Frontline Advances Continue in Castration-Sensitive Prostate Cancer

James Luke Godwin, MD

The first-line treatment of patients with metastatic castration-sensitive prostate cancer has undergone a significant number of changes in the last few years. Most recently, the FDA approved abiraterone acetate (Zytiga) in combination with prednisone for patients with metastatic high-risk castration-sensitive disease.

This approval of abiraterone was based on findings from the phase III LATITUDE trial. In the study, there was a 38% reduction in the risk of death with the addition of abiraterone and prednisone to androgen deprivation therapy (ADT) compared with ADT alone.¹

Another pivotal trial of abiraterone in prostate cancer was STAMPEDE. This trial showed that the addition of abiraterone to standard initial therapy lowered the relative risk of death by 37% and improved progression-free survival by 71% in both nonmetastatic and metastatic patients with high-risk hormone-naïve disease.²

Although there is much excitement with androgen receptor (AR)-directed agents, docetaxel remains a staple of treatment. James Luke Godwin, MD, says that clinicians have now reached an interesting decision point on how to treat their patients in the frontline setting moving forward.

OncLive: How has first-line treatment for patients with castration-sensitive prostate cancer evolved?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Prostate Cancer, Godwin, assistant professor, Kimmel Cancer Center Network, Thomas Jefferson University Hospital, recapped recent advancements in frontline metastatic castration-sensitive prostate cancer and highlighted emerging agents with potential in this space.Godwin: This is a space that has been evolving over the past couple of years. Since 2014 or 2015, we have learned that adding docetaxel upfront provides a survival benefit when added to ADT as opposed to ADT alone. That became a standard of care in 2017, with data from 2 large studies—LATITUDE and STAMPEDE—showing impressive data with the addition of abiraterone to ADT upfront in this setting. Currently, we have good data for 2 separate agents that have different toxicity profiles.

What are the differences in toxicity profiles between the 2 agents?

For clinicians, when you meet a patient with metastatic castration-sensitive prostate cancer, it is an interesting decision point. What therapy should clinicians add to standard ADT in the first-line setting? That is an open question. Docetaxel is a traditional chemotherapy; it is an old drug that has been used for a very long time. Common side effects include neutropenia, decreased cell counts, fatigue, and neuropathy. The benefit of docetaxel is that you give it for a set time period—only 6 cycles—and then that therapy is complete. You would then continue with ADT alone. Although there is a period where a patient may experience more toxicity, they are only on the therapy for a definitive amount of time. The majority of men in the CHAARTED study, which showed the survival benefit for docetaxel upfront, completed all 6 cycles as planned without dose reduction.

Is there any rationale to look at other agents, such as enzalutamide?

Abiraterone is generally well tolerated. The side effect profile does include some cardiovascular risk and hypertension, which can be managed. However, when considering first-line treatment with abiraterone, you are considering committing a patient to a longer treatment course than with docetaxel. When making that decision, the clinician should work with the patient and consider toxicity, length of treatment, and cost to figure out what works best for that particular patient. Absolutely, there are trials ongoing looking at enzalutamide in the frontline space. There are the ENZAMET and ARCHES studies. There is also the PEACE1 study, which is looking at a variety of combinations. That trial will have some head-to-head data looking at docetaxel plus ADT versus abiraterone plus ADT, also with or without local radiation therapy dependent on the patient population. There are many subgroups in that study, so that will hopefully add some extra data for us to consider when choosing therapy.

What is the potential for immunotherapy in this setting?

There are also trials looking at combinations of all of the above, such as chemotherapy plus a next-generation AR-targeting agent. There is a trial looking at the combination of abiraterone and enzalutamide upfront. There are also multiple large phase III clinical studies that are ongoing, which will probably read out over the next few years and give us more data in which to decide the best possible therapies for our patients. Immunotherapy in prostate cancer is a complex topic. Of the genitourinary malignancies that we treat, prostate cancer has been the most resistant to experience those responses to immunotherapy that we see in our patients with renal cell carcinoma or urothelial carcinoma. However, there are some strategies that have been looked at to sensitize the local tumor microenvironment in prostate cancer, to try to figure out how to infiltrate that space better or to make the prostate cancer cells seem more visible to the immune system.

Combination therapies using vaccines plus immunotherapy are being looked at. There are multiple National Institutes of Health studies looking at that sort of approach, and there are large studies looking at the addition of immunotherapy to AR-targeted agents. For instance, the KEYNOTE-199 trial is looking at the addition of pembrolizumab (Keytruda) to enzalutamide in patients with metastatic castration-resistant prostate cancer.

What are the remaining questions in this population?

These are questions that we are continuing to ask, and we hope that we can find a way to select patients who may have prostate cancer and could respond to immunotherapy. It is pretty clear that men with high-volume metastatic disease significantly benefit from the addition of either docetaxel or abiraterone upfront. For even earlier disease states, or disease states where there is not as much disease burden, the question is a little more open. As we get longer follow-up from those trials such as STAMPEDE and LATITUDE, we will get more information about abiraterone in particular.

The other question is sequencing. Does it make sense to do AR-targeted therapy first and then chemotherapy, or vice versa? Where do combinations fit in? There is also the potential for immunotherapy. Those are all open questions asking how to best combine agents and sequence them. That is the purpose of a lot of these trials, and hopefully we will get some of these answers in the next few years.

References

1. Fizazi K, Tran N, Fein LE, et al; the LATITUDE investigators. LATITUDE: A phase 3 double-blind, randomized trial of androgen deprivation therapy (ADT) with abiraterone acetate (AA) plus prednisone (P) or placebos (PBOs) in newly diagnosed high-risk metastatic hormone-naïve prostate cancer (mHNPC) patients (pts). J Clin Oncol. 2017;35 (suppl; abstr LBA3).
2. James ND, DeBono JS, Spears MR, et al. Adding abiraterone for men with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Survival results from STAMPEDE (NCT00268476). J Clin Oncol. 2017;35 (suppl; abstr LBA5003).