Yasser Mohamed Ali Ged, MBBS, co-director, Kidney Cancer Research Program, assistant professor of oncology, Johns Hopkins Medicine, discusses the background of launching the phase 2 ORCHID trial (NCT03786796) evaluating olaparib (Lynparza) monotherapy in patients with metastatic renal cell carcinoma (RCC) harboring 

 or other DNA repair (DDR) gene mutations.

 from an interim analysis of patients enrolled (n = 13) in the single-arm trial at the 2023 Kidney Cancer Research Summit. Findings showed that among 11 evaluable patients, olaparib elicited a disease control rate (DCR) of 18%, including an objective response rate of 9% and astable disease rate was 18%. Additionally, 27% of patients experienced tumor reduction, including 2 patients with 

-mutated disease. One of those patients experienced a durable partial response, and the other had prolonged stable disease lasting for 10 months.

This phase 2 study is exploring the role of PARP inhibitors in patients with metastatic RCC, Ged begins. Patients enrolled onto the phase 2 study are receiving oral olaparib at 150 mg twice per day for 4 weeks throughout the duration of the safety run-in, followed by olaparib at 300 mg twice per day until disease progression, unacceptable toxicity, or patient withdrawal. Additionally, the primary end point of the study is DCR.

The rationale for this investigation stems from the knowledge that DDR gene alterations are prevalent in multiple cancers, including RCC, Ged explains. Notably, several PARP inhibitors are approved in different indications for other solid tumors for patients who harbor DDR gene alterations, Ged adds.

 mutations are of particular interest in the RCC space, he expands. This is a tumor suppressor gene that is known to lead to aggressive kidney cancer subtypes and has activity in the DDR pathway, Ged says. Notably, preclinical studies led to the rationale to investigate PARP inhibitors in this subset of patients with metastatic RCC, Ged concludes.

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Yasser Mohamed Ali Ged, MBBS, discusses the background of launching the phase 2 ORCHID trial evaluating olaparib monotherapy in patients with metastatic renal cell carcinoma harboring BAP1 or other DNA repair gene mutations.


Dr Ged on the Background of the ORCHID Trial in BAP1-Mutated Metastatic RCC

Yasser Mohamed Ali Ged, MBBS, co-director, Kidney Cancer Research Program, and assistant professor of oncology, Johns Hopkins Medicine, discusses the phase 2 ORCHID trial (NCT03786796).

ORCHID is a single-arm trial evaluating olaparib (Lynparza) in 20 patients with metastatic renal cell carcinoma (RCC) who harbor 

 (BRCA1-associated protein 1) or other DNA repair gene mutations, which are known to confer aggressive disease, Ged says. Notably, this is the first and only study evaluating PARP inhibitor monotherapy in patients with advanced RCC. The study was enriched for patients with 

 mutations because it confers sensitivity to DNA damage repair agents like PARP inhibitors.

Eligible patients received 150 mg of oral olaparib twice daily for 4 weeks for the safety run-in considering the possibility for kidney injury, followed by 300 mg of olaparib twice daily until disease progression, unacceptable toxicity, or patient withdrawal, Ged says. The primary end point of the study is disease control rate, which included complete response, partial response (PR), and stable disease (SD) for at least 6 months. 

Interim findings, which were presented at the 2023 Kidney Cancer Research Summit, demonstrated that 13 patients had been enrolled to date. Most patients were heavily pretreated, having received more than 3 prior lines of therapy, Ged says. Additionally, all patients received prior immunotherapy, Ged says. Notably, the predefined threshold for efficacy was met, Ged says.

Among 11 evaluable patients, 2 patients achieved disease control and 3 experienced tumor shrinkage. Additionally, 2 patients who achieved durable deep PR and SD, respectively, had a 

 mutation, supporting the idea that this class of agents may be effective in this population. Regarding safety, olaparib was well tolerated with minimal grade 3 or greater adverse effects. Limited kidney toxicity was seen with olaparib, Ged concludes.

Yasser Mohamed Ali Ged, MBBS, discusses the phase 2 ORCHID trial (NCT03786796).

Yasser Mohamed Ali Ged, MBBS

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