Sequencing of Novel Prostate Cancer Agents Is a Work in Progress

William K. Oh, MD

Over the past decade, the availability of new agents with varying mechanisms of action has greatly enhanced the treatment landscape in castration-resistant prostate cancer (CRPC). Physicians are now tasked with determining the optimal sequencing of these diverse treatments. At the 2012 Chemotherapy Foundation Symposium, William K. Oh, MD, discussed challenges and potential strategies for treatment sequencing in patients with CRPC.

Oh, who is the chief of Hematology/Oncology at the Tisch Cancer Institute, Mount Sinai School of Medicine in New York City, identified several key questions regarding optimal sequencing:

• Should you use immunotherapy after chemotherapy or with prednisone?
• Can you combine androgen receptor—targeted therapies with each other or chemotherapy?
• Is the natural progression from oral agents to IV, or is that irrelevant?
• Are there natural synergies (or antagonisms) that should lead to rational combinations?
• How many therapies will patients reasonably complete?

Table. Recent Trials in Castration-Resistant Prostate Cancer

Trial

Therapy

Disease State

Comparator

Overall Survival

Hazard Ratio

P Value

IMPACT

Sipuleucel-T

Chemo-näive

Placebo

0.775

0.032

TAX327

Docetaxel

Chemo-näive

Mitoxantrone

0.76

0.009

TROPIC

Cabazitaxel

Post-Docetaxel

Mitoxantrone

0.70

<0.0001

COU-AA-301

Abiraterone acetate

Post-Docetaxel

Placebo

0.646

<0.0001

COU-AA-302

Abiraterone acetate

Pre-Docetaxel

Placebo

0.75

0.0097*

AFFIRM

Enzalutamide (MDV3100)

Post-Docetaxel

Placebo

0.631

<0.001

ALSYMPCA

Alpharadin (Radium-223)

Post-Docetaxel

Placebo

0.70

0.002

*Not statistically significant.

The primary challenge to answering these questions and determining a blueprint for sequencing is a paucity of data. “There is very little data to drive a rational discussion about what the answers [to these questions are],” said Oh. He added that few comparative data exist because the critical trials that examined these drugs were not head-to-head comparisons (Table). Rather, the efficacy of the drugs was established against inactive comparators—either mitoxantrone or placebo.

Based on his interpretation of the data that are available, Oh summarized the current treatment landscape in prostate cancer (Figure). He also offered some basic principles for sequencing that physicians can follow as they await further results from ongoing trials:

• Start with the most effective treatment with the least toxicity.
• Switch classes of therapy if there is clear evidence of resistance (eg, hormones to chemo).
• Avoid overlapping treatments that may be antagonistic (eg, steroids and vaccines).
• Participate in clinical trials whenever possible.

Looking ahead, Oh identified factors that will affect treatment sequencing over the next 5 years. “I do think we’ll have more agents [available], but the concern I have is that we don’t want to be in the ‘me too’ era. We want to really figure out how these different classes of drugs work together by understanding the biology [of CRPC],” said Oh. He also expects that clinical trials will continue to test the novel prostate drugs in earlier-stage settings, and that personalized care will be enhanced through a focus on molecular diagnostics and prostate cancer subtypes.

Figure. Current Treatment Landscape in Prostate Cancer

Oh concluded by discussing what he considers the “elephant in the room” regarding optimal sequencing: cost. With the high cost of new treatments, insurers are becoming stricter in authorizing certain drugs, which could limit a physician’s autonomy in selecting a treatment sequence, said Oh. He added that as healthcare reform continues to be implemented, new metrics for the efficacy and value of care could affect treatment decisions. “In the next Obama administration I think we’re going to see more and more comparative effectiveness research, so that we are really forced to decide which treatments really improve quality of care,” said Oh.