ASCO GU 2020: Emerging Therapies in RCC: From PARP Inhibitors to Novel Immunotherapeutics

San Francisco, California (UroToday.com) The Developing Management Options in Metastatic Renal Cell Carcinoma Session at the 2020 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) featured Dr. Tracy Rose who discussed novel immunotherapeutics and PARP inhibitors. A driving event in the pathogenesis of clear cell renal cell carcinoma (RCC) is inactivation of the VHL tumor suppressor gene. The VHL protein regulates the cellular response to hypoxia and VHL inactivation leads to stabilization of the alpha subunit of the hypoxia-inducible factor (HIF) family, leading to uncontrollable activation of HIF target genes. The (vascular endothelial growth factor) VEGF pathway is a key transcriptional target of hypoxia-inducible factor (HIF), and many approved therapies for RCC target this pathway.


HIF2-alpha regulates the expression of hundreds of hypoxia-associated genes – HIF2-alpha was once thought of as “undruggable”, however, is now discovered to contain a cavity that can bind inhibitors. HIF2-alpha inhibitors are now emerging in the clinical setting: 51 patients have been treated with PT2385 with an overall response rate (ORR) of 14%, and 55 patients have been treated with PT2977 with ORR of 24%. There is currently a Phase III trial underway testing PT2977 versus everolimus. According to Dr. Rose, there is still more work to be done, as acquired resistance mutations occur and on-target side effects have emerged including hypoxia.

Hypoxia broadly reduces DNA repair mechanisms and represses DNA double-strand break repair via homologous recombination deficiency (HRD) with downregulation of BRCA1 and RAD51. Since VHL loss acts a lot like hypoxia, it may also drive genomic instability. Indeed, in vitro studies suggest that VHL status correlates with the expression of HR associated genes and sensitivity to PARP inhibition. At first glance, the rationale for PARP inhibition in RCC is less clear than for other tumors, as classically RCC does not respond to DNA damaging strategies such as platinum-based chemotherapy or radiation. Furthermore, germline DNA damage repair (DDR) and MMR gene mutations are relatively uncommon. Poly (ADP-ribose) polymerase (PARP) inhibition has been most effective in tumors where synthetic lethality can be demonstrated. Inhibition of PARP leads to the accumulation of DNA single-strand breaks and eventually catastrophic double-strand breaks. Loss of either homologous recombination repair or inhibition of PARP is tolerated by the cell, but both result in lethality and catastrophic cell death. But, the question remains: Is the HRD and/or DNA repair defects in RCC enough to cause synthetic lethality with PARP inhibition in RCC?

BAP1 is intimately involved in DNA double-strand break repair, and BAP1 is a frequently mutated gene in RCC and is associated with a poor prognosis. BAP1 is a deubiquitinase that is required for efficient assembly of the HR factors after a double-strand break. BAP1 loss leads to tumors with homologous recombination repair deficiency and sensitivity to PARP inhibition.

Fumarate hydratase (FH) and succinate dehydrogenase (SDH) are thought to have a “BRCAness” phenotype due to loss of HR DNA repair. In patient-derived FH- and SDH-deficient RCC tumors, the levels of double-strand breaks are increased compared to normal kidney and other RCC tumors. The homologous recombination repair (HRR) deficient phenotype can be recapitulated by overexpression of fumarate or succinate in cells that are wildtype for FH and SDH. PARP inhibition shows profound sensitivity in patient-derived xenografts of SDH- and FH-deficient tumors. There is a rationale to combine PARP inhibition with immunotherapy in patients with DDR altered tumors. Increased DNA damage can lead to the activation of stimulator of interferon genes leading to immunogenicity. The presence of somatic and germline deleterious DDR gene alterations may associate with survival in immunotherapy but not TKI-related patients. There are several clinical trials with PARP inhibitors in progress:

clinical trials with PARP inhibitors in progress

Combination approaches of PARP and telaglenastat are targeted toward decreasing the cellular metabolic ability to repair DNA. Glutaminase converts glutamine to glutamate, which is used to drive the TCA cycle, make amino acids and nucleotides, and fuel cancer growth. Telaglenastat is an oral glutaminase inhibitor that could be potentially synergistic with PARP inhibitors due to a decrease in nucleotide pools and synergy in preclinical models. Initial Phase I data also shows tolerability and promising response rates for telaglenastat in combination with cabozantinib:

tumor burden over time

The CANTATA study has completed enrollment and is randomizing patients to telaglenastat (800 mg PO BID) + cabozantinib vs placebo + cabozantinib. The primary endpoint for this study is IRC-adjudicated progression-free survival (PFS) per RECIST v1.1 and secondary endpoints include overall survival (OS), and investigator-assessed PFS.

ENTRATA was a randomized Phase II study of telaglenastat + everolimus vs. placebo + everolimus in heavily pre-treated metastatic renal cell carcinoma (mRCC) patients, with initial results presented at ESMO 2019. Eligible patients for ENTRATA had ≥2 prior lines of systemic therapy for mRCC, including ≥1 VEGFR-targeted tyrosine kinase inhibitor, a Karnofsky performance status of ≥70%, and measurable disease (RECIST 1.1). The primary endpoint was investigator-assessed PFS (RECIST 1.1; 1-sided alpha <0.2). The trial schema for ENTRATA is as follows:

enrata phase II study design

There were 69 patients randomized, including 46 to telaglenastat + everolimus and 23 to placebo + everolimus. Approximately two thirds were intermediate/poor risk, ~90% had received prior immunotherapy, and the median number of prior treatments was three. The median PFS was 3.8  months for telaglenastat + everolimus compared to 1.9 months for placebo + everolimus (HR 0.64, 95% CI 0.34-1.20, 1-sided p = 0.079).

Sitravatinib also shows promise in combination with immune checkpoint inhibition in RCC. This molecular is a TKI targeting several receptors, including TAM, VEGFR, and c-Met. Sitravatinib synergizes with anti-PD1 preclinically and had an ORR of 39% among 38 patients when combined with nivolumab.

Dr. Rose concluded her presentation of novel immunotherapeutics in mRCC with several concluding points:

  • HIF inhibitors show promise, but where they will fit in a crowded treatment landscape is not clear
  • There is a rationale for PARP inhibition in RCC-based on preclinical studies, however, it remains to be seen if this will translate to clinical success. Combination approaches and patient selection for these studies should be thoughtful
  • Glutaminase inhibition may synergize the current strategies
  • New combinations with immune checkpoint inhibition are exciting
Presented by: Tracy L. Rose, MD, MPH, Assistant Professor of Medicine, Division of Hematology and Oncology, University of North Carolina, Chapel Hill, North Carolina

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California