Analysis of Genomic Alterations in Metastases Moves Research Toward Personalized Approaches in RCC

Rana R. McKay, MD

Research into mutations associated with various sites of disease could provide valuable insight into optimal treatments for patients with renal cell carcinoma (RCC), according to Rana R. McKay, MD.

“The sites of metastases have different genomic underpinnings compared with the kidney, and that could impact outcomes,” said McKay, a medical oncologist and associate professor of medicine at Moores Cancer Center, UC San Diego Health, in California.

In an interview with Targeted Therapies in Oncology™ (TTO) during the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), McKay discussed findings from a real-world study on genomic alterations of metastases in RCC,¹ further research in the RCC field, and findings from the phase 1/2 COMRADE trial (NCT03317392) in patients with metastatic castration-resistant prostate cancer (mCRPC).²

Targeted Therapies in Oncology: Could you provide an overview of the real-world data set you presented at ASCO GU that analyzed genomic alterations and transcriptional signatures across the spectrum of metastatic sites in patients with RCC?

MCKAY: We know from several large databases that the site of metastasis is prognostic in RCC. We and others have demonstrated that bone and liver metastases are associated with worse prognosis, and pancreas metastases are associated with better prognosis. We are lacking underlying data as to why that is. Why does the site of metastasis matter?

We sought to utilize a commercial database through [Caris Life Sciences] of RCC tumors from primary and distant metastases to comprehensively characterize the molecular features across sites of metastases.

Our analysis was 3-pronged in nature. We looked at mutations and polymorphisms initially using a 592-gene panel and whole-exome sequencing. We did whole-transcriptome sequencing and PD-L1 expression [testing] on [more than] 650 distinct samples.

We identified that there are mutations and [that in] the distribution of mutations of selected genes across different metastatic sites there are common mutations that exist in kidney cancer, whether they are in the primary [tumor] or in the metastasis. Those are VHL mutations, PBRM1, SETD2, and KDM5C.

We also realized that there are differences when you look at the various sites compared with the kidney, and we did observe that PBRM1 alterations were more frequent in the lung, bone, [and] endocrine glands relative to the kidney. SETD2 seemed to be more prevalent in lung and gastrointestinal [GI] metastases. P53 was more prevalent in the bone and central nervous system [CNS], and P10 was more prevalent in liver and CNS [metastases].

The other thing we did was look at the [phase 3 IMmotion151 trial (NCT02420821) led by Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, which examined] gene clusters across the different sites of metastasis. We [saw] differences in the molecular subgroup classifications between primary and metastatic sites. As we look at the breakdown more granularly, lung, bone, liver, skin, and GI metastases seem to have divergent molecular subtypes relative to the kidney, lung, and bone, [which] were enriched for the angiogenic stromal signature, whereas liver [tissue] seemed to be more enriched for the complement/Ω-oxidation signature.

That is important because these signatures have been associated with differential outcomes to treatments. For example, the angiogenic stromal signature seems to be associated with a more robust response to tyrosine kinase inhibitor–based therapies, whereas a T-effector proliferative signature seems to be associated with a more robust response to immunotherapy. The complement/Ω-oxidation signature, for example, is one of those signatures that has been shown to be associated with poor outcomes in general.

As we think about the application of [these] data, understanding the molecular underpinnings for organotropism is going to help us personalize strategies for patients with kidney cancer in the future.

What are the next steps toward applying these data?

[Clinical outcomes are] lacking from this data set right now. We do not have the overlay of “How did these patients do in this data set? How did those patients with bone metastases that had X signature do with immunotherapy? How did they do with targeted therapy?” Applying the clinical outcomes will help us understand how to optimize therapy selection based on sites of metastases for any given patient.

What should be emphasized about the study results?

Although there are some similarities between the kidney and distant metastatic sites when we are looking at various genes of interest, there are key differences with the predominance of select genes in different metastatic sites relative to the kidney. There are differences between the gene signatures in different metastatic sites relative to the kidney and the tumor microenvironment, which could play a role with regard to treatment outcomes.

What has it been like to see research advance at such a fast pace in RCC?

Over the past almost 2 decades, we have seen the life expectancy for patients with advanced kidney cancer lengthen and lengthen and lengthen, and that is because of advances in the therapeutic paradigm, which is excellent to see. We still have work to do, but it has been exciting to be a part of that process.

Are there any specific areas within RCC that warrant additional research?

The big question is what to do in the adjuvant setting. We saw data at the symposium that were presented from the phase 3 KEYNOTE-564 study [NCT03142334] with updated 30-month follow-up of the effi - cacy of pembrolizumab [Keytruda] given in the adjuvant setting. There are a lot of questions around the role of adjuvant immunotherapy. What is the right patient population? [Should we give a] single agent or can we combine [agents in the adjuvant setting]?

These are the next questions in the field. For patients who have received adjuvant immunotherapy, what is the best frontline option for them? Do the data of all the [immunotherapy] combinations in frontline studies still apply to somebody who is not naïve to checkpoint inhibitors and has progressed despite checkpoint inhibitors? As the treatments improve, new questions come up, and the landscape is shifting.

Are there any other clinical trials you want to highlight?

We presented the data about the differential outcomes for sites of metastases, and historically patients with bone metastases have done poorly in kidney cancer. We have designed a study that is looking at cabozantinib with or without radium-223 [Xofi go] to see if we can improve symptomatic skeletal-related events with the combination. The phase 2 RadiCaL trial [NCT04071223] is open through the cooperative groups being led through Alliance. We are eager to promote the study and encourage involvement.

You also presented a poster at ASCO GU on the phase 1/2 COMRADE trial, which examined olaparib (Lynparza) and radium-223 dichloride in mCRPC. Would you provide an overview of this study?

This was a trial looking to assess the potential synergy of radium-223, which is an α-emitting radiopharmaceutical that induces DNA damage with olaparib, a PARP inhibitor that prevents repair of single-strand DNA breaks within the tumor. The trial was designed as a phase 1/2 study. Phase 1 [was designed] to test the safety of the combination and the recommended phase 2 dose [RP2D] for olaparib when olaparib is given in combination with radium-223. Phase 2 was designed to test the efficacy [of the combination].

Phase 1 has been completed, and [in] the data presented at the symposium we identified that olaparib when combined with radium223 was safe and that the RP2D was 200 mg twice daily. In our data set, we presented the correlative data for all 12 patients who had enrolled onto the phase 1 portion of the trial. Patients underwent genomic testing to define their homologous recombination repair [HRR] gene status. Of 9 patients who had enough tissue to be profiled, 2 were found to have pathogenic HRR gene alterations. One was in BRCA2 and 1 was in CDK12. The patient who had the BRCA2 alteration had a progression-free survival [PFS] of 11.8 months compared with 3.1 months for the patient with the CDK12 alteration.

[We also looked] at RAD51 staining in archival tumor specimens. These are still early [data], but there was an individual with a CTNNB1 alteration that was negative for RAD51, which is a functional readout of HRR, suggesting that there is a homologous recombination deficiency. That individual had a PFS of 10.2 months.

The summary here is that olaparib and radium-223 can be safely combined. We have identified the RP2D for the 2 drugs in combination, and there are biomarkers being developed to try to understand responses to therapy and enriching responses.

What are the next steps for this combination?

Phase 2 is accruing patients. We have [approximately] 60 patients who have enrolled onto the phase 2 study. There will be an upcoming interim analysis to look at efficacy with radiographic PFS as a key primary end point for the trial. The results of the randomized phase 2 portion hopefully will be telling regarding next steps and moving this combination forward.

How could positive data from the phase 2 trial affect the treatment paradigm?

A lot of studies are looking at the combination of PARP inhibitors with various agents that have already demonstrated efficacy in prostate cancer. Data were presented with abiraterone acetate [Zytiga] combined with olaparib at this year’s meeting, and olaparib and other PARP inhibitors are being combined with other agents. There is a potential for synergy with olaparib and radium-223 in a safe manner. That could be practice changing, but it is still very early.

REFERENCES

1. McKay RR, Barata PC, Elliott A, et al. Molecular alterations across sites of metastasis in patients with renal cell carcinoma (RCC). J Clin Oncol. 2022;40(suppl 6):287. doi:10.1200/JCO.2022.40.6_suppl.287

2. McKay RR, Xie W, Ajmera A, et al. Updated biomarker results from a phase 1/2 study of olaparib and radium-223 in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases (COMRADE). J Clin Oncol. 2022;40(suppl 6):119. doi:10.1200/ JCO.2022.40.6_suppl.119