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Durvalumab in Combination With Olaparib Versus Durvalumab Alone as Maintenance Therapy in Metastatic NSCLC: The Phase
Myung-Ju Ahn1, Igor Bondarenko2, Ewa Kalinka3
1Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Introduction:
Increased DNA damage triggered through poly (ADP-ribose) polymerase inhibition may modify tumor immunogenicity, sensitizing tumors to immunotherapy. ORION (NCT03775486) evaluated the combination of olaparib with durvalumab as maintenance therapy in patients with metastatic NSCLC.
Methods:
ORION is a phase 2, randomized, multicenter, double-blind, international study. Patients with metastatic NSCLC (without activating EGFR or ALK aberrations) and Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled to receive initial therapy with durvalumab (1500 mg intravenously; every 3 wk) plus platinum-based chemotherapy for four cycles. Patients without disease progression were then randomized (1:1) to maintenance durvalumab (1500 mg; every 4 wk) plus either olaparib (300 mg orally) or placebo (both twice daily); randomization was stratified by objective response during initial therapy and tumor histologic type. The primary end point was investigator-assessed progression-free survival (PFS) (Response Evaluation Criteria in Solid Tumors version 1.1).
Results:
Between January 2019 and February 2020, 269 of 401 patients who received initial therapy were randomized. As of January 11, 2021 (median follow-up: 9.6 mo), median PFS was 7.2 months (95% confidence interval: 5.3-7.9) with durvalumab plus olaparib versus 5.3 months (3.7-5.8) with durvalumab plus placebo (hazard ratio = 0.76, 95% confidence interval: 0.57-1.02, p = 0.074). Safety findings were consistent with the known profiles of durvalumab and olaparib. Anemia was the most common adverse event (AE) with durvalumab plus olaparib (26.1% versus 8.2% with durvalumab plus placebo). The incidence of grade 3 or 4 AEs (34.3% versus 17.9%) and AEs leading to treatment discontinuation (10.4% versus 4.5%) was numerically higher with durvalumab plus olaparib versus durvalumab plus placebo.
Conclusions:
Maintenance therapy with durvalumab in combination with olaparib was not associated with a statistically significant improvement in PFS versus durvalumab alone, although numerical improvement was observed.
Insights
The ORION study found that adding olaparib to durvalumab maintenance therapy did not significantly improve progression-free survival (PFS) in metastatic non-small cell lung cancer (NSCLC). While numerical improvements were seen, the combination showed increased adverse events.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Poly (ADP-ribose) polymerase (PARP) inhibition may enhance tumor immunogenicity, potentially sensitizing tumors to immunotherapy.
- The ORION study investigated olaparib combined with durvalumab as maintenance therapy for metastatic non-small cell lung cancer (NSCLC).
Purpose of the Study:
- To evaluate the efficacy and safety of maintenance therapy with durvalumab plus olaparib versus durvalumab plus placebo in patients with metastatic NSCLC.
- To assess the impact of PARP inhibition on tumor immunogenicity and response to immunotherapy in NSCLC.
Main Methods:
- A phase 2, randomized, double-blind, international study (ORION) involving patients with metastatic NSCLC without EGFR/ALK aberrations.
- Patients received initial durvalumab plus chemotherapy, then were randomized to maintenance durvalumab with either olaparib or placebo.
- The primary endpoint was investigator-assessed progression-free survival (PFS).
Main Results:
- Median PFS was 7.2 months with durvalumab plus olaparib versus 5.3 months with durvalumab plus placebo (HR=0.76, p=0.074).
- The combination therapy was generally well-tolerated, with safety profiles consistent with known drug profiles.
- Anemia was the most common adverse event; higher rates of grade 3/4 AEs and treatment discontinuations were observed with the combination.
Conclusions:
- Maintenance therapy with durvalumab plus olaparib did not achieve a statistically significant improvement in PFS compared to durvalumab alone in metastatic NSCLC.
- A numerical improvement in PFS was observed, suggesting a potential but not statistically confirmed benefit.
- Further research may be warranted to explore the role of PARP inhibitors in combination with immunotherapy in specific NSCLC patient populations.
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