2018 Ushers in New Era of Prostate Cancer Treatment

Edwin Posadas, MD

Upfront taxane-based chemotherapy with docetaxel improved survival in patients with metastatic prostate cancer, according to phase III findings from the CHAARTED and STAMPEDE trials, but additional findings have shown strong potential with abiraterone acetate (Zytiga) as well, leading physicians to make varying therapy decisions for their patients.

In both studies, explains Edwin M. Posadas, MD, the use of first-line docetaxel in combination with hormonal treatment had a significant reduction in the risk for prostate cancer death. The field began to move quickly toward the use of docetaxel, but soon thereafter were 2 British studies—the STAMPEDE abiraterone arm and the LATITUDE study.

Both trials found that upfront use of abiraterone—an agent that was initially approved after use of docetaxel—in addition to prednisone and standard androgen-deprivation therapy (ADT), or standard initial therapy, resulted in a 38% and 37% reduction in the risk of death in LATITUDE and STAMPEDE, respectively.^1,2

The only thing lacking, Posadas says, is a comparison between the studies.

“Should you give a man docetaxel or abiraterone?” he asks. “Many physicians will use their clinical judgement to make that decision. The answer probably lies in the molecular makeup of the tumor.”

As the field continues to hone in on targeted therapies in advanced prostate cancer, targeted agents like nonsteroidal antiandrogens are now being developed for patients with nonmetastatic prostate cancer, as well.

OncLive: How has systemic therapy in prostate cancer changed in the past year?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Posadas discussed the evolution of prostate cancer therapy, including the earlier use of advanced-stage agents and the potential for immunotherapy in the field.Posadas: Systemic therapy for advanced prostate cancer has really evolved in the past year. Because of the newer studies that are coming forward, what was used in the most advanced settings are now being used in earlier disease states. This is going to temporarily cause a great deal of confusion as we sort things out. It's critical at this point that physicians who are caring for men with advanced prostate cancer know what tools to use and when to use them. Old paradigms of making treatment decisions based on what line of therapy a patient has been on are probably, and thankfully, going away.

Can you speak to how the CHAARTED, LATITIUDE, and STAMPEDE trials are affecting sequencing strategies?

With advancements being made in molecular biology and in our understanding of the biology of advanced prostate cancers, we are entering an era with better targeting and precision of cancer care. This is incredibly important since some of the treatments are more toxic than others and have undesirable side effects—as in the commonly administered hormonally active agents that we use. In the right setting at the right time, we're finding that it really makes a difference in a patient’s quality of life. I’m very excited to be involved in work at this point in time in prostate cancer.There have been 3 very large and powerful studies that were put forward within the past 3 years. LATITUDE and STAMPEDE were shown at the 2017 ASCO Annual Meeting. Prior to those studies were the CHAARTED and STAMPEDE docetaxel-focused studies. CHAARTED and STAMPEDE showed that upfront taxane-based chemotherapy, also known as hormonal therapy, improved survival. This is a landmark finding and has resulted in a paradigm shift.

Chemotherapy is generally reserved until the very end because of the perception patients and physicians have that it is toxic and has undesirable side effects. While generally this is true, chemotherapy for prostate cancer is somewhat milder than it is for other neoplasms. Using it at the right time is really important.

What has complicated this even further is the data presented by Drs Maha Hussain of Northwestern University Feinberg School of Medicine and Eric Small of University of California, San Francisco at the 2018 Genitourinary Cancers Symposium. Hussein and Small presented the results from the PROSPER and SPARTAN studies. These trials looked at 2 other agents, enzalutamide (Xtandi) and apalutamide (Erleada), other androgen receptor (AR)-blocking agents or nonsteroidal antiandrogens. These are being used by many clinicians in the nonmetastatic castration-resistant prostate cancer (CRPC) space. After castration, men with a rising prostate-specific antigen (PSA) will receive ADT in the absence of detectable metastatic disease.

How are circulating tumor cells (CTCs) being used in metastatic CRPC (mCRPC) as a means of testing for response?

Both of these studies showed that using either enzalutamide or apalutamide significantly improved progression-free survival in this setting. Like abiraterone, these drugs were originally approved after chemotherapy, then before chemotherapy. Now they are being used upfront before metastatic disease is even detectable. The quality of life on these drugs is still considered very high. Overall survival data are still missing, so these studies are not yet mature in that respect. Nonetheless, it's still a landmark finding for men with nonmetastatic prostate cancer.CTC platforms are allowing physicians to conduct molecular studies on cancerous cells to gain biological insight. For those of us who are involved in CTC work, we see the opportunity of using advanced nanotechnologies to examine cancer cells in the bloodstream, similar to how we would analyze the molecular nature and histomorphometric nature of a tissue biopsy. By treating the blood like solid tissue, we may be able to enhance testing for response in mCRPC. These technologies, such as NanoVelcro, are available at Cedars-Sinai Medical Center and others throughout the United States.

What are some unmet needs in prostate cancer you would like to see addressed?

We hope that one day we can use this technology to, if not replace, at least complement solid tissue biopsies. Though some medical centers will take a biopsy of the prostate every month, asking for a blood draw is less invasive. There are many tumors that don’t produce PSA or have alterations that PSA does not reflect. In these cases, something like CTC assay may be complementary and add information that PSA testing may not provide. The combination has given physicians new insights into how prostate cancer behaves.There are several unmet needs in prostate cancer at this point. What we really need to do is identify these lethal cancers before they get to the point of needing abiraterone and/or docetaxel. CTC assays and new imaging technologies may enable us to do that in the future. The second thing is understanding the entities of these prostate cancers that are not AR driven. From the 1940s to 2018, we have relied on interrupting AR signaling to control prostate cancer. As we use these agents earlier, what is likely to emerge after resistance is a more aggressive, devastating prostate cancer. Some physicians refer to this as small cell transformed neuroendocrine or anaplastic prostate cancers.

We don't have a lot of good answers at that point. We have relied on platinum-based chemotherapies. PARP inhibitors are emerging as an interesting area. As we further understand the biology, we will likely find that there are additional subtypes with targetable lesions. I'm very excited to be part of efforts at Cedars-Sinai Medical Center unmasking some of these pathways that are involved in driving these transformed prostate cancers.

A third unmet need is immunotherapy. It is one of the most exciting times in solid tumor oncology—to see that we are able to harness the immune system to improve survival in diseases that were considered to be devastating. Now, there are significant immune-related improvements in survival for diseases such as kidney cancer, melanoma, and lung cancer. It's still early, but we're learning how to use them effectively. More checkpoint inhibitors are coming forward, but the current agents we have are not “home runs” yet. As we learn more about the immune system and research led by the National Cancer Institute, The University of Texas MD Anderson Cancer Center, and other places develops, we will really change the way that we approach prostate cancer in the future.

References

1. Fizaxi 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).