ASCO: Enzalutamide advances in triple-negative breast cancer

CHICAGO – The androgen-receptor inhibitor enzalutamide is active in patients with advanced triple-negative breast cancer that is immunohistochemically positive for this receptor, according to results of a phase II study reported at the annual meeting of the American Society of Clinical Oncology.

One-quarter of the 118 women in the single-arm, open-label trial had a response or achieved stable disease with the drug after 16 weeks, reported lead investigator Dr. Tiffany A. Traina of Memorial Sloan Kettering Cancer Center, New York.

However, more than one-third showed such benefit if their tumor was positive for a novel genomic diagnostic biomarker, PREDICT AR, which is based on genes showing differential expression between patients who do and do not respond to this therapy.

Furthermore, in multivariate analyses, androgen-receptor positivity by immunohistochemistry did not independently predict progression-free survival, but PREDICT AR positivity did.

“We find results of this phase II study to be compelling and warrant further investigation and development of enzalutamide for the treatment of patients with metastatic triple-negative breast cancer enriched by the biomarker,” Dr. Traina maintained.

Invited discussant Dr. Pamela N. Munster, a professor in the department of medicine (hematology/oncology) at the University of California, San Francisco, said, “I think the most exciting [finding] is the long overall survival using PREDICT AR as an assessment of androgen receptor and using enzalutamide as an androgen-receptor modulator.”

“I believe we really need an intense focus on biomarker refinement to move forward” in triple-negative breast cancer, she maintained. “We should use testing of targeted therapy for androgen receptor–positive early-stage breast cancer, possibly in the neoadjuvant setting. And immune therapy potentially in combination with hormone axis targeting for patients with triple-negative disease, at least those who have androgen receptor–positive and PD-L1–positive tumors, should be considered.”

A session attendee asked Dr. Traina whether she thought the androgen receptor is a predictive or prognostic marker. Data from a related poster presented at the meeting showed that PREDICT AR status in a separate, neoadjuvant cohort was not related to survival in the absence of enzalutamide, suggesting that this biomarker at least is not prognostic, she said.

Another attendee asked, “Do you have any plans to evaluate mutations in the androgen receptor, specifically the V7 mutation, which is found to mediate resistance to enzalutamide in prostate cancer?”

“I think there is a lot we could probably learn from our prostate cancer colleagues. I certainly have been,” Dr. Traina replied. “It’s an area that we are looking into, although I don’t think that we can presume to know the mutations or the mechanisms would be the same in breast as they are in prostate.”

Women were eligible to enroll in the Medivation-sponsored trial if their advanced triple-negative breast cancer showed any androgen-receptor positivity by immunohistochemistry, with no restriction on the number of prior therapies. They were treated with 160 mg daily of oral enzalutamide (Xtandi), which currently has Food and Drug Administration approval only for the treatment of prostate cancer.

With a median follow-up of 48 weeks, results showed that the 16-week rate of clinical benefit – a complete or partial response, or stable disease – was 25% in the intention-to-treat population (patients receiving at least one dose of the drug) and 35% in the evaluable population (the subset having androgen-receptor positivity of at least 10% of cells and at least one response assessment).

“This trial provides the first-ever RECIST-confirmed responses seen from an androgen-receptor antagonist,” Dr. Traina noted.

Median progression-free survival was 12.6 weeks in the intention-to-treat population overall, with somewhat greater benefit in patients having at least 10% of cells expressing androgen receptor. “While we could begin to see a group that might have better disease control, androgen receptor alone could not discriminate early on which patients were less likely to benefit,” she commented.

In a preplanned exploratory analysis looking at PREDICT AR (Parker et al.), nearly half of patients in the intent-to-treat population were positive for this marker. The 16-week clinical benefit rate was 39% in positive patients, more than triple the 11% seen in negative patients.

Most of the patients who were PREDICT AR positive but did not meet this endpoint were treated in the third-line setting or beyond, Dr. Traina noted. “PREDICT AR was developed in primary tumor tissue, and it may be that the biology drivers change over time and perhaps that may not apply to third-line therapy.”

Biomarker-positive patients also had better median progression-free survival in the intention-to-treat population (16.1 vs. 8.1 weeks). And in a multivariate analysis, PREDICT AR positivity was the only factor other than number of prior therapies to independently predict progression-free survival (hazard ratio, 0.45; P = .004) , according to Dr. Traina; notably, 10% or greater androgen-receptor positivity by immunohistochemistry did not.

An exploratory analysis additionally showed that patients with PREDICT AR–positive tumors had better median overall survival as well (not reached vs. 32.1 weeks), although data for this outcome are still not mature.

“This hormonal agent reflected a safety profile very much like what has been seen in prostate cancer,” she reported, with fatigue, nausea, and decreased appetite predominating. The overall rate of grade 3 or worse adverse events related to the drug was 10%. “There were no new safety signals found, and this was a well-tolerated regimen,” she added.

Dr. Traina disclosed that she receives honoraria from Celgene, Eisai, and Genentech; has a consulting or advisory role with AstraZeneca, Eisai, Genentech, Genentech/Roche, Halozyme, Medivation, Mundipharma, and Pfizer; and receives research funding from AstraZeneca, Eisai, Genentech, Janssen, Medivation, Novartis, and Ziopharm Oncology.

CHICAGO – The androgen-receptor inhibitor enzalutamide is active in patients with advanced triple-negative breast cancer that is immunohistochemically positive for this receptor, according to results of a phase II study reported at the annual meeting of the American Society of Clinical Oncology.

One-quarter of the 118 women in the single-arm, open-label trial had a response or achieved stable disease with the drug after 16 weeks, reported lead investigator Dr. Tiffany A. Traina of Memorial Sloan Kettering Cancer Center, New York.

However, more than one-third showed such benefit if their tumor was positive for a novel genomic diagnostic biomarker, PREDICT AR, which is based on genes showing differential expression between patients who do and do not respond to this therapy.

Furthermore, in multivariate analyses, androgen-receptor positivity by immunohistochemistry did not independently predict progression-free survival, but PREDICT AR positivity did.

“We find results of this phase II study to be compelling and warrant further investigation and development of enzalutamide for the treatment of patients with metastatic triple-negative breast cancer enriched by the biomarker,” Dr. Traina maintained.

Invited discussant Dr. Pamela N. Munster, a professor in the department of medicine (hematology/oncology) at the University of California, San Francisco, said, “I think the most exciting [finding] is the long overall survival using PREDICT AR as an assessment of androgen receptor and using enzalutamide as an androgen-receptor modulator.”

“I believe we really need an intense focus on biomarker refinement to move forward” in triple-negative breast cancer, she maintained. “We should use testing of targeted therapy for androgen receptor–positive early-stage breast cancer, possibly in the neoadjuvant setting. And immune therapy potentially in combination with hormone axis targeting for patients with triple-negative disease, at least those who have androgen receptor–positive and PD-L1–positive tumors, should be considered.”

A session attendee asked Dr. Traina whether she thought the androgen receptor is a predictive or prognostic marker. Data from a related poster presented at the meeting showed that PREDICT AR status in a separate, neoadjuvant cohort was not related to survival in the absence of enzalutamide, suggesting that this biomarker at least is not prognostic, she said.

Another attendee asked, “Do you have any plans to evaluate mutations in the androgen receptor, specifically the V7 mutation, which is found to mediate resistance to enzalutamide in prostate cancer?”

“I think there is a lot we could probably learn from our prostate cancer colleagues. I certainly have been,” Dr. Traina replied. “It’s an area that we are looking into, although I don’t think that we can presume to know the mutations or the mechanisms would be the same in breast as they are in prostate.”

Women were eligible to enroll in the Medivation-sponsored trial if their advanced triple-negative breast cancer showed any androgen-receptor positivity by immunohistochemistry, with no restriction on the number of prior therapies. They were treated with 160 mg daily of oral enzalutamide (Xtandi), which currently has Food and Drug Administration approval only for the treatment of prostate cancer.

With a median follow-up of 48 weeks, results showed that the 16-week rate of clinical benefit – a complete or partial response, or stable disease – was 25% in the intention-to-treat population (patients receiving at least one dose of the drug) and 35% in the evaluable population (the subset having androgen-receptor positivity of at least 10% of cells and at least one response assessment).

“This trial provides the first-ever RECIST-confirmed responses seen from an androgen-receptor antagonist,” Dr. Traina noted.

Median progression-free survival was 12.6 weeks in the intention-to-treat population overall, with somewhat greater benefit in patients having at least 10% of cells expressing androgen receptor. “While we could begin to see a group that might have better disease control, androgen receptor alone could not discriminate early on which patients were less likely to benefit,” she commented.

In a preplanned exploratory analysis looking at PREDICT AR (Parker et al.), nearly half of patients in the intent-to-treat population were positive for this marker. The 16-week clinical benefit rate was 39% in positive patients, more than triple the 11% seen in negative patients.

Most of the patients who were PREDICT AR positive but did not meet this endpoint were treated in the third-line setting or beyond, Dr. Traina noted. “PREDICT AR was developed in primary tumor tissue, and it may be that the biology drivers change over time and perhaps that may not apply to third-line therapy.”

Biomarker-positive patients also had better median progression-free survival in the intention-to-treat population (16.1 vs. 8.1 weeks). And in a multivariate analysis, PREDICT AR positivity was the only factor other than number of prior therapies to independently predict progression-free survival (hazard ratio, 0.45; P = .004) , according to Dr. Traina; notably, 10% or greater androgen-receptor positivity by immunohistochemistry did not.

An exploratory analysis additionally showed that patients with PREDICT AR–positive tumors had better median overall survival as well (not reached vs. 32.1 weeks), although data for this outcome are still not mature.

“This hormonal agent reflected a safety profile very much like what has been seen in prostate cancer,” she reported, with fatigue, nausea, and decreased appetite predominating. The overall rate of grade 3 or worse adverse events related to the drug was 10%. “There were no new safety signals found, and this was a well-tolerated regimen,” she added.

Dr. Traina disclosed that she receives honoraria from Celgene, Eisai, and Genentech; has a consulting or advisory role with AstraZeneca, Eisai, Genentech, Genentech/Roche, Halozyme, Medivation, Mundipharma, and Pfizer; and receives research funding from AstraZeneca, Eisai, Genentech, Janssen, Medivation, Novartis, and Ziopharm Oncology.

CHICAGO – The androgen-receptor inhibitor enzalutamide is active in patients with advanced triple-negative breast cancer that is immunohistochemically positive for this receptor, according to results of a phase II study reported at the annual meeting of the American Society of Clinical Oncology.

One-quarter of the 118 women in the single-arm, open-label trial had a response or achieved stable disease with the drug after 16 weeks, reported lead investigator Dr. Tiffany A. Traina of Memorial Sloan Kettering Cancer Center, New York.

However, more than one-third showed such benefit if their tumor was positive for a novel genomic diagnostic biomarker, PREDICT AR, which is based on genes showing differential expression between patients who do and do not respond to this therapy.

Furthermore, in multivariate analyses, androgen-receptor positivity by immunohistochemistry did not independently predict progression-free survival, but PREDICT AR positivity did.

“We find results of this phase II study to be compelling and warrant further investigation and development of enzalutamide for the treatment of patients with metastatic triple-negative breast cancer enriched by the biomarker,” Dr. Traina maintained.

Invited discussant Dr. Pamela N. Munster, a professor in the department of medicine (hematology/oncology) at the University of California, San Francisco, said, “I think the most exciting [finding] is the long overall survival using PREDICT AR as an assessment of androgen receptor and using enzalutamide as an androgen-receptor modulator.”

“I believe we really need an intense focus on biomarker refinement to move forward” in triple-negative breast cancer, she maintained. “We should use testing of targeted therapy for androgen receptor–positive early-stage breast cancer, possibly in the neoadjuvant setting. And immune therapy potentially in combination with hormone axis targeting for patients with triple-negative disease, at least those who have androgen receptor–positive and PD-L1–positive tumors, should be considered.”

A session attendee asked Dr. Traina whether she thought the androgen receptor is a predictive or prognostic marker. Data from a related poster presented at the meeting showed that PREDICT AR status in a separate, neoadjuvant cohort was not related to survival in the absence of enzalutamide, suggesting that this biomarker at least is not prognostic, she said.

Another attendee asked, “Do you have any plans to evaluate mutations in the androgen receptor, specifically the V7 mutation, which is found to mediate resistance to enzalutamide in prostate cancer?”

“I think there is a lot we could probably learn from our prostate cancer colleagues. I certainly have been,” Dr. Traina replied. “It’s an area that we are looking into, although I don’t think that we can presume to know the mutations or the mechanisms would be the same in breast as they are in prostate.”

Women were eligible to enroll in the Medivation-sponsored trial if their advanced triple-negative breast cancer showed any androgen-receptor positivity by immunohistochemistry, with no restriction on the number of prior therapies. They were treated with 160 mg daily of oral enzalutamide (Xtandi), which currently has Food and Drug Administration approval only for the treatment of prostate cancer.

With a median follow-up of 48 weeks, results showed that the 16-week rate of clinical benefit – a complete or partial response, or stable disease – was 25% in the intention-to-treat population (patients receiving at least one dose of the drug) and 35% in the evaluable population (the subset having androgen-receptor positivity of at least 10% of cells and at least one response assessment).

“This trial provides the first-ever RECIST-confirmed responses seen from an androgen-receptor antagonist,” Dr. Traina noted.

Median progression-free survival was 12.6 weeks in the intention-to-treat population overall, with somewhat greater benefit in patients having at least 10% of cells expressing androgen receptor. “While we could begin to see a group that might have better disease control, androgen receptor alone could not discriminate early on which patients were less likely to benefit,” she commented.

In a preplanned exploratory analysis looking at PREDICT AR (Parker et al.), nearly half of patients in the intent-to-treat population were positive for this marker. The 16-week clinical benefit rate was 39% in positive patients, more than triple the 11% seen in negative patients.

Most of the patients who were PREDICT AR positive but did not meet this endpoint were treated in the third-line setting or beyond, Dr. Traina noted. “PREDICT AR was developed in primary tumor tissue, and it may be that the biology drivers change over time and perhaps that may not apply to third-line therapy.”

Biomarker-positive patients also had better median progression-free survival in the intention-to-treat population (16.1 vs. 8.1 weeks). And in a multivariate analysis, PREDICT AR positivity was the only factor other than number of prior therapies to independently predict progression-free survival (hazard ratio, 0.45; P = .004) , according to Dr. Traina; notably, 10% or greater androgen-receptor positivity by immunohistochemistry did not.

An exploratory analysis additionally showed that patients with PREDICT AR–positive tumors had better median overall survival as well (not reached vs. 32.1 weeks), although data for this outcome are still not mature.

“This hormonal agent reflected a safety profile very much like what has been seen in prostate cancer,” she reported, with fatigue, nausea, and decreased appetite predominating. The overall rate of grade 3 or worse adverse events related to the drug was 10%. “There were no new safety signals found, and this was a well-tolerated regimen,” she added.

Dr. Traina disclosed that she receives honoraria from Celgene, Eisai, and Genentech; has a consulting or advisory role with AstraZeneca, Eisai, Genentech, Genentech/Roche, Halozyme, Medivation, Mundipharma, and Pfizer; and receives research funding from AstraZeneca, Eisai, Genentech, Janssen, Medivation, Novartis, and Ziopharm Oncology.