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Once-Promising Arzoxifene Flunks Phase III Trial

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Once-Promising Arzoxifene Flunks Phase III Trial 10 OSTEOPOROSIS JANUARY 2010 • CLINICAL ENDOCRINOLOGY NEWS Once-Promising Arzoxifene Flunks Phase III Trial BY BRUCE JANCIN Arzoxifene also significantly reduced the incidence of vertebral fractures by Arzoxifene Reduces Risk For Vertebral, But Not Other Fractures S AN A NTONIO — Arzoxifene, a once- 41% after 36 months of follow-up in Arzoxifene Placebo Risk promising selective estrogen-receptor GENERATIONS participants, who were (n=4,678) (n=4,676) Reduction P Value modulator, experienced a fatal meltdown aged 60-85 years at enrollment. All breast cancers 22 53 58% < .001 EWS in a phase III trial involving nearly 10,000 But there was a deal breaker: the se- N women. lective estrogen-receptor modulator Invasive breast ca 19 43 56% .002 Arzoxifene was being developed for (SERM) produced no significant reduc- Invasive ER+ breast cancer 9 30 70% .001 EDICAL prevention of both tion in nonverte- Vertebral fractures 80 134 41% .001 M Nonvertebral fractures 203 208 none .71 fractures and It’s disappointing, bral fractures. LOBAL G breast cancer in given the time “This is disap- Note: Based on a study of 9,354 postmenopausal women with osteoporosis. postmenopausal and effort ‘put into pointing because Source: Dr. Powles LSEVIER women with os- a major trial with as an antiosteo- E teoporosis or os- good preclinical porosis drug we teopenia. and early clinical really need to have “The overall benefit/risk profile of ar- well as for invasive breast cancer risk re- But the 9,354-pa- data.’ a SERM that zoxifene does not represent a meaning- duction in such women who are at high tient randomized, would not only re- ful advancement in the treatment of os- risk for the cancer or who have osteo- double-blind, DR. POWLES duce vertebral teoporosis, so further development of porosis. placebo-controlled, fractures, but non- this drug will not take place. It’s obvi- In early clinical studies, arzoxifene had multinational GENERATIONS trial has vertebral fractures as well,” explained ously disappointing, given that so much greater effects on bone mineral density put an end to that, Dr. Trevor Powles Dr. Powles, a medical oncologist who is time and effort has been put into a ma- and bone turnover markers than did said at the San Antonio Breast Cancer professor emeritus at the Institute of jor trial with good preclinical and early raloxifene. Symposium. Cancer Research, London. clinical data,” he said. Moreover, in the GENERATIONS tri- The breast cancer prevention portion Moreover, arzoxifene was associated The investigators are still puzzling over al arzoxifene resulted in increased bone of GENERATIONS went well: After 48 with increased rates of venous throm- how the earlier studies could have been density at nonvertebral sites as well as in months of follow-up, arzoxifene reduced boembolism, endometrial polyps, leg so misleading. the spine. the incidence of invasive breast cancer by cramps, hot flashes, and cholelithiasis, Arzoxifene is a benzothiophene GENERATIONS was funded by Eli 56%, compared with placebo, and re- while offering no better protection SERM, like raloxifene, which is approved Lilly & Co. duced estrogen-receptor–positive inva- against cardiovascular events than did in postmenopausal women for the treat- Dr. Powles disclosed that he has no rel- sive breast cancer by 70% (see chart). placebo. ment and prevention of osteoporosis as evant financial relationships. ■ Denosumab Bests Zoledronic Acid for Bone Metastases BY BRUCE JANCIN time to the first on-study skeletal-relat- junction with administration of therapy remain present in bone for years. ed event (SRE), consisting of fracture, ra- occurred in 27.3% of patients in the There is great interest in testing S AN A NTONIO — Denosumab diation to bone for pain control, surgery, zoledronic acid arm compared with denosumab in the adjuvant setting in proved superior to zoledronic acid in de- or spinal cord compression. 10.4% on denosumab. patients with early stage breast cancer laying or preventing complications from There was a highly significant 18% rel- Adverse events related to renal toxic- because of theoretic reasons that RAN- bone metastases in breast cancer patients ative risk reduction favoring denosumab. ity occurred in 8.5% of the zoledronic KL inhibition should curb development in a large phase III clinical trial. The median time to the first SRE was acid group and 4.9% with denosumab; of breast cancer, according to Dr. Denosumab also showed significantly 26.5 months in the severe renal toxic- Stopeck. less toxicity than did zoledronic acid zoledronic acid There is no need ity occurred in Asked how she will incorporate deno- (Zometa), the current standard treat- arm; it has not yet to monitor serum 1.5% of the zole- sumab into her own clinical practice if ment for bone metastases. been reached in the creatinine in dronic acid-treat- the agent receives marketing approval for Particularly noteworthy was the sub- denosumab arm. patients on ed patients com- the treatment of bone metastases, Dr. stantially lower rate of renal toxicity At 34 months of denosumab, pared to 0.2% of Stopeck replied, “I’m going to incorpo- with denosumab; there is no need to follow up, 30.7% of unlike with the those on deno- rate it rather quickly, assuming the price monitor serum creatinine in patients patients on deno- bisphosphonate. sumab. isn’t exorbitant, since it shows better ef- on denosumab, unlike with the bis- sumab and 36.5% Osteonecrosis ficacy, it’s easier to give by subcutaneous phosphonate, Dr. Alison Stopeck not- on zoledronic acid DR. STOPECK of the jaw (ONJ) injection, I don’t have to monitor the ed at the San Antonio Breast Cancer had experienced at occurred in 1.4% serum creatinine, and it has less toxicity.” Symposium. least one SRE, for a 16% relative reduc- of patients on zoledronic acid and a sta- In October, the Food and Drug Ad- Denosumab is an investigational fully tion with the RANKL inhibitor. tistically similar 2.0% of those on deno- ministration held up Amgen’s applica- humanized monoclonal antibody tar- The difference between the two ther- sumab. tion for marketing approval for deno- geting RANK ligand (RANKL), the pri- apies grew in magnitude over time: The More than 80% of cases of ONJ were sumab pending more information. mary mediator of osteoclast formation, relative risk reduction favoring deno- associated with dental extractions, poor In an interview, a company spokesper- function, and survival. sumab was 5.6% at 12 months and 11.5% oral hygiene, or use of a dental appli- son said Amgen plans to resubmit to the Metastatic cancer cells stimulate RAN- at 18 months, Dr. Stopeck continued. ance. FDA, and file for marketing approval in KL activity, resulting in increased bone A total of 608 SREs occurred in the Dr. Theresa Guise, professor of med- Europe sometime in 2010, armed with resorption and destruction, explained zoledronic acid group, compared with icine at Indiana University, Indianapolis, these updated data from the breast can- Dr. Stopeck of the University of Arizona 474 with denosumab, a 23% reduction. commented that it wasn’t clear prior to cer trial, the findings from another phase Cancer Center, Tucson. The time to experiencing moderate or this trial whether ONJ was an adverse III trial involving patients with various She reported on 2,046 breast cancer severe pain was a secondary study out- event limited to bisphosphonate therapy. solid organ cancers or multiple myelo- patients with confirmed bone metas- come—and the most important end These data indicate that it is more glob- ma, and the results of a third phase III tases. point of all from most patients’ per- ally a side effect associated with inhibit- trial in men with prostate cancer, which Participants were randomized double- spectives. ing bone resorption. is expected to report results in the first blind to denosumab at 120 mg given A score greater than 4 on the 11-point Dr. Stopeck said that, interestingly, quarter of 2010. once monthly by subcutaneous injec- validated Brief Pain Inventory occurred some cases of ONJ in denosumab-treat- Collectively, the three studies total tion or to 4 mg of zoledronic acid given for the first time at a median 64 days in ed patients have turned out to be re- roughly 6,000 cancer patients. ■ intravenously on an individualized dos- the zoledronic acid group compared versible. ing schedule governed by serum creati- with 88 days in the denosumab arm, She speculated that this may be a Disclosures: Dr. Stopeck serves as a nine level in accord with the product la- translating to a 23% advantage favoring function of the monoclonal antibody’s consultant to Amgen and Novartis and is beling. the investigational agent (P = .009). limited duration of activity in bone, in on the speakers bureau for Novartis, which The primary study end point was the Flu-like acute phase reactions in con- contrast to the bisphosphonates, which markets zoledronic acid. Pages 10a—10bŅ.
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