No improvement in PFS with FrontlineOlaparib Plus Durvalumab Platinum-Ineligible Metastatic Urothelial Carcinoma

According to data from the BAYOU phase 2 trial (NCT03459846) that were presented to the Colloquium on genitourinary cancers 2022.

Data showed that the median investigator-assessed PFS with the doublet (n=78) in the intention-to-treat (ITT) population was 4.2 months (95% CI, 3.6-5.6 ) versus 3.5 months (95% CI, 1.9-5.1) with durvalumab alone (n=76; RR, 0.94; 95% CI, 0.64-1.39; log-rank P = 0.789).

However, data from a prespecified secondary analysis suggested that olaparib plus durvalumab had a potential benefit on PFS in a subset of patients with homologous recombination repair (HRR) mutations. In this population, the median PFS obtained with the doublet (n=17) was 5.6 months (95% CI, 1.9-8.1) versus 1.8 months (95% CI, 1.7 -2.2) with durvalumab monotherapy (n=14; RR: 0.18; 95% CI: 0.06-0.47; log-rank P

“The PFS results suggest a potential role for PARP inhibitors in the treatment of metastatic urothelial carcinoma with HRR mutations, and further investigation is warranted,” Jonathan E. Rosenberg, MD, Chief of Genitourinary Oncology in the Division of Solid Tumor Oncology, and Enno W. Ercklentz Chair at Memorial Sloan Kettering Cancer Center, said during an oral presentation on the data.

Patients with metastatic urothelial carcinoma are known to have a poor prognosis, especially those who cannot tolerate platinum-based chemotherapy, Rosenberg said. For these patients, atezolizumab (Tecentriq) and pembrolizumab (Keytruda) are administered, regardless of PD-L1 status; however, a high unmet need for additional treatment options remains.

DNA damage repair defects occur in approximately 24% of patients with urothelial carcinoma, and dysregulation of DNA repair genes has been associated with poorer outcomes. Notably, these defects are known to make cancer cells sensitive to PARP inhibitors. As such, the researchers hypothesized that HRR mutations and PARP inhibition might potentiate the antitumor response achieved with immune checkpoint inhibitors.

To this end, BAYOU sought to enroll approximately 150 patients with unresectable stage IV urothelial carcinoma, transitional cell carcinoma of the bladder, renal pelvis, ureter or urethra. Patients had to be at least 18 years old and have an ECOG performance status between 0 and 2.

Study participants were randomized 1:1 to receive either intravenous (IV) durvalumab at a dose of 1500 mg every 4 weeks plus oral olaparib at a dose of 300 mg twice per day or durvalumab alone. The main stratification factors included HRR status (mutant vs wild type) and Bajorin risk score (0 vs 1 vs 2).

The primary endpoint of the trial was PFS according to RECIST v1.1 criteria and investigator assessment. Primary secondary endpoints included PFS per RECIST v1.1 criteria in the subset of patients with HRR mutations, overall survival (OS), duration of response (DOR), objective response rate (ORR) and PFS at 6 months according to RECIST v1. 1 criteria in both the ITT population and the HRR mutated subset. Other end points of interest included safety and tolerability.

The data cut-off date was October 15, 2020. The median follow-up in the investigational arm was 9.8 months (range, 0.0-29.0) versus 10.7 months (range, 1.0-29 .0) in the control group.

Those who received the doublet were slightly older than those who received durvalumab monotherapy, with a median of 79 years (range, 47-89) versus 72 years (range, 45-88). Just over half of the patients in both arms were men. In the investigation group, 51% of the patients were white, 49% were Asian, and none were black or African American; in the control group, these rates were 46%, 51% and 3%, respectively.

Regarding ECOG performance status, 15% of patients who received olaparib plus durvalumab had a status of 0, 38% had a status of 1, and 44% had a status of 2. Of those who received durvalumab in monotherapy, 18% had an ECOG performance status of 0, 45% had a status of 1 and 37% had a status of 2. Most patients in both arms had pure transitional cell carcinoma.

In addition, 67% of patients who received the doublet had visceral metastases and 33% had nodal involvement only; these rates were 63% and 37%, respectively, in those who received monotherapy. In the investigation and control arms, 11.5% and 10.5% of patients, respectively, had received prior therapy.

In the investigation arm, 21% of patients had no Bajorin risk factors, 49% had 1 risk factor, and 31% had 2. In the control arm, 24% had no Bajorin risk factors. Bajorin risk, 47% had 1 and 29% had 2. Seventy-eight percent of patients in the doublet arm had wild-type HRR disease and 22% had mutated HRR disease; in the control group, these rates were 82% and 18%, respectively.

The 20 most common genetic mutations demonstrated a pattern that was found to be consistent with what has been observed previously in bladder cancer, according to Rosenberg. In all patients, the most common HRR gene mutations were loss of p53 function (59.5%) and TERT promoter mutations (55.6%).

Using the validated FoundationOne assay, researchers tested tumor samples for alterations in function in the following 15 predefined HRR genes: AT M, BARD1, CHEK1, PALB2, RAD51C, BRCA1, BRIP1, CHEK2, PPP2R2A, RAD51D, BRCA2, CDK12, FANCL, RAD51Band RAD54L. HRR mutations were found in 7 of the 15 genes analyzed. The most frequent included AT Mwhich was identified in 8.5% of all tumors and in 41.9% of patients in the HRR mutated subset, as well as BRCA2which was found in 4.6% of all tumors and in 22.6% of those in the mutated HRR subgroup.

Exploratory subgroup analyzes also showed that PFS favored olaparib/durvalumab over durvalumab alone in people with a Bajorin risk score of 0 (HR, 0.42; 95% CI, 0.18 -0.92). However, PFS appeared to favor durvalumab monotherapy over doublet in patients with HRR wild-type disease (HR, 1.29; 95% CI, 0.85-1.96), in those with a Bajorin risk score of 1 (HR, 1.90; 95% CI, 1.07-3.49), and in those with a Bajorin risk score of 2 (HR, 1.19; 95% CI, 0 ,63-2,28).

Data from the pre-specified secondary analysis of OS showed that olaparib plus durvalumab did not lead to improved OS compared to durvalumab monotherapy in the ITT population. Specifically, the median OS with the doublet was 10.2 months (95% CI, 7.0-13.9) versus 10.7 months (95% CI, 7.2-17.3) with the durvalumab alone (HR, 1.07; 95% CI, 0.72-1.61; log-rank P = 0.728).

The same was true in the subgroup of patients with HRR wild-type disease. Median OS with olaparib plus durvalumab (n=61) was 10.9 months versus 13.7 months with durvalumab monotherapy (n=62; HR, 1.35; 95% CI, 0.85-2.16 ). However, doublet (n=17) improved median OS in the subgroup of patients with HRR-mutated disease compared to monotherapy (n=14), at 8.6 months versus 5.8 months , respectively (RR 0.56; 95% CI, 0.25-1.23).

Adding olaparib to durvalumab resulted in an ORR of 28.2% in the ITT population versus 18.4% with durvalumab alone. In the investigation group, 3.8% of patients achieved a complete response, 24.4% had a partial response (PR), 34.6% achieved stable disease (SD) for at least 7 weeks, 32.1% experienced disease progression and 5.1% were not evaluable. . The median DOR in the investigation arm was 8.9 months (range, 4.7-12.1) versus 14.8 months (range, 7.5-17.2) in the control group.

In the mutated HRR subset, the combination produced an ORR of 35.3% versus 0% with durvalumab alone. Of those who responded to the doublet, 35.3% achieved PR and 29.4% had SD for 7 weeks or more. In addition, 29.4% had active disease and 5.9% were inevaluable. The median DOR with olaparib/durvalumab was 6.7 months (range: 3.7-12.0) in this subgroup.

No new safety signals were observed with the combination of olaparib and durvalumab, according to Rosenberg. Treatment-related adverse events of any grade were experienced by 72.4% of patients who received the doublet (n=76) vs 60.5% of those who received monotherapy (n=76).

The most common toxicities seen in the investigational group included anemia (any grade, 23.7%; grade 3 or 4, 6.6%), nausea (any grade, 19.7%; grade 3 or 4, 1.3%), fatigue (any grade, 15.8%). %; grade 3 or 4, 1.3%), decreased appetite (any grade, 10.5%), diarrhea (any grade, 10.5%), and hypothyroidism (any grade, 9.2%). In the control group, the most common toxicities included anemia (any grade, 13.2%; grade 3 or 4, 1.3%), pruritus (any grade, 10.5%), fatigue (any grade, 6.6%), rash (any grade, 5.3%), nausea (any grade, 3.9%), hypothyroidism (any grade, 3.9%).

One death was reported in the durvalumab monotherapy arm, and this was due to anemia.


Rosenberg JE, Park SH, Dao TV, et al. BAYOU: A Phase II, Randomized, Multicenter, Double-Blind Study of Durvalumab (D) in Combination with Olaparib (O) for the First-Line Treatment of Platinum-Ineligible Patients With Urothelial Carcinoma (UC) unresectable stage IV. J Clin Oncol. 2022;40(supplement 6):437. doi:10.1200/JCO.2022.40.6_suppl.437.

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