New Life for PARP Inhibitors: Emerging Agents Leave Mark at ASCO | Page 3

Jane de Lartigue, PhD
Published Online: Friday, August 30, 2013
Furthermore, this study indicated that continuous exposure to veliparib in this combination was feasible, while other abstracts presented at ASCO showed that intermittent dosing was required for olaparib and rucaparib in combination with carboplatin. In a separate presentation reviewing these data, Andrew Tutt, MB ChB, PhD, professor of Oncology at King’s College London, suggested that this may reflect differences in the relative activity of the various PARP inhibitors on suppression of PARP catalytic activity and PARP trapping.

Results from a phase I trial of veliparib in combination with temozolomide in pediatric patients with recurrent central nervous system tumors were also discussed (NCT00946335). The combination showed significant activity, was well tolerated, and had pharmacokinetic parameters similar to those observed in adults. A phase II trial is planned.

Niraparib

A single study of niraparib (MK4827) was presented at ASCO, which discussed the final results of a phase I trial in BRCA mutation carriers with sporadic ovarian cancer, and castration-resistant prostate cancer. One hundred patients received niraparib at a variety of dose levels. It was well tolerated and showed promising antitumor activity, with RECIST and/or cancer antigen 125 (CA125) partial response rates up to 50%. Among patients with high-grade serous ovarian cancer, those with platinum-sensitive disease and BRCA mutations had higher response rates.

BMN 673

BMN 673 is the most potent and specific PARP inhibitor in development (with an IC50<1nM). Johann de Bono, MD, PhD, professor of Experimental Cancer Medicine at the Institute of Cancer Research, London, described the results of the first-in-human trial of BMN 673 in patients with solid tumors (NCT01286987). It demonstrated impressive antitumor activity as a single agent, with Response Evaluation Criteria in Solid Tumors (RECIST) or CA125 responses occurring in almost 65% of patients with BRCA-mutant ovarian/peritoneal cancer and more than 30% of patients with BRCA-mutant breast cancer.

Other PARP inhibitors

Two other PARP inhibitors are currently in clinical development. Eisai Inc is sponsoring a small phase II trial into the combination of the PARP inhibitor E7016 with temozolomide in patients with wild-type BRAF stage IV or unresectable stage III melanoma (NCT016052). Cephalon, now part of Teva Pharmaceutical Industries, is investigating CEP-9722, a small pro-drug of CEP-8983 that inhibits PARP-1 and PARP-2, in a phase I/II trials for solid tumors (NCT01311713).

Table. PARP Research Highlights from ASCO

PARP Inhibitor (Company) Stage (Abstract No) Patient Population Key Results
Olaparib
(AstraZeneca)
Phase II retrospective
(5505)
BRCA-mutated serous ovarian cancer; platinum-sensitive disease
  • 82% reduction in risk of disease progression or death
  • Median PFS of 11.2 mo with olaparib vs 4.3 mo for placebo
Phase II
(4013)
Metastatic/recurrent gastric cancer
  • Median OS of 13.1 mo with olaparib/paclitaxel combination vs 8.3 mo with paclitaxel alone (P = .010, 2-sided)
  • Median PFS of 3.91 mo with olaparib regimen vs 3.55 mo with paclitaxel (P = .261, 2-sided)
  • Low ATM protein expression levels may be predictive of greater OS benefit
Phase I
(2514)
Breast and ovarian cancer; BRCA1/2 mutation carriers
  • Olaparib/carboplatin combination tolerable and active at 400-mg dosage
  • FOXO3 and pS209-eIF4e protein expression levels may predict response to therapy
Phase II
(11024)
Heavily treated patients with advanced cancer; BRCA1/2 mutation carriers
  • Overall RR of 26.2%
  • RRs of 50% (4 of 8 patients) in prostate cancer; 31.1% (60 of 193 patients) in ovarian cancer; 21.7% (5 of 23 patients) in pancreatic cancer; 12.9% (8 of 62) in breast cancer)
Phase IB
(2581)
Advanced NSCLC; EGFR mutation carriers
  • Olaparib/gefitinib combination well-tolerated, with significant clinical activity
  • Maximum tolerated dose of 200 mg TDS
Veliparib
(AbbVie)
Phase I
(2036)
Pediatric central nervous system tumors
  • 4 of 29 evaluable patients had SD >6 mo with veliparib/temozolomide combination
  • No objective responses
Phase I
(1024)
Metastatic breast cancer; BRCA1/2 mutation carriers
  • 57% RR (16 of 28 enrolled patients) with veliparib/carboplatin combination
  • 54% confirmed RR (14 of 26 eligible patients)
  • Cytopenias are of concern but combination is tolerable
Phase I
(2065)
Pediatric central nervous system tumors
  • 4 of 29 evaluable patients had SD >6 mo with veliparib/temozolomide combination
  • No objective responses
Phase I
(2584)
Advanced solid tumors
  • Preliminary median PFS of 8.1 mo in BRCA-mutant ovarian cancer (24 patients); 5.9 mo unknown mutation status ovarian cancer (15 patients); 3.9 mo for breast cancer (11 patients) for veliparib with carboplatin and gemcitabine
Rucaparib
(Clovis Oncology)
Phase I
(2586)
Heavily treated advanced solid tumors
  • 57% (4 of 7 patients) with ovarian cancer had either PR or SD >12 wk with rucaparib/ carboplatin combination
Phase I
(2585))
Advanced solid tumors
  • Disease control ratea of 100% ( 7 of 7 patients) for ovarian cancer patients; 63% (5 of 8 patients) for breast cancer, (all with BRCA mutations after 2 cycles of rucaparib)
  • Rucaparib monotherapy well tolerated ≤360 mg BID
Niraparib
(Tesaro, Inc)
Phase I
(2513)
Advanced solid tumors; BRCA mutation carriers
  • RECIST RRs of 75% (3 of 4 patients) in platinum-sensitive ovarian cancer; 40% (8 of 20 patients) in BRCA1/2-mutant ovarian cancer; 50% (2 of 4 patients) in BRCA1/2-mutant breast cancer
BMN 673
(BioMarin Pharmaceutical)
Phase I
(2580)
Solid tumors
  • RECIST RRs of 44% (11 of 25 patients) in ovarian cancer; 39% (7 of 18 patients) in breast cancer, all with BRCA mutations with BMN 673 monotherapy
  • CBR ≥24 wk in 82% (23 of 28 patients) in ovarian cancer; CBR ≥12 wk in 67% (12 of 18 patients) in breast cancer, all with BRCA mutationsb
  • Thrombocytopenia is dose-limiting toxicity

Sources: Abstracts, posters, and oral presentations from the 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL. Available at http://meetinglibrary.asco.org.

aDisease control rate is defined as CR + PR + SD.
bCBR is defined as CR, PR, or SD.

ATM indicates ataxia telangiectasia mutated; BID, twice a day; CBR, clinical benefit rate; CRPC, castration-resistant prostate cancer; CR, complete response; FOXO3, forkhead box 03; NSCLC, non-small cell lung cancer; NFκB1, nuclear factor kappa B1; OS, overall survival; PFS, progression-free survival; PR, partial response; QD, every day; RECIST, Response Evaluation Criteria in Solid Tumors; RR, response rate; SD, stable disease; TDS, three times a day.



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