Challenges Remain Amid Advances in RCC and Prostate Cancer

David I. Quinn, PhD, MBBS

An increased understanding of the molecular markup of renal cell carcinoma (RCC) has allowed investigators to develop effective targeted therapies, but there is still a wealth of knowledge needed before patients can truly receive individualized treatment approaches, said David I. Quinn, PhD, MBBS.

In just the last few years, the frontline setting of advanced RCC has undergone a massive shift from single-agent VEGF TKIs to combination checkpoint inhibition, to, most recently, the combination of PD-1 inhibitors and VEGF TKIs. With the absence of a reliable biomarker, investigators are left with a new challenge of deciding which patients will benefit from which strategy, said Quinn, an associate professor of medicine and section head of Genitourinary Oncology, Division of Cancer Medicine and Blood Diseases in the Department of Medicine, at University of Southern California, Keck School of Medicine.

For example, in the JAVELIN Renal 101 study, investigators looked at the combination of avelumab (Bavencio) and axitinib (Inlyta) in patients with metastatic RCC. The results showed that the combination significantly improved progression-free survival and doubled the overall response rate compared with standard sunitinib (Sutent), but the benefit was seen irrespective of PD-L1 status and risk stratification. As such, where this combination fits into the treatment paradigm with other encouraging regimens is still unclear.

OncLive: How much is known about the biology of RCC?

In an interview with OncLive, Quinn discussed the molecular diagnosis of RCC and also highlighted emerging therapies in the treatment of patients with different subtypes of prostate cancer.Quinn: It's important for us to understand that the modern therapeutics that are available in RCC are predicated on what we've learned about the molecular makeup of the cancer. RCC is particularly driven by pathways such as angiogenesis, mTOR, and an altered immune system that is targetable in most cases. Those 3 factors are very significant when it comes to understanding the therapy of RCC. They are also important when it comes to understanding some underlying principles of treatment. When you're looking at a diagnosis of someone with RCC, that patient might have an underlying germline alteration that will distinguish the behavior of the cancer and some of the treatment. There are particular clinical characteristics that could help us there, but then we have to get the patient tested, counseled, and followed up.

What are the pathways and targets that have shown the most promise in terms of being paired with treatment?

Where do we stand in terms of identifying biomarkers in RCC?

The other issue is the question of whether or not biomarkers in RCC tissue currently help us inform treatment at the moment. The answer is that they don't, but there are some very important proofs of principle related to different therapies that are starting to emerge.For a long time, we have looked at the VEGF-targeted agents, mainly the VEGF TKIs. First, we had sorafenib (Nexavar) and sunitinib approved by the FDA for RCC, and then we have had a subsequent plethora of agents that target either VEGF or other specific pathways. For example, cabozantinib (Cabometyx), a more recently approved agent, also targets MET and AXL. We've been looking to tie those molecular alterations up with therapies that target them. We have seen limited success over the last 20 years or so. For example, we've looked at hypoxia-inducible factor-2 in patients treated with sunitinib. Initial results from a small study suggested that would help us but in actuality, it doesn't. The truth is in the totality of the assessment. It probably isn't going to be an individual molecule that will help us—more likely it will be patents and signatures.At the moment, we're not doing very well. We may end up with a situation where we need to have a marker in order to give certain therapies, such as PD-L1 expression or elevation in the tumor-infiltrating immune cells. However, that’s not certain as of yet. If an oncologist is given the opportunity to use a biomarker or not, they generally will not, unless there is a big advantage to using that marker.

Transitioning to prostate cancer, what novel hormonal therapies are on the rise?

From that perspective, biomarkers are not in common use. What we have seen from a series of studies evaluating different combinations of immunotherapies and VEGF TKIs is an emergence that there are signatures for patients who will do well with each therapy. The tantalizing thing is that the combination of these drugs may help us overcome intrinsic resistance that is present in RCC. However, that’s just postulated at this stage and needs to be proven. Interestingly, we may actually see that proof-of-concept come through in some recent studies.The hope for these therapies has been to try to move them earlier in treatment. We have seen that in 2 broad fronts with a multitude of studies, and still more to come. In these studies, we are giving the agents that were previously FDA approved in castration-resistant prostate cancer (CRPC) to patients with hormone-sensitive disease. We are seeing an advantage in survival that is fairly significant. We now have data with several different agents. The first set of data we saw were with abiraterone acetate (Zytiga) in patients with high-risk hormone-sensitive disease in the LATITUDE study, where there is an improvement in survival equivalent to giving docetaxel to those patients. Therefore, that became a new option for that group of patients.

In the STAMPEDE study, investigators also documented that the use of abiraterone in a broader group of patients resulted in a major benefit, particularly in high-risk patients. From that perspective, the question is, “Do we give abiraterone to everyone who has hormone-sensitive prostate cancer?” I would argue that we probably should [be cautious] in low-risk patients because the risk-benefit ratio may not be quite what we think it is. Those patients do have an excess risk of complications, particularly cardiovascular, from being on abiraterone. We've seen that in the STAMPEDE study. Therefore, we've made some advances and these drugs are being brought into earlier lines. Abiraterone is about to become generic in the United States, so it will be cheap. We will also have choice.

Where will darolutamide fit into the nonmetastatic CRPC treatment paradigm?

We've seen great data with some of the androgen receptor inhibitors, such as enzalutamide (Xtandi), apalutamide (Erleada), and now darolutamide. Data from some of those studies have been presented, while some of them we know only through press releases. We are hoping to see new data read out at upcoming meetings in 2019 and 2020. Early usage is going to be important; we just need to be a little bit selective about how we do it. Whether one drug will be better than the other for an individual patient is going to be the subject of a lot of debate.I think it will be approved by the FDA; the place where these drugs are also being approved is in nonmetastatic CRPC. We've seen an extension of indications for enzalutamide and apalutamide based on data from the PROSPER and SPARTAN trials. Now, we are seeing similar data from the ARAMIS study, which was presented at the 2019 Genitourinary Cancers Symposium, showing an advantage to darolutamide that looks similar to the other drugs.

Is there a role for immunotherapy in prostate cancer?

The interesting thing about darolutamide is that it doesn't penetrate the CNS. For many patients who are going on to these drugs, the CNS effects with cognitive issues and frailty may be due to the drugs penetrating the CNS. We are going to have to see if darolutamide has a significantly lower rate of those adverse events. As such, I see darolutamide being approved by the FDA and competing with the other drugs being used in the nonmetastatic CRPC setting as well as those in hormone-sensitive prostate cancer. If we want to use it later, maybe it will also have a role in metastatic CRPC.We need immunotherapy. We have proof of principle with sipuleucel-T (Provenge), which is now a decade old; this drug was probably underutilized and misunderstood. The checkpoint inhibitors are interesting. In a small percentage of patients, they seem to produce really marked, durable responses. This is interesting and encourages us to try to experiment. We know that if a patient has a microsatellite instability-high tumor, or if they have mismatch repair deficiency and Lynch syndrome, they might do well with checkpoint inhibitors.

There is an FDA approval for pembrolizumab (Keytruda) across the board for those patients. Beyond that, we don't know how to select. We have seen some cohort studies that suggest that there is interesting combination activity; for example, with pembrolizumab and hormonal agents. The problem is that assessing the impact of immunotherapy is probably best done with OS because assessing intermediate endpoints in prostate cancer is difficult.

Motzer RJ, Penkov K, Hannen JBAG, et al. JAVELIN Renal 101: a randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA6_PR.