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-301 pivotal trial shows.

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 Manhattan, presented the findings during the 2013 European Cancer Congress.

In the study, 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 post-treatment mark in the COU-AA-301 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 post-treatment 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 post-treatment 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,” he noted.

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 observed.

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 high-risk 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.

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 (

“Criterion 2 requires that the treatment have a significant effect on the proposed biomarker,” Scher explained. And in fact, the proportion of patients on the prednisone-alone arm who met high-risk 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 (

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.

“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,” Scher explained. “In other words, the drug has done what it’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.”

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

	Scher HI, Heller G, Molina A, et al. Evaluation of a composite biomarker panel including circulating tumor cell enumeration as a surrogate for survival in metastatic castration-resistant prostate cancer. Presented at: European Cancer Congress 2013; September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract 2851.

View more from the 2013 European Cancer Congress

Articles

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 

Biomarkers Predict Prognosis for Patients With mCRPC

 A post-hoc analysis of the VELOUR trial demonstrated additional improvements in both overall survival (OS) and progression-free survival (PFS) in favor of aflibercept plus FOLFIRI in patients with metastatic colorectal cancer (mCRC). The analysis was presented at the European Cancer Congress 2013 (ECCO-ESMO-ESTRO), held September 27 to October 1 in Amsterdam, The Netherlands.

The VELOUR trial of aflibercept plus FOLFIRI versus FOLFIRI plus placebo was designed to include important subgroups of patients with mCRC encountered in the second-line setting, including those who had received prior bevacizumab therapy. VELOUR also included patients who progressed rapidly (<6 months) following adjuvant treatment with oxaliplatin—one of the few phase III trials to do so. The post-hoc analysis of the intent-to-treat (ITT) population excluded these rapid adjuvant progressors. The analysis also found improvements in both OS and PFS regardless of whether or not patients had been exposed to prior bevacizumab therapy.

According to the authors of the post-hoc analysis, rapid adjuvant progressors are usually refractory to any subsequent therapy and have an extremely poor prognosis, thus negatively affecting outcomes regardless of the treatment received. Despite this, an incremental increase in OS of 1.4 months was observed with aflibercept compared with placebo in the overall “all-takers” second-line VELOUR population. A total of 1226 patients were included in the overall VELOUR ITT population.

Of these, 186 in the aflibercept/FOLFIRI arm had received prior bevacizumab as had 187 of the placebo controls. A total of 17 patients in the prior bevacizumab arm were rapid adjuvant progressors, 9 of them having been randomized to aflibercept and the remaining 8 to placebo. Among patients who had not received prior bevacizumab, 426 and 427 had been randomized to aflibercept vs placebo, respectively. Fifty-one patients randomized to aflibercept, and 56 randomized to placebo within the non-bevacizumab subgroup were rapid adjuvant progressors. All rapid adjuvant progressors were excluded from the current post-hoc analysis.

“As expected, when rapid adjuvant progressors were excluded from the overall ITT population, a 1.9-month incremental benefit was observed with aflibercept over placebo…demonstrating a 22.1% relative risk reduction for death,” the authors observe. “These findings reinforce the benefit of aflibercept treatment in clinically relevant populations of mCRC patients, including those with prior bevacizumab use.”

	Van Cutsem E, Ferry DR, Lakomy R, et al. Aflibercept/FOLFIRI vs placebo/FOLRIRI in metastatic colorectal cancer: post-hoc analysis of survival by prior bevacizumab use subsequent to exclusion of patients who had recurrence during or within 6 months of completing adjuvant oxaliplatin-based therapy. Presented at: European Cancer Congress 2013; September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract 2260. 

A post-hoc analysis of the VELOUR trial demonstrated additional improvements in both overall survival and progression-free survival in favor of aflibercept plus FOLFIRI in patients with metastatic colorectal cancer 

Additional OS and PFS Benefits Seen With Aflibercept in Post-Hoc VELOUR Analysis

Co-targeting metastatic castrate resistant prostate cancer (mCRPC) with the combination of enzalutamide plus abiraterone acetate may circumvent the compensatory mechanisms observed with either agent alone and lead to more profound suppression of androgen signaling, according to findings of a new study presented at the 2013 European Cancer Congress.

“We are now moving to the concept that CRPC is largely driven by androgen signaling that is amplified as a result of therapy,” Eleni Efstathiou, MD, PhD, associate professor of Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, told delegates. In several studies, Efstathiou and colleagues first demonstrated that treatment with abiraterone acetate, an androgen biosynthesis inhibitor, reduced testosterone levels in the blood and bone marrow to undetectable levels.

“Soon after initiation of treatment, however, we observed a compensatory feedback mechanism leading to an increase in androgen receptor copy numbers as a result of testosterone depletion,” she said. Similarly, following inhibition of nuclear androgen receptor (AR) localization with enzalutamide (an AR inhibitor), they observed an induction of testosterone both in the blood and bone marrow—“suggesting that there is a feedback mechanism leading to an increase in testosterone,” she added.

They thus tested the hypothesis that a “two-component” approach may be able to cancel out the compensatory response of mCRPC to either drug alone.

A total of 57 evaluable patients with mCRPC with metastases to the bone have been enrolled in the study to date. Patients received 160 mg of once-daily enzalutamide, plus abiraterone acetate (1 g/day), plus prednisone, 5 mg, twice daily. Patients were monitored every 4 weeks for blood and ECG irregularities, while immunohistochemistry was used to assess the effect of the combination strategy on the tumor microenvironment. PSA levels were primarily used to assess disease progression. More than 70% of the group had a Gleason score of ≥8 on enrollment, and 41% had ≥20 bone lesions. The median baseline PSA concentration was 23.3 ng/mL, (range, 1-606.3 ng/mL).

“No new safety concerns have arisen,” Efstathiou said. Two patients discontinued treatment due to adverse events, but no grade 4 or 5 toxicities have been observed thus far—a sign that the combination approach is reasonably well tolerated, she added.

In 49 patients evaluable for disease impact, investigators also noted significant declines in PSA levels. At a median of 5.5 months of treatment exposure, approximately 45% of the 49 evaluable patients had a 90% or greater decline in PSA from baseline. Three-quarters of the group achieved a 50% or greater decline in PSA values from baseline while approximately 84% achieved a 30% or greater decline from baseline PSA values.

“These findings confirm the hypothesis that co-targeting mCRPC with enzalutamide and abiraterone acetate avoids the adaptive response observed with either agent alone and suggest that the combination may have a more profound response rate than either agent alone and that it is well tolerated,” the researchers concluded. Discussant Gerhardt Attard, MD, PhD, Cancer Research UK Clinical Scientist, Royal Marsden NHS Foundation Trust, UK, agreed with MD Anderson investigators that their study confirms the tolerability of the combination.

Nevertheless, he cautioned that comparable declines in PSA in comparable proportions of patients have been reported by other investigators following treatment with either drug alone.

“This is only a single-arm study of 2 highly active drugs, and this really limits any conclusion on the increased activity of the 2 drugs given together,” he said.

A more definitive answer is expected from the ALLIANCE study in men with mCRPC who have not yet received docetaxel. Men will receive either enzalutamide or enzalutamide plus abiraterone acetate. The study is ongoing and the primary endpoint will be overall survival.

	Efstathiou E, Titus M, Wen AS, et al. The effects of enzalutamide (ENZA) in combination with abiraterone acetate (AA) in patients with bone metastatic castration resistant prostate cancer (mCRPC). Presented at: European Cancer Congress 2013; September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract 2854.

Co-targeting metastatic castrate resistant prostate cancer with the combination of enzalutamide plus abiraterone acetate may circumvent the compensatory mechanisms observed with either agent alone and lead to more profound suppression of androgen signaling.

Patrice Olson

Articles

Biomarkers Predict Prognosis for Patients With mCRPC

Additional OS and PFS Benefits Seen With Aflibercept in Post-Hoc VELOUR Analysis

Enzalutamide Plus Abiraterone May Have Higher Response Rate in mCRPC Than Either Agent Alone