June 2012, Vol 1, No 2
Neoadjuvant Abiraterone Potential ApproachConference Correspondent
Abiraterone, which is FDA-approved for the treatment of advanced prostate cancer, had encouraging results in one of the first studies to evaluate use of this targeted agent earlier in the course of disease. Targeted hormonal therapy with abiraterone plus leuprolide was able to eradicate cancer in the prostate in some high-risk prostate cancer patients prior to radical prostatectomy in a phase 2 study reported at ASCO 2012 (Abstract 4521).
“Most patients with early prostate cancer are cured with primary surgery and/or radiotherapy. However, patients with high-risk features [such as those in this study] generally progress. The study was conducted to determine if neoadjuvant therapy with abiraterone plus leuprolide could increase the cure rate. To date, no other treatment has shown a benefit in the neoadjuvant setting. Larger studies are needed to validate this finding,” said lead author Mary- Ellen Taplin, MD, Harvard Medical School and Dana- Farber Cancer Institute in Boston, Massachusetts.
Standard hormone therapy with injectable leuprolide acts to suppress testosterone. Abiraterone, an oral inhibitor of CYP17, has a different mechanism of action, blocking the synthesis of androgens in the testes, adrenal glands, and prostate. In this neoadjuvant study, abiraterone was given along with leuprolide and low-dose prednisone to abrogate the side effects of abiraterone prior to radical prostatectomy.
The study included 56 men with localized high-risk prostate cancer. High risk was defined as Gleason score ≥8 (71% of the sample); PSA ≥20 mg/mL (19% of the sample); T3 or T4 bulky disease (24% of the sample); and high PSA velocity (16% of the sample). Slightly more than one-third of patients also had lymph node involvement, which is associated with aggressive disease.
Patients were treated with either 3 months of leuprolide or 3 months of abiraterone, leuprolide, and low-dose prednisone (5 mg) and then underwent biopsy of the prostate for analysis of androgen levels; patients then received treatment with abiraterone/leuprolide/prednisone for another 3 months, after which radical prostatectomy was performed.
In the prostate specimen obtained at prostatectomy, pathological complete response (pCR) was observed in 10% of those treated with 6 months of abiraterone versus 4% in those treated with 3 months of abiraterone; near pCR was seen in 24% versus 11%, respectively.
“It is rare to eliminate prostate cancer with hormone therapy,” Taplin said at a pre-meeting press telecast. “pCR with hormonal therapy is usually 5% or less. The response rate of 34% is impressive, given the high-risk features of the patient population,” she noted.
Grade 3 adverse events included elevated liver enzymes in 9% and hypokalemia in 5%. Use of low-dose prednisone appeared to prevent some of the side effects associated with abiraterone, she noted.
Other neoadjuvant trials with some of the newer prostate cancer agents are now being planned, including MDV 3100, Taplin said.
“This is an exciting step forward, showing that neoadjuvant abiraterone can make cancer disappear in a percentage of high-risk patients,” stated Nicholas Vogelzang, MD, Chair of ASCO’s communications committee and moderator of the press telecast.
He explained that neoadjuvant therapy is standard in the treatment of breast cancer, rectal cancer, and bladder cancer.
“When cancer disappearance is achieved with primary treatment in these other cancers, long-term survival is improved,” Vogelzang noted.
Advocating for biomarker-driven “smart” trials, making the case for patient selection for specific drugs, and the concept of rational combinations as potential targeted therapies in order to improve the efficacy of clinical trials were topics of an insightful presentation delivered by Dr Aleksandar Sekulic on behalf of Dr Pat LoRusso [ Read More ]
Plexxikon, a member of the Daiichi Sankyo Group since 2011, works in the structureguided discovery and development of novel small-molecule pharmaceuticals to treat human disease. The company’s lead drug Zelboraf (vemurafenib/PLX4032) was approved by the FDA in August 2011 and is copromoted in the United States by Daiichi Sankyo, Inc. [ Read More ]