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William K. Oh, MD, discusses treatment with abiraterone versus docetaxel in patients with prostate cancer, other remaining questions in the field, and what role immunotherapy is poised to play.
William Oh, MD
The management of metastatic hormone-sensitive prostate cancer continues to evolve as new findings emerge, such as results from the LATITUDE and CHAARTED studies.
The FDA based its recent approval of abiraterone acetate (Zytiga) and prednisone in metastatic high-risk castration-sensitive disease on results from LATITUDE. After a median follow-up of 30.4 months, the median overall survival (OS) was not reached in the abiraterone/prednisone plus androgen-deprivation therapy (ADT) versus 34.7 months with ADT plus placebo (HR, 0.62; 95% CI, 0.51-0.76; P <.001).1
In CHAARTED patients were randomized to ADT alone or ADT plus docetaxel. After a median follow-up of 28.9 months, the median OS was 13.6 months longer with ADT plus docetaxel versus ADT alone, at 57.6 versus 44.0 months (HR, 0.61; 95% CI, 0.47-0.80; P <.001).2
In an interview with OncLive, William K. Oh, MD, chief, Division of Hematology and Medical Oncology, professor, Medicine and Urology, Mount Sinai School of Medicine, associate director, Clinical Research, The Tisch Cancer Institute, discussed treatment with abiraterone versus docetaxel in patients with prostate cancer, other remaining questions in the field, and what role immunotherapy is poised to play.Oh: One of the biggest developments in the treatment of advanced prostate cancer over the past several years has been the management of metastatic hormone-sensitive prostate cancer. This is primarily in patients who are newly diagnosed. In 2014, a plenary session at the ASCO Annual Meeting presented the results of CHAARTED. The results, favoring the use of early chemotherapy, were subsequently published in the New England Journal of Medicine. A second study, STAMPEDE, confirmed those findings. At that time, we started using docetaxel in the treatment of newly diagnosed metastatic disease.
At the 2017 ASCO Annual Meeting, LATITUDE was presented at the plenary session. LATITUDE was another large, randomized trial of ADT plus or minus abiraterone and showed an extremely comparable benefit for up to 2 to 3 years of abiraterone plus prednisone in the treatment of metastatic hormone-sensitive prostate cancer. An arm of STAMPEDE looked at abiraterone compared with ADT alone and also showed a similar benefit. Now, we have 4 clinical trials that show either docetaxel or abiraterone compared with ADT alone significantly improve survival. The big question remains: which is better?My practice, like in most practices, adapts new therapies as they come about. In 2014, I administered docetaxel after the data were released. However, the challenge after that study was determining whether one or both treatments should be used. Patients have difficulty understanding the nuances of these questions, but they do have their own preferences. Most patients, if given a choice, may prefer not to have chemotherapy.
However, I have had some patients prefer chemotherapy because the treatment, administered 6 times, is over in about 4.5 months. Though a patient may choose abiraterone, it may not be financially feasible for them either because their insurance does not [cover] it, or because the copay can be too expensive. You have to look at the individual characteristics of the patient and incorporate their personal preferences before deciding which treatment best suits them. For most patients, abiraterone has become a more popular choice because it’s an oral therapy and may have a more favorable side effect profile.Enzalutamide hasn’t been studied in this situation yet. In theory, enzalutamide and abiraterone work similarly mechanistically, so it shouldn't necessarily be any different. It just hasn’t been studied in a large, randomized trial in this setting. There are ongoing studies, and it may have the exact same benefit, but we don't know as of now. The use of abiraterone and docetaxel was established in metastatic castration-resistant prostate cancer (mCRPC). Even in that setting, there are a lot of conversations about both combinations. Should we combine them if they both work and are mechanistically different? Is there an optimal sequence? Is abiraterone followed by docetaxel or docetaxel followed by abiraterone any better or worse?
In the mCRPC setting, there’s not a clear answer to that question. Some people believe that abiraterone might have a greater benefit early. That preference may translate to its use in early metastatic hormone-sensitive disease. However, a lot of oncologists have a bias. If your cancer is extremely aggressive or has features that are very poorly differentiated, such as a neuroendocrine kind of cancer that doesn’t make a lot of PSA, maybe that patient would be better suited to receive chemotherapy upfront. Do we have good data on that? Not necessarily, but is it something that I might factor into my consideration of who to give chemotherapy to.In the hormone-sensitive setting, people are recognizing that this may be a good area to test new agents. That’s partly because developments are made more quickly in this setting. If you wait for a patient who relapses with a rising PSA to develop metastatic disease, and then castration-resistant disease, getting a quick answer will be more difficult with all of the drugs we have approved in that setting.
However, in a setting where patients present with metastatic disease, their overall outcomes may be more limited. With ADT alone, they may progress, on average, within 1.5 years, but as agents such as abiraterone and/or docetaxel crowd the treatment landscape and become the new standard of care in the metastatic hormone-sensitive setting, it may be more difficult to get a survival endpoint. This is because these patients are getting subsequent therapies for CRPC, such as radium-223 dichloride (Xofigo), sipuleucel-T (Provenge), or cabazitaxel (Jevtana).We've been left off of the immunotherapy train, relatively speaking, and that’s ironic because prostate cancer was one of the first diseases where immunotherapy was approved with sipuleucel-T. The checkpoint inhibitors do have a response rate in prostate cancer, but it’s very modest. The small studies that have been completed so far suggest that the rate is approximately 10% to 20%. We are waiting for the large studies, such as KEYNOTE-199, to tell us what the more accurate response rate is.
We all recognize that this is not going to be a disease such as melanoma or lung cancer where there will be very high response rates. That said, there is some hope that combinations in prostate cancer will make a difference, namely combinations of vaccines, such as sipuleucel-T with checkpoint inhibitors. There’s potential for combinations with checkpoint inhibitors.
Some people forget that prostate cancer was one of the first diseases after melanoma that ipilimumab (Yervoy) was tested in. Even though that was a negative randomized trial, it suggested that there was some subset of patients who would benefit. In the rest of the field, the issue of PD-L1 staining remains a somewhat unclear biomarker for predicting response or benefit from checkpoint inhibitors. In prostate cancer, it may be the thing that puts us over the top. We are going to see more immunotherapy in prostate cancer in the very near future, but it has been a tougher slog for us to be able to get these drugs to our patients.