Background

Olaparib (Lynparza^®) is a poly(ADP-ribose) polymerase (PARP) inhibitor approved as maintenance treatment of PSR OC. MEDIOLA assessed olaparib in combination with the anti-programmed cell death ligand1 antibody, durvalumab, in germline BRCA1 and/or BRCA2 mutated (gBRCAm) PSR OC (NCT02734004). The 12-week (wk) disease control rate (DCR) = complete response [CR] + partial response + stable disease) was presented at SGO 2018 (late-breaker abst. 4).

Methods

Pts had PSR OC, gBRCA1 or gBRCA2 mutation, and had received at least one prior line of platinum. Pts received olaparib 300 mg PO BID for a 4-wk runin, then olaparib 300 mg PO BID and durvalumab 1.5 g IV q 4 wks until progressive disease. Tumours were assessed by RECIST 1.1 at baseline, 4 wks, then every 8 wks. Primary endpoints were 12wk DCR and safety. Secondary endpoints were 28-wk DCR, objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and biomarker analyses.

Results

Thirty-two/thirty-four pts treated were eligible. With the data cut-off on 1 Nov 2018, 28% pts were still on treatment. Most common ≥Grade 3 AEs were anaemia (17.6%), elevated lipase (11.8%), neutropenia (8.8%), and lymphopenia (8.8%). Five pts discontinued olaparib and three discontinued durvalumab due to an adverse event. The 28-wk DCR was 65.6% (90% CI: 49.6%, 79.4%). ORR was 71.9% (95% CI: 53.25%, 86.25%) with a total of seven CRs. Median PFS was 11.1 months (95% CI: 8.2, 15.9) with a median DoR of 10.2 months (25/75th percentile: 5.6, NC). Second-line pts (N = 13, 40.6%) had not yet reached the medians for PFS or DoR. Median OS for all pts was not yet reached, with 87.0% of pts alive at 24 months (median follow up = 20.4 months). Updated results will be presented.

Conclusions

The combination of olaparib and durvalumab was well tolerated and showed promising median PFS and DoR. Median PFS and DoR for pts with fewer prior lines of chemotherapy was not yet reached, suggesting that these pts may derive a greater benefit from the combination. The CR rate was higher than anticipated. This cohort has been expanded to further explore the durability of this chemotherapy-sparing combination.

Clinical trial identification

NCT02734004.

Editorial acknowledgement

Emma Robinson, Mudskipper Business, Ltd, funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

Y. Drew: Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Merck; Advisory / Consultancy, Research grant / Funding (institution): Tesaro ; Advisory / Consultancy: Genmab; Research grant / Funding (institution): Oncology; Research grant / Funding (institution): Veratsem. B. Kaufman: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Medison. S. Banerjee: Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self): Tesaro; Honoraria (self): Clovis Oncology; Honoraria (self): Merck; Honoraria (self): PharmaMar; Honoraria (self): Roche; Honoraria (self): Seattle Genetics; Honoraria (self): Nucana. A. Lortholary: Honoraria (self): AstraZeneca; Honoraria (self): Tesaro. P. Roxburgh: Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro. R.H. Alvarez: Honoraria (self): Eisai; Honoraria (self): Puma; Leadership role: Cancer Treatment Center of America. S. Domchek: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Clovis Oncology; Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (institution): PharmaMar. C. Gresty: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. H.K. Angell: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. V. Rocher Ros: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. K. Meyer: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. M. Lanasa: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P. Herbolsheimer: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. All other authors have declared no conflicts of interest.

Background

O (olaparib, Lynparza^®) is approved for gBRCAm HER2(-) MBC based on the OlympiAD study. O-induced DNA damage may increase tumor antigen release, activate cGAS/STING, attract tumor-infiltrating lymphocytes and upregulate programmed cell death ligand-1 (PD-L1). In OlympiAD (single-agent olaparib), median duration of response (DoR) and median progression-free survival (PFS) were 6.4 months (m) and 7.0 m, respectively. MEDIOLA assessed the efficacy and safety of the combination of O and D (durvalumab, Imfinzi^®), an anti-PD-L1 antibody, in gBRCAm HER2(-) MBC (NCT02734004). Early results were reported (SABCS 2017 PD6-11, 2018 PD5-04).

Methods

Pts with gBRCAm HER2(-) MBC were eligible; prior platinum was allowed; prior PARPi or anti-PD(L)1 was not. Pts received O 300 mg BID for a 4-wk run-in, then O 300 mg BID and D 1.5g IV q 4 wks until disease progression. Tumors were assessed at baseline, 4 wks, then every 8 wks. Dual primary endpoints were disease control rate (DCR) at 12 wks and safety. Secondary endpoints were 28-wk DCR, objective response rate (ORR), DoR, PFS, overall survival (OS), and biomarker analysis.

Results

34 pts were in the safety, and 30 pts in the efficacy analyses. The 12-wk DCR was 24/30 (80%), greater than the target of 75%. The 28-wk DCR was 15/30 (50%). Other efficacy endpoints are presented below. The most common adverse events ≥Grade 3: anemia (Gr 3, 4 pts), neutropenia (Gr 3, 3 pts), and pancreatitis (Gr 3, 1pt, Gr 4, 1 pt). Efficacy and safety results with longer follow-up will be presented. Efficacy results correlated to genomic data and intrinsic subtypes will also be presented.Table:

1191O

Conclusions

The data suggest that pts with fewer prior lines of chemotherapy (0/1) had higher ORR, longer mDoR, mPFS and mOS than those with 2 prior lines. The chemo-free combination was well-tolerated, with safety consistent with the individual agent profiles. Confirmation of these results in early-line patients is warranted.

Clinical trial identification

NCT02734004.

Editorial acknowledgement

Writing assistance was provided by Martin Goulding, PhD, of Mudskipper Ltd and funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca and the authors.

Funding

AstraZeneca.

Disclosure

S. Domchek: Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Clovis Oncology; Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (self): PharmaMar. S. Postel-Vinay: Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: AstraZeneca; Research grant / Funding (self), Non-remunerated activity/ies: Boehringer Ingelheim; Research grant / Funding (self), Non-remunerated activity/ies: Bristol-Myers Squibb; Research grant / Funding (institution): Janssen-Cilag; Advisory / Consultancy, Research grant / Funding (self), Non-remunerated activity/ies: Merck; Research grant / Funding (self): Novartis; Research grant / Funding (self), Non-remunerated activity/ies: Pfizer; Research grant / Funding (self), Non-remunerated activity/ies: Roche; Research grant / Funding (self): Sanofi; Non-remunerated activity/ies: Bayer; Non-remunerated activity/ies: Johnson & Johnson; Non-remunerated activity/ies: Lilly; Non-remunerated activity/ies: MedImmune; Non-remunerated activity/ies: NH TherAGuiX. S. Im: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy: Amgen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Hanmi; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche. J. Alexandre: Honoraria (self): AstraZeneca; Honoraria (self): Roche; Honoraria (self): PharmaMar; Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self): Ipsen; Research grant / Funding (self), Travel / Accommodation / Expenses: Janssen. M.G. Krebs: Advisory / Consultancy, Research grant / Funding (self): Roche; Advisory / Consultancy: Janssen; Advisory / Consultancy: Octimet; Advisory / Consultancy: Achilles; Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (self), Travel / Accommodation / Expenses: BerGenBio; Research grant / Funding (self): MSD. M. Lanasa: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. H.K. Angell: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. Z. Lai: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C. Gresty: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. L.M. Opincar: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P. Herbolsheimer: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. B. Kaufman: Advisory / Consultancy: AstraZeneca. All other authors have declared no conflicts of interest.