Beth Israel Deaconess Medical Center and Dana-Farber Cancer Institute, Boston, MA
Nadine M. Tung , Mark E. Robson , Steffen Ventz , Cesar Augusto Santa-Maria , Paul Kelly Marcom , Rita Nanda , Payal D Shah , Tarah Jean Ballinger , Eddy Shih-Hsin Yang , Adam Brufsky , Shaveta Vinayak , Michelle Demeo , Colby Jenkins , Susan M. Domchek , Gerburg M. Wulf , Ian E. Krop , Antonio C. Wolff , Eric P. Winer , Judy Ellen Garber , Michelle E. Melisko
Background: Olaparib, a PARP inhibitor, is approved for HER2-negative MBC in gBRCA1/2 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 sBRCA 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 1st and 2nd 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 sBRCA2 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, sBRCA1/2, 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): gPALB2 and sBRCA 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 sBRCA1/2 or gPALB2 mutations but not with ATM or CHEK2 mutations. Clinical trial information: NCT03344965.
Gene/ cohort | N | Germline | Somatic |
---|---|---|---|
PALB2 | 13 | 8/11 | 0/2 |
sBRCA1^ | 7 | 0/0 | 4/7 |
sBRCA2 | 9 | 0/0 | 4/9 |
ATM# | 10 | 0/6 | 0/4 |
CHEK2^ | 7 | 0/7 | 0/0 |
CDK12 | 2 | 0/0 | 1/2 |
BLM | 1 | 0/0 | 1/1 |
BARD, RAD50 | 2 | 0/2 | 0/0 |
BRIP1, FANCA | 2 | 0/0 | 0/2 |
^ 1 with gCHEK2 and sBRCA1 analyzed with sBRCA1 # 2 also had gCHEK2 mutations
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