ONCAlert | Upfront Therapy for mRCC

Durvalumab Plus Olaparib Combo Shows 50% Pathologic Complete Response in MIBC

Wayne Kuznar
Published Online: 3:25 PM, Sat February 15, 2020
The combination of durvalumab (Imfinzi) and olaparib (Lynparza) may have activity as neoadjuvant therapy in the treatment of muscle-invasive bladder carcinoma (MIBC). In a single-arm phase II study (NCT03534492), the pathologic complete response rate (pCR) with the combination was 50%,1 reported Juan Francisco Rodriguez-Moreno, MD, at the 2020 Genitourinary Cancers Symposium.

The combination was well tolerated, with only 3 grade-4 adverse events (AEs) and only 3 treatment interruptions in 27 patients evaluated for safety.

The trial enrolled 29 patients with cT2 to T4a resectable muscle-invasive bladder cancer who were treated for 6 to 8 weeks prior to planned cystectomy with durvalumab given 1500 mg every 4 weeks for up to 2 months (up to 2 doses/cycles) plus olaparib administered at 150 mg twice daily for up to 56 days (2 cycles of 28 days each cycle). The 20 patients who were to undergo cystectomy were evaluated for treatment efficacy; 27 patients were evaluated for safety.

ECOG performance status was 0 in 55.2% of enrolled patients and 1 in 44.8%. Median patient age was 71 years. TNM stage was pT2 in 82.2% of patients, pT3 in 7.1%, and pT4 in 7.1%. About 14.3% of patients presented with nodal spread.

Ten patients (50%) had a pathologic complete response (pCR), defined as absence of tumor in the bladder and lymph nodes.

“The study was not designed to assess the efficacy of the combination. With this consideration, the data on efficacy are very interesting because a pCR rate of 50% is superior to other therapies in the neoadjuvant setting,” said lead author Rodriguez-Moreno, medical oncologist at HM Hospitales – HM CIOCC, Madrid, Spain.

The principal aim of the study was to characterize the impact of the combination on the molecular profile but the biomarker data are currently being analyzed, he said. “We hope that these data will be available at the ESMO 2020 meeting in Madrid,” he said.

Standard of care for muscle-invasive bladder cancer is radical cystectomy, which is rarely curative, he said. Although cisplatin-based neoadjuvant chemotherapy is the perioperative standard, only a few patients can benefit from this approach. New neoadjuvant treatments are therefore needed.

Recent evidence suggests that immune checkpoint inhibitors could be incorporated in this setting, said Rodriguez-Moreno, and immune checkpoint inhibitors have been approved by the FDA for the treatment of patients with advanced bladder cancer who are refractory or ineligible for platinum-based chemotherapy. However, response rates to single-agent immune checkpoint inhibition in patients with MIBC top out at about 30%, he said.

Durvalumab had demonstrated activity in patients with advanced urothelial carcinoma who were pretreated with platinum-containing chemotherapy and is being evaluated as first-line treatment both as monotherapy and in combination with tremelimumab.

Preliminary results from a single-arm trial of durvalumab combined with tremelimumab in patients with high-risk MIBC who were ineligible for cisplatin-based neoadjuvant chemotherapy were presented at the 2019 ASCO meeting. Of 21 patients who had completed cystectomy, the pCR rate was 43% (9 of 21) and the disease was downstaged in 14 (67%) patients.2

PARP inhibitors such as olaparib amplify DNA damage to augment tumor mutational burden and may make bladder tumors more immunogenic by increasing neoantigen production and upregulating PD-L1 expression. In this way, olaparib and durvalumab may exert synergistic activity, said Rodriguez-Moreno.

Tumor samples were collected at the time of diagnosis and cystectomy. Some 21.4% of specimens showed pathologic progressive disease.

One patient experienced pruritus, a grade 1 immune-related adverse event (AE). AEs attributed to olaparib include grade-1 nausea and vomiting and grade-1 anemia. 

The most common grade-3 AEs were infection (18.5%) followed by wound evisceration (7.4%). Other grade-3 AEs were anemia, neutropenia, asthenia, hematuria, pulmonary embolism, and hypertension, each experienced by 1 patient. The 3 grade-4 AEs were wound evisceration, hemorrhage, and septic shock (1 patient each). The 3 treatment interruptions were due to personal decision, progressive disease, and an exacerbation of chronic obstructive pulmonary disease.

Pre- and post-treatment blood samples are being analyzed for PD-L1 expression and pattern of immune infiltration. Whole exome sequencing is being performed in all tumor samples.
 
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References
  1. Rodriguez-Moreno JF, de Velasco G, Bravo Fernandez I, et al. Impact of the combination of durvalumab (MEDI4736) plus olaparib (AZD2281) administered prior to surgery in the molecular profile of resectable urothelial bladder cancer: NEODURVARIB Trial. Presented at: GU Cancers Symposium; February 13-15, 2020; San Francisco, CA. Abstract 542.
  2. Gao J, Siefker-Radtke AO, Navai N, et al. A pilot presurgical study evaluating anti-PD-L1 durvalumab (durva) plus anti-CTLA-4 tremelimumab (treme) in patients (pts) with high-risk muscle-invasive bladder carcinoma (MIBC) who are ineligible for cisplatin- based neoadjuvant chemotherapy (NAC). J Clin Oncol. 2019;37 (suppl 15):4551.Abstr 4551. doi: 10.1200/JCO.2019.37.15_suppl.4551.


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