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Prostate Cancer: Promising Results with Cabozantib, Abiraterone, and Degarelix

Laino, Charlene

doi: 10.1097/01.COT.0000396391.82767.3d
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GU Cancers Symposium

GU Cancers Symposium

ORLANDO—Prostate cancer is the most common genitourinary cancer, and it dominated the Genitourinary Cancers Symposium here this year, accounting for more than half of the 413 abstracts. At the center of attention: two investigational agents—cabozantinib (XL184) and abiraterone—and a strategy of switching from the gonadotropin-releasing hormone receptor (GnRH) agonist leuprolide to the GnRH blocker degarelix.

The meeting is cosponsored by ASCO, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

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Cabozantinib (XL184)

Bone metastases partially or completely resolved in 85% of the 62 patients with castration-resistant prostate cancer treated with the tyrosine kinase inhibitor cabozantinib, reported David C. Smith, MD, Professor of Internal Medicine and Urology at the University of Michigan.

The primary cause of morbidity and mortality in patients with castration-resistant prostate cancer is metastasis to the bone, which occurs in about 90% of cases, he said.

Bone metastases in castration-resistant prostate cancer are associated with increased expression of MET, which plays a role in tumor cell proliferation, invasion, and spread. MET also acts synergistically with vascular endothelial growth factor (VEGF)-type 2 receptor to stimulate angiogenesis.

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PHILIP W

Additionally, both the MET and (VEGF)-type 2 receptor signaling pathways appear to play important roles in the function of osteoblasts and osteoclasts.

Cabozantinib simultaneously targets both the MET and the VEGF-type 2 receptor, Dr. Smith said.

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Open-Label Study

At the meeting, Dr. Smith presented interim findings from an ongoing open-label Phase II adaptive randomized discontinuation trial of men with bone and visceral metastases from castration-resistant prostate cancer.

As of the end of January, the trial, which was funded by cabozantib's manufacturer, Exelixis, was fully enrolled with 168 patients; 100 patients were evaluable with 12 weeks of follow-up, and bone scan response was evaluable in 62.

All patients had measurable soft tissue disease, approximately half (47%) had evidence of visceral disease, and approximately half (47%) were pretreated with docetaxel.

The bone scan evaluable population included patients with a baseline bone scan, evidence of bone metastasis, and at least one post-baseline assessment.

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98% Disease Control

Of the 62 patients evaluable by bone scan, 53 (85%) achieved either complete or partial resolution of metastatic lesions on bone scan by independent radiologist review.

Eight other patients (13%) had stable disease on bone scan, resulting in an overall rate of disease control in bone of 98%.

Of 43 evaluable patients with bone metastases and bone pain, 26 (60%) had improvement in pain relief as early as six weeks after starting cabozantinib, Dr. Smith reported.

Of the 33 patients who required narcotics for bone pain, 21 (64%) had improvement in pain relief at six or 12 weeks, and 13 (46%) were able to decrease their dosage or discontinue narcotics.

The median progression-free survival time has not yet been reached with cabozantinib versus 40 days for placebo, he said.

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Markers of bone turnover decreased by as much as 80% at 12 weeks.

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Adverse Events

Of the 100 evaluable patients, 26 discontinued prior to 12 weeks—10 due to progressive disease and nine due to adverse events.

The most common adverse events were fatigue (71% of patients), decreased appetite (52%), diarrhea (46%), nausea (40%), constipation (34%), dysphonia (33%), vomiting (29%), hypertension (25%), and dysgeusia (24%).

The most common Grade 3 or 4 adverse events were fatigue (15%) and hypertension (8%). At least one dose reduction was required in 51% of patients.

“Docetaxel pretreatment doesn't seem to affect response to XL-184. And you may not need a bisphosphonate or denosumab with this; that's what the data suggest,” Dr. Smith said. “Clearly, XL-184 has an anti-tumor effect.”

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Positive Feedback

Other doctors at the meeting were very excited about the results.

“The bone scan changes are unprecedented,” said A. Oliver Sartor, MD, Medical Director of Tulane Cancer Center and the C.E. and Bernadine Laborde Professor of Cancer Research in the Departments of Medicine and Urology at Tulane University. “This honestly appears to be a whole new mechanism of action.”

Said Philip W. Kantoff, MD, Chief of the Division of Solid Tumor Oncology at Dana-Farber Cancer Institute: “A dramatic removal of metastases is the norm, a common event. This is something we have never seen in prostate cancer patients.

“In the past, we've seen bone scans get better, but it takes many, many months. This is very unusual; it is a dramatic effect,” he said.

The drug also appears to be effective in other cancers, commented Nicholas J. Vogelzang, MD, Chair and Medical Director of the Developmental Therapeutics Committee of US Oncology in Las Vegas.

“This is a dark horse drug that came out of nowhere. The trial in solid tumors was like putting nine lines in the water to see which fish bite, but right away they got bites.

“The first liver cancer patient had a benefit. The first ovarian cancer patient had a benefit. The first prostate cancer patient had a benefit.

“One of my patients had a dramatic drop in pain right away: Bam! This drug is like a Star Wars-type cloaking device,” he said.

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Abiraterone

Also at the meeting, researchers reported that the investigational drug abiraterone significantly improved survival rates in 15 of 16 subgroups of patients with metastatic castrate-resistant prostate cancer.

The trial, which was stopped early for efficacy, was presented at the European Society for Medical Oncology meeting in October.

Results showed that after 12.8 months of follow-up, abiraterone significantly extended overall survival times in men with castrate-resistant prostate cancer who had disease progression after docetaxel: 24.8 months vs 10.9 months for placebo.

The new analysis showed that abiraterone outperformed placebo in every subgroup except in the 10% of patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, said Howard I. Scher, MD, Chief of the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center.

A total of 222 of the 797 patients originally assigned to abiraterone were still being treated with the drug, compared with 54 patients of the 398 men on placebo.

The key adverse events–fluid retention, liver function test abnormalities, hypokalemia, and hypertension–were “manageable,” Dr. Scher said.

In the trial, patients were randomized in a two-to-one ratio to receive 1,000 mg of abiraterone plus 5 mg of prednisone twice a day, or placebo plus 5 mg prednisone twice a day.

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A Game Changer

“The results establish that considering castrate-resistant prostate cancer to be ‘hormone refractory’ may deny patients a safe and life-prolonging therapy,” Dr. Scher said.

A new drug application for abiraterone was submitted to the FDA in December, and physicians told OT that they expect it to be approved soon.

Commented Dr. Sartor, “This drug is a game changer. It will be a new alternative for patients with castrate-resistant disease who progress on docetaxel.”

The study was funded by Cougar Biotechnology, which is now part of Johnson & Johnson.

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Degarelix

A third report at the meeting showed that switching patients to degarelix after 12 months of leuprolide therapy significantly reduced the risk of PSA failure.

After a median follow-up of 27.5 months, the PSA progression-free survival (PFS) hazard rates dropped significantly from 0.20 events per year after 12 months of leuprolide to 0.08 events per year after another 12 months of treatment with degarelix.

PSA-PFS was defined as at least a 50% increase in PSA from baseline on two occasions two weeks apart and a PSA value of 5 ng/mL or greater.

The findings came from an open-label extension of a Phase III pivotal trial showing degarelix to be superior to leuprolide in suppressing PSA and testosterone levels.

At the end of the randomized trial, which was supported by Ferring, patients taking degarelix could opt to continue on maintenance treatment with the drug.

“These data support the durability of the significant PSA progression-free survival benefit of degarelix over leuprolide,” said Neal D. Shore, MD, Medical Director of Carolina Urologic Research Center in Myrtle Beach, South Carolina. “The data also support the use of degarelix as first-line androgen deprivation therapy.”

© 2011 Lippincott Williams & Wilkins, Inc.
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