, diarrhea, respiratory tract infections, fatigue/asthenia, and headache.[4] The investigators concluded that there was a statistically significant improvement in PFS in patients treated with olaparib.[4]

Rucaparib (Rubraca)

In 2016, the FDA approved rucaparib for deleterious BRCA mutation-associated (germline and/or somatic) advanced ovarian cancer if patients had received ≥2 prior chemotherapies.[5,23] Study 10 (cited in the package insert) and ARIEL2 evaluated a total of 106 patients (aged 33 to 84 years, median age 59 years) who had advanced BRCA-mutant ovarian cancer and progressed after ≥2 prior chemotherapies.[5,24] All patients received rucaparib tablets 600 mg twice daily until disease progression or unacceptable toxicity occurred.[5] All patients had an ECOG PS of either 0 or 1 and had received ≥2 prior (43% had ≥3 prior) platinum-based regimens.[5] There was an objective response rate of 54% (range: 44% to 64%), CR rate of 9%, partial response (PR) rate of 45%, and median duration of response of 9.2 months (95% CI, 6.6–11.6).[5] Of note, in the ARIEL2 study, the median PFS of rucaparib in patients with BRCA mutations, compared with patients with high and low loss of heterozygosity, was 12.8 months (95% CI, 9–14.7) versus 5.7 months versus 5.2 months, respectively (HR, 0.27 [95% CI, 0.16–0.44]; P <.0001).[24] Grade 3 reactions included nausea, vomiting, constipation, diarrhea, abdominal pain, fatigue/asthenia, neutropenia, anemia, thrombocytopenia, dysgeusia, decreased appetite, dyspnea, increased serum creatinine, increased liver function tests (AST, ALT), and increased cholesterol.[5] The investigators of the ARIEL2 study concluded that there was a statistically significant and relatively longer improvement in PFS for BRCA mutant (vs. wild type) patients treated with rucaparib.[24]

Earlier this year, the FDA approved rucaparib for the maintenance treatment of recurrent epithelial ovarian/fallopian tube/primary peritoneal cancers if patients had a CR or PR to platinum-based chemotherapy.[5,25] The ARIEL3 study evaluated 564 patients (ages 39 to 84 years, median age 61 years, in the rucaparib group) with recurrent epithelial ovarian/fallopian tube/primary peritoneal cancer who had had a prior response (CR or PR) to recent platinum-based chemotherapy.[5] Patients received either rucaparib tablets 600 mg twice daily or placebo until disease progression or unacceptable toxicity.[5] All patients had an ECOG PS of either 0 or 1 and had received ≥2 prior (up to 7) platinum-based regimens.[5] About 34% of patients were in CR after their most recent chemotherapy, and in the rucaparib group 22% had prior bevacizumab use.[5] The median PFS of rucaparib compared with placebo was 10.8 versus 5.4 months (HR, 0.36 [95% CI, 0.30–0.45]; P <.0001), but complete OS data have yet to be published from this study.[5] Grade 3 reactions included nausea, abdominal pain/distention, constipation, vomiting, diarrhea, stomatitis, fatigue/asthenia, rash, increased liver function tests (AST/ALT), increased serum creatinine, increased cholesterol, neutropenia, anemia, thrombocytopenia, nasopharyngitis, upper respiratory tract infections, and decreased appetite.[5] The investigators concluded that there was a statistically significant improvement in PFS in patients treated with rucaparib, including the homologous recombination deficiency and tumor BRCA subgroups.[5]

Niraparib (Zejula)

In 2017, the FDA approved niraparib for the maintenance treatment of recurrent epithelial ovarian/fallopian tube/primary peritoneal cancers if patients had a CR or PR to platinum-based chemotherapy.[6,26] The NOVA study evaluated 553 patients (aged 57 to 64 years, in the niraparib group) with platinum-sensitive recurrent epithelial ovarian/fallopian tube/primary peritoneal cancers who had had a prior response (CR or PR) to recent platinum-based chemotherapy.[6] Patients received either niraparib capsules 300 mg daily or placebo within 8 weeks of recent chemotherapy.[6] All patients had received ≥2 prior (40% had ≥3 prior) platinum-containing regimens.[6] In the niraparib group, 76% of patients had an ECOG PS of 0, and 26% had prior bevacizumab use.[6] In the gBRCAm cohort, the median PFS of niraparib compared with placebo was 21 versus 5.5 months (HR, 0.26 [95% CI, 0.17–0.41]; P <.0001).[6] In the non-gBRCAm cohort, the median PFS of niraparib compared with placebo was 9.3 versus 3.9 months (HR, 0.45 [95% CI, 0.34–0.61]; P <.0001).[6] Complete OS data have yet to be published from this study.[6] Grade 3 reactions included neutropenia, anemia, thrombocytopenia, nausea, constipation, vomiting, abdominal pain/distention, mucositis/stomatitis, diarrhea, xerostomia, fatigue/asthenia, decreased appetite, urinary tract infection, increased liver function tests (AST/ALT), myalgia, back pain, arthralgia, headache, insomnia, anxiety, dyspnea, rash, and hypertension.[6] The investigators concluded that there was a statistically significant improvement in PFS in patients treated with niraparib (versus placebo), in both gBRCAm and non-gBRCAm cohorts.[6] Table 1 lists characteristics of approved PARP inhibitors.

Investigational PARP Inhibitors and Combinations

There are various PARP inhibitors under investigation, either as monotherapy or in combination with other chemotherapeutic drugs.[27] Olaparib has been combined with other drugs for the following cancers: bladder (with durvalumab); colorectal (with irinotecan); endometrial (with cyclophosphamide); gastric (with paclitaxel); head and neck (with cisplatin); prostate (with degarelix or abiraterone/prednisone); and small cell lung (with temozolomide, AZ6738 [ATR inhibitor], or CRLX101 [modified camptothecin]).[27] Rucaparib has been combined with other drugs for the following cancers: breast (with cisplatin); cervical/endometrial (with bevacizumab); non-squamous nonsmall cell lung (with pembrolizumab); and prostate (with docetaxel/carboplatin or nivolumab).[27] Niraparib has been combined with other drugs for the following cancers: breast (with pembrolizumab); pancreatic (with nivolumab or ipilimumab); prostate (with radium-223, enzalutamide, JNJ-63723283 [PD-1 inhibitor], apalutamide, or abiraterone/prednisone); and urothelial (with cabozantinib).[27]

Additional PARP inhibitors include talazoparib (BMN-673), veliparib (ABT-888), pamiparib (BGB-290), iniparib (BSI-201, SAR240550), INO-1001, ABT-767, CEP-9722, E7016/GPI-21016, and 2X-121.[27]

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