Grivas Expands on Therapeutic Developments and Future Research Directions in GU Cancers

Petros Grivas, MD, PhD

As the body of research on immunotherapy and targeted therapy across genitourinary (GU) cancers continues to increase alongside improving understanding of genomics and disease biology, it is crucial to focus these efforts on the continued exploration of novel targets and optimizing immunotherapy approaches, according to Petros Grivas, MD, PhD.

“We are very excited about ongoing trials, and the progress being made in the field is tremendous,” Grivas said in an interview with OncLive® regarding a recent OncLive State of the Science Summit™ on GU cancers, which he had chaired. “We need to capitalize on the great momentum we have built and the knowledge coming from basic science, translational research, biology, and immunotherapy.”

In the interview, Grivas expanded on key research and future directions in prostate cancer and renal cell carcinoma (RCC) that his colleagues had discussed at the event. This included the role of single-agent and combination PARP inhibitor regimens in prostate cancer, as well as the importance of genetic testing in this setting. Grivas also touched on the potential role for adjuvant regimens in resected RCC, the continued exploration of doublet vs triplet regimens in the frontline setting, and salvage/second-line treatment in metastatic RCC.

Grivas is a physician and professor in the Clinical Research Division at Fred Hutch as well as clinical director of the Genitourinary Cancers Program and a professor in the Division of Medical Oncology at the University of Washington School of Medicine in Seattle, Washington.

OncLive: According to the presentations given by Tian Zhang, MD, MHS, and Michael Schweizer, MD, how has PARP inhibition redefined the standard of care in mCRPC?

Grivas: Dr Zhang and Dr Schweitzer both talked about the data regarding single-agent PARP inhibition with olaparib [Lynparza] or rucaparib [Rubraca], with corresponding FDA approvals in patients with metastatic castration-resistant prostate cancer [mCRPC], based on susceptible genomic alterations. The gene panel that is associated with the olaparib indication is broader, shorter, and much more restricted [than] rucaparib’s.

Dr Zhang and Dr Schweitzer went through the data from both the [phase 3] PROfound (NCT02987543) and TRITON3 [NCT02975934] trials. They also presented data on combinations of novel anti-androgen therapy plus PARP inhibition. For example, we discussed the data from the [phase 3] PROpel [NCT03732820], MAGNITUDE [NCT03748641], and TALAPRO-2 [NCT03395197] trials. They went through the nuances of efficacy and toxicity data, as well as details of the FDA and European Medicines Agency approvals—there are some differences in the indications between [these regulatory bodies].

They also went through details and scenarios where they could envision using the combination. It can be hard to apply the data in patients who already have received a novel anti-androgen therapy for hormone-sensitive disease. For example, if a patient received abiraterone acetate [Zytiga], apalutamide [Erleada], or enzalutamide [Xtandi] for hormone-sensitive metastatic prostate cancer, these data are hard to apply in the mCRPC setting because patients were already exposed to a novel anti-androgen. There were many good discussions about [such] scenarios, pros and cons of these relevant and important trials, challenges with trial designs, and key data. [We also discussed] ongoing trials looking at these interesting combinations.

How does genetic testing improve the navigation of the current therapeutic landscape?

We need to make sure we have next-generation sequencing [NGS] performed in all patients with metastatic prostate cancer. We went through some details about primary vs metastatic tumor tissue testing. Metastatic [tissue] is ideal, but sometimes it’s hard to retrieve or get a biopsy. Primary tissue can be acceptable, especially if metastatic tissue is not available. If you have both, you may get complementary information.

In addition to tumor tissue, circulating tumor DNA [ctDNA] can be a source of somatic tumor NGS for those patients and sometimes it can give complementary information to tumor tissue. We try to use both tumor tissue genomic sequencing and ctDNA at the University of Washington, but cDNA seems to have a higher yield in patients with higher prostate-specific antigen [PSA] and there is some correlation with cancer burden. Accordingly, we will send for ctDNA in those with higher PSA [levels]. [For] those with poorly differentiated prostate cancer that does not make much PSA, we may still send [for] ctDNA.

We also discussed the importance of germline testing. That is very important for treatment selection for potential PARP inhibition and for broader family cascade testing, cancer prevention, screening, [and so on]. We also talked about the implications based on the FDA approvals of olaparib and rucaparib. Dr Schweitzer tends to use either of those agents before chemotherapy based on their [approvals] and [in this scenario], the patient [typically] does not need chemotherapy. There will be rare scenarios [in which] he would use a combination of novel anti-androgen therapy and PARP inhibition. Dr Zhang was more open to using the combinations in patients with high disease burden or symptomatic visceral metastases that didn’t respond right away, especially if they did not have prior anti-androgen therapy and did have a relevant DNA repair gene alteration. These patients can benefit more from PARP inhibitors based on the data.

It comes down to patient selection and careful review of the literature, but these discussions continue to evolve. We’re very glad to have had the opportunity to discuss these nuances in our excellent State of the Science Summit.

As per the presentation by Lisa Tachiki, MD, what is the potential for adjuvant immunotherapy in resected RCC?

Dr Tachiki set the stage [with a] historical perspective on adjuvant TKI trials and [followed up with] the plethora of adjuvant immunotherapy trials in RCC, but most of those patients had clear cell RCC [ccRCC]. We outlined the need for more trials in non-ccRCC. Dr Tachiki discussed the phase 3 KEYNOTE-564 trial [NCT03142334] showing both disease-free survival [DFS] and overall survival [OS] benefit [with adjuvant pembrolizumab vs placebo]. This trial led to the FDA approval of adjuvant pembrolizumab in resected RCC.

We also discussed a plethora of adjuvant trials [that did not meet their primary end point], and why that happened. [This included the] adjuvant trial of ipilimumab [Yervoy] and nivolumab [Opdivo], the adjuvant atezolizumab [Tecentriq] trial, [and] the phase 3 PROSPER-RCC trial [NCT03055013]. These trials have tempered a little bit of enthusiasm for adjuvant immunotherapy for some patients. However, the results from KEYNOTE-564 are very strong. It’s a clean trial, with a clear DFS and OS benefit, and it was well designed. The consensus based on the trial criteria [was that] adjuvant pembrolizumab is being offered by [our discussants] in clinic for high-risk patients.

[Lastly], we discussed ongoing and future trials [assessing] whether there’s any potential use for adjuvant combination therapies. More trials [of these regimens] and more biomarkers are needed to properly select patients [who will benefit most].

How has the use of frontline doublets and triplets in metastatic RCC evolved as per the presentation from Scott Tykodi, MD, PhD?

There is so much ground to cover in the frontline setting. We have different doublets, such as ipilimumab and nivolumab, showing significant benefit over sunitinib. We also have the other trials with cabozantinib [Cabometyx] and nivolumab, pembrolizumab and axitinib [Inlyta] or lenvatinib [Lenvima], and so on. Dr Tykodi went through all the data, nuances, details, and logistics of those trials. He also discussed [the investigation of] triplet vs doublet therapy in the [phase 3] COSMIC-313 trial [NCT03937219] of ipilimumab and nivolumab plus cabozantinib vs placebo. This trial was positive for progression-free survival [PFS], meeting its coprimary end point. However, our consensus was that there was a lack of enthusiasm for using the triplet in clinical practice because of lack of OS benefit and significant toxicity. Everybody still applauded the effort and agreed that we need ongoing trials in the frontline setting. We covered some of those and we’re waiting to see what will happen in the future.

[Lastly], we discussed data from the [phase 3] CONTACT-03 trial [NCT04338269] presented recently. Patients who experienced progression [while receiving] immunotherapy as their immediate prior therapy for metastatic RCC received cabozantinib plus atezolizumab vs cabozantinib alone. Data from this trial [did not show any] benefit from continuing immunotherapy in those patients who have prior progression [while receiving] immunotherapy. They can instead switch to a different agent, such as another TKI, based on the physician’s preference. Despite [failing to meet its primary end point], CONTACT-03 was important to answering this question in this field.

What recent developments have occurred in the second line and beyond for patients with metastatic RCC as discussed in the presentation given by Evan Hall, MD, MPhil?

Dr Hall discussed the CONTACT-03 trial in much detail and then discussed the ongoing [phase 3] TiNivo-2 trial [NCT04987203] with a similar design. This ongoing trial [is evaluating] tivozanib [Fotivda] plus nivolumab vs tivozanib and trying to [determine the viability of] immunotherapy rechallenge in metastatic RCC. He also discussed data on tivozanib and belzutifan [Welireg] monotherapy.

Belzutifan received FDA approval in [pretreated advanced RCC] based on the [phase 3] LITESPARK-005 trial [NCT04195750]. The agent showed significant benefit in PFS compared with everolimus [Afinitor]. We then discussed the patient characteristics, design, and end points of the trial. We also discussed some differences in toxicity between tivozanib and belzutifan. [Lastly], we outlined the need for additional trials looking at combinations, single agents, and biomarkers to try to select the right treatment for the right place at the right time.

What ongoing or planned research in GU cancer are you most excited about?

We need to involve patient advocacy groups in trial designs, regulations, and policies, [and we must] request more funding across the board for GU cancers. [There should also be more exploration of] novel targets, immunotherapy agents and [combination] approaches, potential antibody–drug conjugates, and novel imaging. [Additionally], the field of theragnostics is developing rapidly. We also discussed the importance of germline mutation testing for prostate cancer, urothelial cancer, and RCC. Cascade testing and cancer prevention strategies are important for the patient and their broader family.