A NEW SERM WITH BETTER TOXICITY PROFILE

November 5, 2010 – Lasofoxifene (Oporia, Pfizer) is the third drug that has been shown to be effective in preventing breast cancer, and it might tip the balance toward wider use of these agents, says an expert.

Two other agents, tamoxifen and raloxifene, which, like lasofoxifene, is a selective estrogen-receptor (ER) modulator (SERM), have been proven to reduce the risk for breast cancer, but so far there has been little use of these drugs for chemoprevention in healthy women.

The latest results show that lasofoxifene, which is not yet marketed, at 0.5 mg a day reduced the risk for ER-positive invasive breast cancer by 79% and the overall risk for breast cancer by 83% in postmenopausal women with osteoporosis. The data come from a 5-year placebo-controlled randomized clinical trial with the acronym PEARL (Postmenopausal Evaluation and Risk-Reduction With Lasofoxifene).

The risk reduction for breast cancer with lasofoxifene is similar to that reported for tamoxifen and raloxifene, say the authors.

The findings by the PEARL investigators, led by Andrea Z. LaCroix, PhD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle, Washington, were published online November 4 in the Journal of the National Cancer Institute.

Compared with placebo, lasofoxifene 0.5 mg daily also reduced the risk for coronary events by 32% and for strokes by 36% — effects not seen in trials with tamoxifen or raloxifene. Lasofoxifene also reduced vertebral fractures by 42% and nonvertebral fractures by 24%; raloxifene has not been shown to reduce the latter.

Notably, use of lasofoxifene was not associated, at 5 years, with a risk for other cancers, including endometrial cancer, which is a risk associated with tamoxifen.

Advance in This Drug Class

"Lasofoxifene appears to represent an advance in the progression of pharmacological agents at our disposal," writes Victor G. Vogel, MD, in an editorial that accompanies the study.

Dr. Vogel, who is from Geisinger Medical Center in Danville Pennsylvania, says that lasofoxifene has a favorable risk/benefit profile, compared with the tamoxifen and raloxifene. Neither of these "has been able to tip the clinical utility scale to broad usage within the high-risk population for breast cancer risk reduction," he says.

The scales might be ready to be tipped with the anticipated approval of lasofoxifene, which might be more potent than the other agents, "possibly because it binds with high affinity to both ER-alpha and ER-beta," writes Dr. Vogel.

"We have been waiting for a tipping point in breast cancer chemoprevention for more than a decade. Perhaps with lasofoxifene, the time has arrived," he speculates, borrowing a phrase from journalist Malcolm Gladwell's book The Tipping Point to describe how social change occurs incrementally until a critical point catapults it full-speed ahead.

At the same time, Dr. Vogel acknowledges the considerable array of stars that need to be aligned for breast cancer chemoprevention to be widely embraced.

"For a preventive strategy to be both effective and efficient, we need an easily identified target population, criteria for identifying those who would benefit from a risk-reduction strategy, a safe and effective agent, an informed group of practitioners who can provide care to the high-risk group, and an educated population of patients who understand the advantages and the risks of taking a drug to modify their risk," he writes.

In short, implementing breast cancer chemoprevention widely is a tall order. Nevertheless, the absence of its general acceptance vexes experts.

This past summer, at the annual ASCO meeting, when long-term data from the landmark Study of Raloxifene and Tamoxifen (STAR) trial were presented, a number of experts uttered comments such as: "We need to reassess why we don't use these drugs more broadly," and "It's a mystery [why raloxifene is not more widely used]."

As PEARL, which was funded by Pfizer, indicates, lasofoxifene does not escape another problem with breast cancer chemoprevention — the increased risk for venous thromboembolism.

PEARL Has Handicaps

In the international PEARL trial, 8556 postmenopausal women (aged 59 to 80 years) with low bone density and normal mammograms were randomly assigned to 1 of 2 doses of lasofoxifene — 0.25 or 0.50 mg daily — or placebo. The participating women were not at high-risk for breast cancer.

The primary end points of the PEARL trial were incidence of ER-positive breast cancer and nonvertebral fractures at 5 years.

Of the women in the trial, 77% completed the final visit; of these women, at 5 years, 62% in the lasofoxifene groups were taking the study medication, as were 64% in the placebo group.

Compared with placebo, lasofoxifene 0.50 mg statistically significantly reduced the risk for total breast cancer by 79% (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.08 - 0.55) and for ER-positive invasive breast cancer by 83% (HR, 0.17; 95% CI, 0.05 - 0.57), write the authors.

The effects of lasofoxifene 0.50 mg on total breast cancer were similar, regardless of a patient's Gail score; the effects were markedly stronger for women with baseline estradiol levels above the median (odds ratio [OR], 0.11; 95% CI, 0.02 - 0.51) than for those with levels below the median (OR, 0.78; 95% CI, 0.16 - 3.79; P interaction = .04).

These findings about estradiol levels are in agreement with a meta-analysis that showed a 2-fold increased risk for breast cancer among postmenopausal women in the highest quintile of estradiol, compared with the lowest quintile, say the authors.

With regard to gynecological problems at 5 years, there was an increase in benign endometrial thickening among women receiving lasofoxifene 0.50 mg, but no increase in endometrial hyperplasia, atypia, or cancer.

The study authors point out that PEARL has some important limitations, including the small number of incident breast cancer cases (n = 49) and a lack of follow-up data after 5 years.

Dr. Vogel agrees about the limitations. The "PEARL trial was handicapped by a small number of both subjects and adverse events," he writes. For instance, only 5 breast cancer events occurred in the 0.50 mg dose group, compared with 24 in the placebo group.

Dr. Vogel also suggests that comparing the PEARL and STAR trials is not straightforward. Women in PEARL were, on average, about 9 years older than STAR trial participants at entry (mean age, 67 vs 58.5 years). Also, average Gail score risk for breast cancer in 5 years in the PEARL trial was lower than in the STAR trial (1.7% vs 4.03%). Rates of venous thromboembolism were also lower with raloxifene in STAR than with lasofoxifene 0.5 mg in PEARL (1.38 vs 2.9 events per 1000 woman-years), "possibly reflecting the older age of the PEARL participants," says Dr. Vogel.

More information is needed about this new SERM in the long term, says Dr. Vogel. "We need more complete information about the long-term effects of lasofoxifene on both beneficial and unfavorable outcomes, but the early data regarding its risks and benefits are encouraging," he writes.

This study was funded by Pfizer, and editorial assistance was provided by Annie Neild, PhD, from PAREXEL.

J Natl Cancer Inst. Published online November 4, 2010.