In the phase Ib/II JAVELIN PARP Medley trial reported in JAMA Oncology, Timothy A. Yap, MBBS, PhD, and colleagues found that the combination of the anti–PD-L1 agent avelumab and the poly (ADP-ribose) polymerase (PARP) inhibitor talazoparib produced objective response rates in patient subgroups with advanced solid tumors that would be expected from single-agent PARP inhibitor or immune checkpoint inhibitor therapy. The combination was also associated with prolonged response durations in some subgroups.
Timothy A. Yap, MBBS, PhD
As stated by the investigators, “Preclinical data suggest that PARP inhibitors have synergistic activity when combined with immune checkpoint inhibitors; however, it is unknown which tumor types or molecular subtypes may benefit from this combination.”
Study Details
In the international trial, 223 patients were enrolled between October 2017 and November 2019, including 12 in phase Ib and 211 in phase II. The recommended dose for phase II identified in phase Ib was avelumab at 800 mg every 2 weeks plus talazoparib at 1 mg once daily.
Cohorts in phase II treated with this combination dose consisted of patients with:
- Non–small cell lung cancer (NSCLC)
- DNA damage response (DDR)-positive NSCLC
- Triple-negative breast cancer
- Hormone receptor (HR)-positive, HER2-negative, DDR-positive breast cancer
- Recurrent, platinum-sensitive, BRCA wild-type ovarian cancer
- Recurrent, platinum-sensitive, BRCA1/2-altered ovarian cancer
- Urothelial cancer
- Metastatic castration-resistant prostate cancer (mCRPC)
- DDR-positive mCRPC
- BRCA1/2- or ATM-altered solid tumors.
Due to slow enrollment, the DDR-positive NSCLC and BRCA- or ATM-altered solid tumor cohorts were closed early.
Responses
Among the 211 patients treated in phase II, objective response rates and median response durations were: 16.7% and 17.5 months among 42 patients with NSCLC; 20.0% and 11.1 months in the 1 responder among 5 with DDR-positive NSCLC; 18.2% and 11.1 months among 22 with triple-negative breast cancer; 34.8% and 15.7 months among 23 with HR-positive, HER2-negative, DDR-positive breast cancer; 20.0% and 3.9 months among 20 with BRCA wild-type ovarian cancer; 63.6% and not reached among 11 with BRCA1/2-altered ovarian cancer; 15.0% and not reached among 40 with urothelial cancer; 0% and not available among 21 with mCRPC; 11.1% and not available among 18 with DDR-positive mCRPC; and 11.1% and not estimable among 9 with BRCA- or ATM-altered solid tumors.
Particularly durable responses were observed in patients with triple-negative breast cancer (median = 11.1 months, range = 3.4–20.4 months); HR-positive, HER2-negative, DDR-positive breast cancer (median = 15.7 months, range = 3.9 to ≥ 20.6 months); and BRCA-altered ovarian cancer (median = not reached, range = 5.6 to ≥ 18.4 months).
KEY POINTS
- Objective response rates ranged from 0% to 63.6% across cohorts of varying size.
- Prolonged durations of response were observed in patients with triple-negative breast cancer; HR-positive, HER2-negative, DDR-positive breast cancer; and BRCA1/2-altered ovarian cancer.
Adverse Events
In phase II, treatment-related grade 3 or 4 adverse events occurred in 57.0% of patients, most commonly anemia (33.6%), thrombocytopenia (21.5%), and neutropenia (13.9%). Treatment-related adverse events led to discontinuation of any study drug in 7.6% of patients. Immune-related adverse events of any grade occurred in 13.0% (most common = hypothyroidism, in 5.4%) and were grade 3 or 4 in 3.6%. Infusion-related reactions of any grade occurred in 21.5% of patients (grade 3–4 in 1 patient). Death considered related to treatment occurred in one patient, due to acute respiratory syndrome.
The investigators concluded, “This nonrandomized controlled trial found that objective response rates for avelumab plus talazoparib were comparable with those with PARP inhibitor or immune checkpoint inhibitor monotherapy. Prolonged durations of response in patients with triple-negative breast cancer; HR-positive, HER2-negative, and DDR-positive breast cancer; and BRCA1/2-altered ovarian cancer warrant further investigation in randomized clinical trials. These data highlight the importance of prospective patient selection in future studies of immune checkpoint inhibitor and PARP inhibitor combinations.”
Dr. Yap, of The University of Texas MD Anderson Cancer Center, is the corresponding author for the JAMA Oncology article.
Disclosure: The trial was supported by Pfizer and Merck Germany. For full disclosures of the study authors, visit jamanetwork.com.
