ORCHID Trial of Olaparib Monotherapy Could Lay Groundwork for Investigating PARP Inhibitors in Advanced RCC

The efficacy and safety demonstrated by olaparib (Lynparza) monotherapy in patients with renal cell carcinoma (RCC) harboring BAP1 or DNA damage repair (DDR) gene mutations in the phase 2 ORCHID trial (NCT03786796) could help inform current and future investigations of PARP inhibitor–based regimens in this space, according to Yasser Mohamed Ali Ged, MBBS.

“One of the strengths of this study is that this is the first and only study of PARP inhibitor monotherapy in kidney cancer,” Ged noted. “There are other studies which are ongoing combining PARP inhibitors with immunotherapy and other agents, [but] it's important to understand the activity of monotherapy before we can look into other combination strategies.”

In data from an interim analysis of the trial presented during the 2023 Kidney Cancer Research showed that patients who received olaparib (n = 11) achieved a disease control rate (DCR) of 18% with an objective response rate of 9% and stable disease (SD) rate of 18%. Genetic mutations included BAP1 (61.5%), ATM (15.4%), PALB2 (15.4%), BRCA1 (7.7%), BRCA2 (7.7%), and 1 patient had co-mutations of BAP1 and PALB2. Of 3 patients who experienced tumor reduction, 2 had BAP1 alterations.

In an interview with OncLive^®, Ged, the co-director of the Kidney Cancer Research Program and an assistant professor of oncology at Johns Hopkins Medicine in Baltimore, Maryland, highlighted the early efficacy seen in patients with BAP1 mutations and next steps for the research.

OncLive: What was the rationale initiating the investigation of olaparib monotherapy in the ORCHID trial?

Ged: The ORCHID study explored the role of PARP inhibitors in patients with metastatic RCC with DDR gene alterations. The rationale stems from [the fact] that DDR gene alterations are prevalent in multiple cancers, including kidney cancer. There are several PARP inhibitors which are approved in multiple solid tumors for patients who harbor DDR gene alterations, in particular those involved in the hormone receptor pathway. Of particular interest is BAP1,which is a tumor suppressor gene which is known to lead to aggressive kidney cancer subtypes and also has activity in the DDR pathway.

What were the key design elements of ORCHID?

The study was designed to be enriched for patients who have BAP1 mutations—we wanted to explore the activity in further depth in these patients. It was a single-arm study, and eligible patients received olaparib at a starting dose of 150 mg twice daily for 4 weeks as a safety run-in phase. After that, they received the full dose of olaparib at 300 mg twice daily until disease progression, unacceptable toxicity, or withdrawal from the study for other reasons. The primary end point of the study was the DCR, which included partial response [PR], complete response, or SD for at least 6 months. The study was designed with Simon’s minimax 2 stage design with a sample size of 20 patients. At this meeting, we reported the interim analysis after the Simon first stage design was completed.

What were some of the key efficacy and safety findings?

In total, we enrolled 13 patients on the study. Most were heavily pretreated, including a lot of patients [46.2%] who received 3 or more prior lines of therapy. Some patients received 5 or 6 prior lines of therapy, and all received prior immunotherapy. The majority of patients had BAP1 mutations, and some had other DDR gene alterations.

[Looking] at the efficacy analysis, the study met the predefined Simon stage-one design. We saw disease control was achieved in 2 out of 11 [efficacy-evaluable] patients, and tumor shrinkages were seen in 3 patients, including 1 with a BAP1 mutation who had a durable, deep PR. Another patient [with a] BAP1 mutation had stable disease for 10 months. Overall, we saw activity, but the activity was mainly in patients with BAP1 mutations.

In terms of the safety analysis, olaparib monotherapy was well tolerated with very limited grade 3 and higher adverse effects. Olaparib is known to cause some kidney damage, and that was the rationale for starting with a small dose, but we did not see a lot of kidney toxicity in this population.

What are the next steps with this research?

The study is still enrolling. We hope to finish the study soon and learn more about the activity of PARP inhibitors in kidney cancer. The interesting finding [was] that we saw a lot of activity in patients with BAP1-mutated kidney cancer. When we finish the study, we have a lot of correlative studies and exploratory analyses which are ongoing; this will help us to design the next iteration of olaparib or PARP inhibitor studies in kidney cancer.

Reference

Ged Y, Elias R, Rifkind I, et al. Interim analysis of the ORCHID study (a phase II study of olaparib in metastatic renal cell carcinoma patients harboring BAP1 or other DNA repair gene mutations). Presented at: 2023 Kidney Cancer Research Summit; July 13-14, 2023. Boston, MA. Abstract 32.