Biomarkers at 12 Weeks Predict Prognosis in mCRPC at 2 Years

Howard Scher, MD

A new biomarker panel taken 12 weeks after initiating treatment with abiraterone acetate plus prednisone can predict prognosis at 2 years in men with metastatic castration-resistant prostate cancer (mCRPC), a recent analysis of the phase III COU-AA-30 pivotal trial demonstrated. The analysis was presented at the European Cancer Congress 2013 (ECCO-ESMO-ESTRO), held in Amsterdam, The Netherlands, September 27 to October 1.

Howard Scher, MD, chief of Genitourinary Oncology Services at the Sidney Kimmel Center for Urologic and Prostate Cancers at Memorial Sloan- Kettering Cancer Center in New York City, presented the findings. Scher and colleagues determined that a biomarker panel consisting of the number of circulating tumor cells (CTC) plus levels of lactate dehydrogenase (LDH) can predict how well the drugs have worked at 12 weeks, after which the therapies will not accomplish more.

Based on individual risk assessment of 711 patients at the 12-week posttreatment mark in the COU-AA-30 trial, “the probability of being alive at 2 years was 46% for patients in a good risk category, while if patients were in a high-risk category at the same time point, the probability of being alive was 2%,” Scher said in an interview.

“This is a huge difference, and it’s telling us that the 12-week posttreatment measurement of this biomarker gives you a pretty good estimate of a patient’s prognosis,” he said. “We would argue that if patients are still in a high-risk category at the 12-week point, physicians should consider doing something else.”

Researchers had previously incorporated the number of circulating pre- and posttreatment CTCs as an outcome variable during the phase II clinical trials of abiraterone acetate plus prednisone, Scher said. “Because we were interested in early measures that would predict outcome, we used the same measurement of CTC in the phase III trial.”

CTCs were enumerated in both settings using the FDA-approved Veridex CellSearch assay. “The most important thing in any biomarker work is that you have to know the measurement is reliable,” Scher said.

In the analysis, the investigators measured CTC monthly, and also measured other markers, including prostate- specific antigen (PSA) at week 12 only. Among all the biomarkers, “what fell out” in terms of risk stratification were the numbers of CTCs and LDH levels, Scher said.

Patients were categorized as highrisk if they had 5 or more CTCs and LDH >250 IU/L; intermediate-risk if the numbers of CTCs were ≥5 but LDH was ≤250 IU/L; and low-risk with a CTC count of ≤4 and normal LDH levels.

Clinical Pearls

• A biomarker panel of CTC numbers and LDH levels predicted how well abiraterone acetate plus prednisone for mCRPC worked at 12 weeks
• The assessment predicted prognosis at 2 years

Individual-level surrogacy was assessed using four well-defined Prentice criteria.

First, the study demonstrated a statistically significant difference in survival in favor of the combination group (P= 0.039).

&ldquo;Criterion 2 requires that the treatment have a significant effect on the proposed biomarker,&rdquo; Scher said. In fact, the proportion of patients on the prednisone-alone arm who met highrisk biomarker criteria at 12 weeks was significantly higher than it was in the combination arm. Conversely, he added, the proportion of patients in the low-risk category was significantly higher in the combination arm (P<.001 for both endpoints).

Criterion 3 requires that the biomarker have a significant impact on survival and was met when the surrogate biomarker was able to discriminate between low- and high-risk patients with a concordance probability estimate of 0.79.

Last—and the most difficult criterion to satisfy&mdash;was that the biomarker needed to capture the treatment effect on survival.

&ldquo;At 12 weeks, you want to show that the group who had abiraterone plus prednisone who are still at high risk, as well as the ones who received prednisone alone and are also still at high risk, have the same survival,&rdquo; Scher said. &ldquo;In other words, the drug has done what it&rsquo;s going to do by 12 weeks, and you are now in either a high-risk or a low-risk category, and treatment no longer influences that difference in risk. And we were able to satisfy criterion 4, as well.&rdquo;

Future studies are under way to confirm individual patient-level surrogacy using different data sets.