PARP inhibitors in Urothelial carcinoma (UC): Hit or miss?

Chemotherapy, immune checkpoint inhibitors, targeted therapies, and antibody-drug conjugates are being used for treating Urothelial Carcinoma(UC) patients and now PARP inhibitors are being studied in UC in the neoadjuvant, first-line, maintenance therapy, and subsequent lines of the setting. It is worth noting that PARP inhibitors have precedence of failure in earlier trials in Urothelial Carcinoma. The data from ATLANTIS, BAYOU, and Meet-URO12 Trials in Urothelial Cancer were presented at ASCO GU 2022. 

Lynparza in combination with Durvalumab fails to impress in platinum ineligible metastatic Urothelial Carcinoma patients: Data from BAYOU trial

As per the data from the phase II BAYOU trial (NCT03459846) presented at the 2022 ASCO GU symposium, after the median follow-up of 9.8 months, the median investigator-assessed PFS with doublet in the intent-to-treat (ITT) population was 4.2 months compared to 3.5 months with Durvalumab alone. Surprisingly, the data from secondary analysis suggested that the doublet had a potential PFS benefit in a subgroup of patients with homologous recombination repair (HRR) mutations. In this population, the median PFS achieved with doublet was 5.6 months vs. 1.8 months with single-agent Durvalumab.

As analyzed in PARP inhibitors making inroads towards the first line metastatic Castrate-resistant prostate cancer (CRPC) market soon? Lynparza demonstrated the longest rPFS in mCRPC patients, but incase of UC, the drug failed to even achieve its primary endpoint of PFS in platinum-ineligible patients suffering from metastatic urothelial cancer. However, we look forward to its efficacy in HRR mutant patients.

“The combination of Durvalumab and olaparib does have activity in HRR-mutant patients compared to Durvalumab [alone], but it’s unclear if this would be superior to PARP inhibitor monotherapy.” – Expert Opinion

Rubraca (rucaparib) in ATLANTIS trial extended PFS but not significantly in DNA repair deficiency biomarker-positive patients with metastatic urothelial carcinoma 

The treatment options available to patients with urothelial cancer after first-line chemotherapy are very limited, and it remains unclear whether targeting DNA damage repair with PARP inhibitors will result in meaningful single-agent activity in patients. Similar to BAYOU trial, this study was also unable to meet the primary endpoint of progression-free survival. Although Rucaparib did not show a significant improvement in PFS or OS with Rubraca (Rucaparib), the trial’s findings suggest that Rucaparib could play an important role in the maintenance treatment of patients with metastatic urothelial cancer who have responded to first-line platinum-based chemotherapy because the treatment was tolerable. In the ATLANTIS trial, Rucaparib treatment resulted in a median PFS of 35.3 weeks for Rucaparib versus 15.1 weeks for placebo.

“Further investigation of PARP inhibition is warranted in urothelial carcinoma within a molecularly-selected group of patients” – Expert Opinion

3) Meet-URO12 Phase II Study of Zejula (Niraparib) did not improve PFS following initial platinum-based chemotherapy 

At ASCO GU 2022, another PARP inhibitor setback was disclosed. PARP inhibitors are failing back-to-back in the same setting where Bavencio (avelumab) is thriving and regarded as a standard. As of August 2021, Niraparib as maintenance treatment in advanced urothelial carcinoma has a median PFS of 2.1 months and a 6-month progression-free rate of 28.2 percent. 

Analyst opinion: The latest findings of the ATLANTIS, BAYOU, and Meet-URO12 trials were similar to the results of the ATLAS (Rubraca monotherapy in patients who had previously received two lines of therapy) and BISCAY (Lynparza plus Imfinzi in patients who had previously received platinum-based chemotherapy), both of which failed to show a meaningful benefit. Rucaparib did not show significant activity in ATLAS study in unselected patients with advanced urothelial carcinoma regardless of HRD status. In both genomically selected and unselected patients in BISCAY trial, response rates of Lynparza were modest (35.7% and 9.1%, respectively). In the Atlantis trial, although the PFS with Rubraca was roughly doubled, it was still not significant, and the OS was not met. In individuals with urothelial carcinoma, both Niraparib and Lynparza fail to impress. To summarize, there are many more questions about PARP inhibitors in Urothelial carcinoma that need to be resolved, and only future research will be able to assess their potential alone or in combination. More research on the effects of PARP inhibition in urothelial carcinoma is needed to fully understand their role in this disease type.