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‘Hormone Refractory’ May Be Misnomer

Carlson, Robert H.

doi: 10.1097/01.COT.0000311428.60208.b6
Chemotherapy Foundation Symposium

NEW YORK CITY—Assigning the term “hormone refractory” to castrate metastatic prostate cancer resistant to chemotherapy may be misleading and dangerous. So said a researcher from Memorial Sloan-Kettering Cancer Center, speaking here at the Chemotherapy Foundation Symposium.

“It's not only a misnomer, it also has the potential to deny patients potentially effective treatments,” said Daniel Danila, MD, a medical oncology fellow in the Department of Hematology/Medical Oncology.

Prostate cancers that progress despite androgen depletion continue to express the androgen receptor and are dependent on signaling through the androgen receptor for growth, he explained. He presented data from two Phase II trials of the investigational androgen synthesis inhibitor abiraterone (CB7630), which has been shown to decrease testosterone production to undetectable levels, he said.

These and smaller studies with abiraterone have shown activity in men with castration-resistant metastatic prostate cancer whose disease has progressed on docetaxel-based chemotherapy and who have rising prostate-specific antigen (PSA) levels, he said.

Figure. Da

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In preliminary results of the Phase II COU-AA-003 study, nine of the first 10 patients receiving abiraterone experienced PSA declines, seven had a reduction of at least 50% from baseline, and four showed sustained responses for more than three months after starting treatment.

“That's significant in this patient cohort with heavily pretreated patients,” Dr. Danila said. “This is a drug that works excellently in a post-chemotherapy setting with patients who have been pretreated.”

Four of the 10 patients did discontinue treatment due to biochemical, radiologic, or symptomatic progression of disease, he said.

In a continuation of that Phase II trial, 23 more patients in protocol COU-AA-004 received abiraterone at 1,000 mg/day in 28-day cycles, just as in COU-AA-003, but additionally received oral prednisone at 5 mg twice daily. The median age of all 33 patients was 72, and the median PSA level at enrollment was 92.01 ng/mL.

Outcome data for the COU-AA-004 study will be presented at the Genitourinary Cancers Symposium, Dr. Danila said. In addition, a Phase III randomized trial is planned to open early this year, which will compare abiraterone with prednisone versus placebo with prednisone.

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Out of the Loop

The co-moderator of the session where he reported the data, Anna Ferrari, MD, Associate Professor in the Department of Medicine at New York University, said that the exciting aspect of abiraterone treatment is that it suppresses testosterone, as opposed to the luteinizing hormone-releasing hormone (LHRH) therapies that only suppress testosterone made by the testes through the feedback loop of the LHRH agonist effect.

“It has been shown that enzymes that metabolize androgens coming from other sources—for instance, from the adrenals—are in high enough levels at the intracellular level of the prostate cell to stimulate the androgen receptor,” Dr. Ferrari said.

Prostate cancer cells themselves upregulate enzymes that metabolize other steroid hormones into androgens—for example, dihydrocondosterone. “Abiraterone appears to suppress testosterone production in all those organs that produce testosterone—not only the testes but also the adrenal glands and the actual prostate cell itself,” she said, in an interview after the session.

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Broken Arrow Curve Shows PSA Velocity Decrease

If PSA velocity were represented as a rising straight line on a graph, any treatment that slows velocity would cause that line to “break” at the point where treatment takes effect and to angle flatter. Oncology-urology researchers at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins call that a “broken arrow” curve.

In another presentation at the meeting, Michael Carducci, MD, Associate Professor of Oncology and Urology there, said that he and his colleagues hope to see a broken arrow curve using GVAX allogeneic cellular immunotherapy in men with prostate cancer who had not previously received hormone therapy.



“There's a lot of emerging data about PSA doubling times and velocity, and the idea is that if your prognosis is related to how fast your PSA is elevating, that if we slow that down, it would really correlate with clinical benefits,” Dr. Carducci said in an interview after his report. “So the idea is that a broken arrow would suggest clinical and biological activity of an agent.”

Dr. Carducci described results from completed Phase II GVAX trials that have led to the current Phase III studies.

Two prostate cancer cell lines are used in GVAX immunotherapy for prostate cancer, modified to secrete granulocyte macrophage colony-stimulating factor (GM-CSF). Irradiation prevents further cell division but cells remain metabolically active.

In the GVAX Phase II trial G-9803, 34 previously untreated asymptomatic patients received low- and high-dose therapies. GVAX was found to be safe with no autoimmunity detected, and there was one complete response in the higher-dose arm.

A decrease in post-GVAX PSA velocity was seen in 67% of the low-dose arm, and velocity decreased by 80% in the high-dose arm.

In a second Phase II trial, G-0010, one of 80 patients had a partial reponse and 13 had stable PSA for more than 90 days. Median survival was 26.2 months for the 34 patients in the G-9803 study and 29.1 months for the 80 patients in the G-0010 study.

Those survival times compared favorably with the standard-setting Southwest Oncology Group 9916 and TAX 327 docetaxel trials in the same patient population, which showed median survival times of approximately 18 months, Dr. Carducci said.

“Taken together, these Phase II studies demonstrate the safety of the immunotherapy approach, but suggest a relatively low overall response rate.”

In addition, he said, two new, concurrent Phase III trials of the vaccine in men with metastatic hormone-refractory prostate cancer are nearing completion. VITAL 1, a head-to-head trial of GVAX compared with docetaxel-prednisone in asymptomatic metastatic patients, finished enrollment of 600 subjects in July. And Vital 2 is still open, aiming to test GVAX immunotherapy plus docetaxel-prednisone versus docetaxel-prednisone in 600 men with symptomatic, metastatic disease.

“That's the patient population who typically receives docetaxel in the US, and so we're now asking in these studies whether the addition of immunotherapy in conjunction with docetaxel would have an advantage over docetaxel alone,” Dr. Carducci said.

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‘One of Best Targets’

Dr. Ferrari commented after the session that, “it's really an extremely exciting era for immunology in cancer, and in particular in tumors such as prostate, which seems to be one of the best targets because it's slow dividing so the immune system has time to respond and recognize it.”

She called GVAX very promising because it combines the two human cell lines that represent androgen-dependent and androgen-independent prostate cancer, LN CAP and PC-3.

Using these cell lines, the researchers “are really loading the patient's body with all the potential antigens that the immune system now has the ability to see in great quantities, and mount an immune response—helped, obviously, by GM-CSF,” Dr. Ferrari said.

She said that she is also watching the PROSTVAC vaccine, which she finds very interesting because it uses only one antigen: PSA. “One might say that maybe not all cells express PSA in prostate cancer and that it decreases with time—that's one issue. But if it's given early enough in the disease, there are enough cells.

She noted that PROSTVAC and GVAX research is being done in men with rising PSA levels but normal testosterone—“Men who are ‘watching and waiting,’ those would be the ideal [trial] candidates,” she said.

© 2008 Lippincott Williams & Wilkins, Inc.
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