Challenges Remain in Prostate Cancer Paradigm

Walter M. Stadler, MD

Following the wave of FDA approvals in prostate cancer, Walter M. Stadler, MD, explained that the field has undergone a dramatic transformation, but research should be focused on immunotherapy, sequencing strategies, and biomarkers.

It has been theorized that PARP inhibitors provide synergistic effects in combination with immunotherapy, and a cohort of the ongoing phase I KEYNOTE-365 trial is examining the combination of pembrolizumab (Keytruda) and olaparib (Lynparza; NCT02861573) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Moreover, a randomized phase II trial is investigating the combination of abiraterone acetate (Zytiga) and prednisone with or without olaparib versus single-agent olaparib in the same population (NCT03012321).

Additional work on an assay for the androgen receptor splice variant 7 (AR-V7) protein in circulating tumor cells may help direct treatment for patients with mCRPC. In a study, the assay selected patients with mCRPC who performed better with taxane-based chemotherapy (AR-V7—positive patients) and androgen receptor (AR)-signaling inhibitors (AR-V7–negative patients).

OncLive: What is emerging in the field of prostate cancer?

How have notions of active surveillance evolved?

In an interview with OncLive, Stadler, Fred C. Buffett Professor of Medicine and Surgery, chief of the Section of Hematology/Oncology, and director of the Genitourinary Program at the University of Chicago Medicine, gave an overview of the current prostate cancer landscape and discussed future directions.Stadler: Over the last 10 years, we have sort of seen an explosion of agents that have allowed us to treat and manage our patients for much longer periods of time. Everybody is asking us about the immunotherapy regimens. There are some promising hints of activity with immunotherapy in prostate cancer, but unlike kidney cancer or even bladder cancer, these are not yet ready for standard of care. This is in large degree because the percentage of those who respond to these agents are very small, and we don't yet know who those patients might be.Active surveillance plays an important role in 2 very important patient scenarios. The first is in patients who are diagnosed with especially low-grade localized prostate cancer. Many of those patients have a disease that is unlikely to have any impact on them within their lifetime. These are patients for whom active surveillance is perfectly appropriate.

Where does sequencing stand?

The other group of patients are those who may have received local therapy and now have biochemical progression of their disease, but with very slow doubling times of their PET prostate specific antigen (PSA). These are doubling times on the order of 2 years or more. Many of those patients, especially if they're elderly or have comorbidities, may not need any intervention either. Active surveillance in those patients may also be appropriate.Prostate cancer is becoming quite complicated in terms of sequencing therapy. The major question is in patients who have early castration-resistant disease and have disease progression after standard androgen ablation. There, we're beginning to have a number of different options, including things like sipuleucel-T (Provenge), which is an immunotherapy. We have second-line AR-targeted therapies, hormone therapies, and chemotherapies, or what I like to call “tubule” targeted therapies with cabazitaxel and docetaxel. Emerging are other targeted therapies for specific subsets, such as PARP inhibitors in patients with DNA repair mutations.

What about imaging modalities?

It's not always clear what to use first. There is a tendency within the community and in early castration-resistant disease to use the second-line hormonal therapies. There are lots of data to suggest that that's the right thing to do. However, some selectable markers are emerging, such as AR-V7 that may help us make choices. Right now, that is emerging, but it looks very promising.The most important development in imaging for prostate cancer is MRI of localized disease or potential localized disease. Up until recently, the prostate cancer diagnosis was the only cancer I know of where biopsies were done once there was an elevated PSA. With the use of modern MRI techniques and the PI-RADS scoring system, one can now do more directed biopsies. They allow us to more confidently identify patients who have significant prostate cancer.

Are there any combination regimens poised to impact the landscape in the near future?

What other clinical trials are you anticipating?

There is also a whole series of PET imaging for identifying what used to be called undetectable or microscopic disease. We're still trying to learn where that might play a role. One of the potential roles is in patients who have recurrent disease after prostatectomy. [We may be able to use this to] select patients who might be appropriate for additional radiotherapy versus those who may not benefit from it because they have more widespread disease.I'm not sure whether there are any combinations. One of the concepts that has been out there is whether more aggressive hormonal therapy that's attacking the hormone system with multiple agents may have a long-term benefit, even if given for a short duration of time. Those trials are ongoing. We're going to have to wait to see.Some of the most important trials are looking at the various PARP inhibitors, both in specific subsets of DNA repair mutations as well as in combination with different agents. The other set of clinical trials that are important are looking at various immunotherapies and trying to select patients for immunotherapy. Finally, what is likely to rapidly emerge over the next few years are prostate specific membrane antigen—targeted antibodies. Those will likely join our portfolio of drugs relatively soon.

Scher HI, Graf RP, Schreiber NA, et al. Assessment of the validity of nuclear-localized androgen receptor splice variant 7 in circulating tumor cells as a predictive biomarker for castration-resistant prostate cancer. JAMA Oncol. 2018;4(9):1179-1186. doi: 10.1001/jamaoncol.2018.1621.