ASCO GU 2020: Rucaparib for Recurrent, Locally Advanced, or Metastatic Urothelial Carcinoma (mUC): Results from ATLAS, A Phase II Open-Label Trial

San Francisco, California (UroToday.com) PARP inhibitors have recently gained popularity for patients with pathogenic DNA damage repair gene mutations for a variety of cancers including prostate cancer, ovarian cancer, and pancreatic cancer. In prostate cancer, Olaparib very recently gained FDA approval on January 21, 2020, for the treatment of men with metastatic castration-resistant prostate cancer and homologous recombination repair gene mutations who progressed on treatment with a new hormonal agent based on the phase 3 PROfound study. In PROfound, the median radiographic progression-free survival was 7.39 months vs 3.5 months representing a 66% reduction in the risk of disease progression or death for patients harboring a BRCA1, BRCA2, or ATM alteration.1 For ovarian cancer, there are three PARP inhibitors approved (olaparib, rucaparib, and niraparib) both in the metastatic setting as well as maintenance setting.2 For pancreatic cancer, the FDA just recently granted olaparib approval for the maintenance therapy for patients with germline BRCA-mutated metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.

For muscle invasive bladder cancer, DNA damage repair (DDR) gene alterations can be seen in 30% - 60% of patients.3 Frequent somatic alterations have also been observed in BRCA1 associated protein-1 (BAP1).Given that PARP inhibitors have demonstrated success targeting these pathways in other cancers, it is reasonable to evaluate PARP inhibitors in bladder cancer.

Summary

ATLAS is phase II open-label study of rucaparib in patients with locally advanced or metastatic urothelial carcinoma (mUC).

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Patients with and without genomic loss of heterozygosity were recruited. Rucaparib was dosed at 600 mg BID. The primary endpoint of this study was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (defined as genomic loss of heterozygosity ≥10%) populations. Clinical benefit rate was defined as an objective response or stable disease lasting 16 weeks or greater.

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97 patients were enrolled in the study. Baseline characteristics are shown below.

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The majority of patients were men (78%) with a performance status of ECOG 1 (67%). 68% of patients had previously been treated with platinum-based chemotherapy and immunotherapy. 20.6% of patients were defined as HRD positive, 30% HRD negative, and 48% were HRD unknown. There were no confirmed responses and 28% of patients had a best response of stable disease.

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Median progression-free survival was 1.8 months.

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Clinical activity did not correlate with HRD status. The most common adverse events were fatigue (57%), nausea (41%), and anemia (35%).

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Conclusions

Rucaparib did not demonstrate a meaningful clinical benefit for patients with metastatic urothelial carcinoma.  

Presented by: Petros Grivas, MD PhD, Associate Professor, Clinical Director of Genitourinary Cancers Program, University of Washington, Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center

Written by: Jason Zhu, MD. Medical Oncologist, Division of Genitourinary Cancers, Levine Cancer Institute Twitter: @TheRealJasonZhu at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California

References:

  1. Hussain M, Mateo J, Fizazi K, et al. LBA12_PR - PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations. Annals of Oncology 2019;30:v881-v2.
  2. Jiang X, Li W, Li X, Bai H, Zhang Z. Current status and future prospects of PARP inhibitor clinical trials in ovarian cancer. Cancer management and research 2019;11:4371.
  3. Pietzak EJ, Bagrodia A, Cha EK, et al. Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets. European Urology 2017;72:952-9.
  4. Nickerson ML, Dancik GM, Im KM, et al. Concurrent Alterations in;, and the BRCA Pathway in Bladder Cancer. Clinical Cancer Research 2014;20:4935.