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PARP Inhibition for Urothelial Carcinoma… Enrichment or Combinations?

We are now using PARP inhibitors for DNA repair-deficient patients with breast, ovarian, fallopian tube or primary peritoneal cancer.  In the realm of genitourinary oncology, we are meticulously exploring PARP inhibition, particularly for enriched patient populations with prostate cancer.  This is due to the fact that DNA repair deficiency occurs in approximately 23% of men with metastatic castration-resistant prostate cancer,1 and approximately 12% of men with metastatic prostate cancer harbor germline alterations.2 Therapy for these patients who harbor biallelic loss in a DNA repair gene, such as BRCA2, is beginning to take advantage of synthetic lethality when the single-strand repairing PARP protein is inhibited with a PARP inhibitor.  Agents like olaparib, rucaparib, niraparib and talazoparib are all currently being explored for prostate cancer and offer serious promise in the near future for these men.

But is there a strong rationale for patients with urothelial carcinoma?  A recent analysis performed at Memorial Sloan Kettering initially found 19% of patients with urothelial carcinoma to harbor pathogenic or likely pathologic DNA repair alterations.3  An expanded cohort of 176 patients with either muscle-invasive or metastatic urothelial carcinoma, which was presented at ASCO 2018, reveals the pathogenic or likely pathogenic alteration DNA damage repair germline mutation rate to be 29% in patients overall, with 13% in those with bladder primaries.4  This is rather impressive and surprising data, and it begs for validation in other centers with different patient populations. 

This data may have implications beyond PARP inhibition and may even portend respond to checkpoint inhibitors, as metastatic urothelial cancer patients harboring DNA repair deficiency have recently been shown to have a higher response rate to PD-1/PD-L1 blockade.5   These results are not surprising, given the increased mutational burden and increased number of tumor-infiltrating lymphocytes seen in breast and ovarian tumors harboring DNA repair deficiency.6, 7  Additionally, there is data in breast cancer that supports induction of PD-L1 expression after exposure to a PARP inhibitor.8

In genitourinary malignancies, prostate cancer continues to lead the charge with multiple ongoing PARP inhibitor phase 2 and 3 trials.  Additionally, there are a growing number of combination trials with PARP inhibitor plus PD-1/PD-L1 antibody therapy.  Urothelial cancer is now starting to follow these trends, given the exciting early findings described above.  As a result, there are clinical trials exploring either single agent PARP inhibition or PARP inhibition combined with PD-L1 blockade.  Currently, most trials are studying unselected patient populations.  Although we have potential to see interesting results, as PARP inhibitor is known to have other potential mechanisms of action, the field is moving rapidly towards enrichment trials.  With next-generation sequencing testing of tumors becoming more commonplace, identified DNA repair deficiency is likely to be mandated for trial eligibility in most new trials.  In the meantime, we must further the knowledge by enrolling in the trials highlighted below, which are a mix of unselected, a combination with PD-L1, and early enrichment trials.

Highlighted Urothelial Cancer PARP Inhibitor Trials

  • Rucaparib (NCT03397394) ATLAS
  • Olaparib + Durvalumab (NCT02546661) BISCAY
  • Olaparib + Durvalumab in cisplatin-ineligible patients (NCT02516241) BAYOU
  • Olaparib in patients with DNA Repair Deficiency (NCT03375307) 
  • Olaparib in Patients with Metastatic Urothelial Cancer Harboring DNA Damage Response Gene Alterations (NCT03448718)

References

  1. Robinson D et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015 May 21;161(5):1215-1228.
  2. Pritchard CC et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. 
  3. Carlo MI et al Cancer predisposing germline mutations in patients (pts) with urothelial cancer (UC) of the renal pelvis (R-P), ureter (U) and bladder (B). Carlo MI et al.  J Clin Oncol35, 2017 (suppl; abstr 4510).
  4. Carlo MI et al.  J Clin Oncol 36, 2018 (supple; abstr 1516). 
  5. Teo MY et al. Alterations in DNA Damage Response and Repair Genes as Potential Marker of Clinical Benefit From PD-1/PD-L1 Blockade in Advanced Urothelial Cancers. J Clin Oncol. 2018 Jun 10;36(17):1685-1694.
  6. Nolan E et al. Combined immune checkpoint blockade as a therapeutic strategy for BRCA1-mutated breast cancer. Sci Transl Med. 2017 Jun 7;9(393).
  7. Strickland KC et al. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget 2016; 7:13587-98.
  8. Jiao S et al. PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression. Clin Cancer Res. 2017 Jul 15;23(14):3711-3720.

Written by: Evan Yu, MD