TBCRC 048: A phase II study of olaparib monotherapy in metastatic breast cancer patients with germline or somatic mutations in DNA damage response (DDR) pathway genes (Olaparib Expanded).
Nadine Tung, Mark E. Robson, Steffen Ventz, Cesar Augusto Santa-Maria, P. Kelly Marcom, Rita Nanda, Payal D. Shah, Tarah J. Ballinger, Eddy S. Yang, Michelle Melisko, Adam Brufsky, Shaveta Vinayak, Michelle K. DeMeo, C. David Jenkins, Susan M. Domchek, Gerburg M. Wulf, Ian E. Krop, Antonio C. Wolff, Eric P. Winer, Judy E. Garber
Abstract
1002 Background: Olaparib, a PARP inhibitor, is approved for HER2-negative MBC in g BRCA1/2 mutation carriers. Olaparib Expanded, an investigator-initiated study, assessed the response to olaparib in MBC patients with sBRCA1/2 mutations or g/s mutations in DDR-pathway genes other than BRCA1/2. Methods: Eligibility included: MBC with measurable disease; progression on < 2 metastatic chemotherapy regimens. Prior PARP inhibitor or progression on platinum was not allowed. Cohort 1 included patients with germline mutations in non- BRCA1/2 DDR-pathway genes. In Cohort 2 were those with somatic mutations in these genes or BRCA1/2; germline testing was required only to exclude a gBRCA mutation if a s BRCA mutation was present. Patients received olaparib 300 mg bid until progression or unacceptable toxicity. For each cohort, a single-arm Simon two-stage design was used with 13 then 14 patients in the 1 st and 2 nd stages, respectively. The null hypothesis within each cohort [≤ 5% objective response rate (ORR)] would be rejected if > 4 responses were seen at the end of stage 2. Secondary endpoints include clinical benefit rate, progression-free survival, and duration of response. Results: 54 patients enrolled from March 2018 to Jan 2020; 1 ineligible s BRCA2 was excluded. Median age was 59 yrs (range: 30-87). 40 patients had ER+ HER2-, 3 HER2+, and 10 TNBC. 87% had a mutation in PALB2, s BRCA1/2, ATM or CHEK2. ORR was 29.6% (8/27, 90%-CI: 15.6%-47.1%) in Cohort 1 and 38.5% (10/26, 90%-CI: 22.5%-56.4%) in Cohort 2. Responses were gene specific (Table): g PALB2 and s BRCA mutations predicted response; no responses were seen with only a CHEK2 or ATM mutation. To date, responses as long as 16.4 months have been observed. Responses were seen in all subtypes: 5/10 TNBC, 1/3 HER2+, 12/40 ER+ HER2-. 11 responses occurred after prior CDK4/6 inhibitor. In June 2020, final data for confirmed ORR and secondary endpoints will be reported. Conclusion: In this proof-of-principle study, single-agent olaparib successfully met its primary endpoint in both cohorts. Activity was seen largely in patients with MBC and s BRCA1/2 or g PALB2 mutations but not with ATM or CHEK2 mutations. Clinical trial information: NCT03344965 . [Table: see text]