publication date: Jan. 25, 2019

Clinical Roundup

Finasteride found to be safe, effective prevention for prostate cancer

Finasteride, a generic hormone-blocking drug, was found to reduce the risk of prostate cancer by 25 percent in the landmark Prostate Cancer Prevention Trial.

Long-term data, initially published in the New England Journal of Medicine in 2003, show that reduction in prostate cancer risk has continued, and fewer than 100 men on the trial died from the disease.

SWOG Cancer Research Network, an international cancer clinical trials group funded by the NCI opened the PCPT for enrollment 25 years ago. The PCPT enrolled 18,882 men from 1993 to 1997, making it one of the largest prostate cancer clinical trials ever conducted.

New results, which reported participant deaths over two decades, show that finasteride has the lasting effect of reducing prostate cancer risk. Results also eliminate concerns over initial findings of a possible risk of more aggressive cancers with finasteride use.

“Finasteride is safe, inexpensive, and effective as a preventive strategy for prostate cancer,” said Ian Thompson, principal investigator of the PCPT for SWOG. “Doctors should share these results with men who get regular prostate-specific antigen tests that screen for the presence of prostate cancer. The drug will have its greatest effect in this group of men.”

Thompson is chair of SWOG’s genitourinary cancer committee and serves as president of CHRISTUS Santa Rosa Hospital Medical Center in San Antonio, Tex., and as emeritus professor at the University of Texas Health Science Center.

Along with SWOG biostatisticians Catherine Tangen, and Phyllis Goodman, of Fred Hutchinson Cancer Research Center, Thompson sought to determine whether the increased number of high-grade cancers detected through the PCPT years ago would result in more prostate cancer deaths over time.

SWOG published the first PCPT results in 2003. Investigators reported a significant, positive result: finasteride reduced prostate cancer risk by 25 percent. But the study also cast a shadow on the drug, the first 5-alpha-reductase inhibitor which targets and blocks the action of androgen, like testosterone and is commonly used to treat lower urinary tract problems in men and also male pattern baldness.

The results showed that finasteride increased the number of high-grade prostate cancers, a finding that resulted in a drug label warning posted by FDA. That warning remains in effect.

Thompson, Tangen, and Goodman matched participants to the National Death Index, a centralized database of death record information managed by the U.S. Centers for Disease Control and Prevention.

This analysis allowed the SWOG team to determine if a trial participant had died, and if so, the cause of death. With almost 300,000 person-years of follow-up and a median follow- up of 18.4 years, they found 42 deaths due to prostate cancer on the finasteride arm and 56 on the placebo arm. Thus, there was no statistically significant increased risk of prostate cancer death with finasteride.

In the NEJM letter, the team notes that a cheap, reliable prostate cancer prevention drug will have a big impact on public health. Due to a rise in screening for the disease, prostate cancer diagnoses are on the rise, with the American Cancer Society estimating that 164,690 American men would be diagnosed in 2018.

While many of these cancers will be slow-growing,and not life-threatening, they are still often treated with surgery and radiation, resulting in common complications such as impotence and incontinence.

“There are significant negative consequences to patients’ health and quality of life that can result from prostate cancer treatment, as well as to their finances and their peace of mind,” Thompson said. “If we can save people from surgeries, and scores of examinations and tests, and spare them from living for years with fear, we should. The best-case scenario for patients is prevention, and this trial has found an inexpensive medication that gets us there.”

NCI and the NIH funded the study through grants CA037429 and CA182883.


Remote participation enables patients with ALK-positive lung cancer to enroll in study of treatment resistance

The Addario Lung Cancer Medical Institute and researchers from the Dana-Farber Cancer Institute are launching a novel nationwide study to understand why treatment resistance develops in a specific group of lung cancer patients.

The Study of Plasma Next Generation Sequencing for Remote Assessment, Characterization, Evaluation of Patients with ALK Drug Resistance uses the latest gene-sequencing technology on blood plasma of patients with a rare form of lung cancer.

The SPACEWALK study seeks to better understand the molecular causes of drug resistance to help doctors determine if switching to a different ALK inhibitor could prove beneficial.

Advances in gene-sequencing now allow doctors to understand a tumor’s genetic composition from a sample of a patient’s blood, sometimes called a “liquid biopsy.” In the past, genomic analysis required patients to undergo an invasive biopsy to collect tumor tissue for testing.

With a liquid biopsy, doctors can analyze tumor DNA shed into the bloodstream, which means patients only need to go through a simple blood test. By using liquid biopsies, with blood samples shipped for analysis, the study enables patients across the country to participate. A study open to patients throughout the U.S. is especially important in conducting a meaningful study of uncommon conditions.

To learn more about this study, click here.


Servier & Taiho present Lonsurf data at ASCO 2019 GI Symposium

Note: The Cancer Letter has previously published information regarding this and can be found here.

Servier and Taiho Oncology Inc., said the safety and efficacy data in the gastrectomy patient subgroup of the global phase III trial TAGS evaluating Lonsurf (trifluridine/tipiracil, TAS-102) in patients with metastatic gastric cancer are consistent with the overall study results published in The Lancet Oncology. These data were highlighted in an oral presentation at the ASCO 2019 Gastrointestinal Cancers Symposium.

In TAGS, 221 (44%) of the 507 randomized mGC patients had undergone prior gastrectomy (147 LONSURF, 74 placebo), which is reflective of the real-world patient population diagnosed with mGC. The results confirmed that trifluridine/tipiracil prolonged survival versus placebo regardless of prior gastrectomy.

The overall results of TAGS demonstrated that patients treated with oral trifluridine/tipiracil showed a clinically meaningful and statistically significant improvement in overall survival compared with placebo and a 31 percent risk reduction of death (HR 0.69 one sided p=0.00029), which translated into a prolonged median survival of 2.1 months (5.7 months for trifluridine/tipiracil versus 3.6 months for placebo).

Trifluridine/tipiracil is indicated in E.U. for the treatment of adult patients with mCRC who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan- based chemotherapies, anti-VEGF agents, and anti- EGFR agents.

Applications for an additional indication in mGC for LONSURF are under review by health authorities in Japan, the US and the EU.

TAS-102 Gastric Study is a Taiho-sponsored pivotal phase III, multinational, randomized, double-blind study evaluating trifluridine/tipiracil, also known as TAS-102, plus best supportive care versus placebo plus BSC in patients with metastatic gastric cancer, including gastroesophageal junction cancer, refractory to standard treatments.

The primary endpoint in the TAGS trial is OS, and the main secondary endpoint measures include progression-free survival, and safety and tolerability, as well as quality of life.

TAGS enrolled 507 adult patients with metastatic gastric cancer who had previously received at least two prior regimens for advanced disease. The study was conducted in Belarus, the European Union, Israel, Japan, Russia, Turkey and the United States.

In Japan, Taiho Pharmaceutical Co., Ltd. has been marketing Lonsurf for the treatment of unresectable advanced or recurrent colorectal cancer since 2014. In the U.S., beginning in 2015, Taiho Oncology Inc., began marketing the drug for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

In June 2015, Taiho and Servier entered into an exclusive license agreement for the co-development and commercialization of Lonsurf in Europe and other countries outside of the US, Canada, Mexico and Asia.


New test for esophageal cancer could save millions of lives

Stephen Meltzer, a professor of medicine and oncology at the Johns Hopkins University School of Medicine, along with a team of researchers, clinicians and biomedical engineers have created a test—the “EsophaCap”—that uses specific genetic biomarkers to detect dangerous changes in the cells that line the inside of the esophagus. The paper was published in Clinical Cancer Research.

Previous studies have demonstrated Meltzer’s biomarkers’ ability to detect a condition called Barrett’s esophagus, which causes the body to replace the tissue that lines the organ with cells that can turn cancerous.

But large-scale methods to deploy those biomarkers as a screening tool have been elusive until now.

The principle behind the EsophaCap is simple, said Meltzer. The patient swallows a small capsule that has a long string attached to it. After the capsule makes its way down the esophagus and into the stomach, the gelatin coating on the capsule begins to dissolve.

From that capsule emerges a 2-centimeter polyurethane sponge, still attached to the string, much of which still hangs from the patient’s mouth.

The screener gently pulls the string and the sponge begins its return journey, out of the stomach, into the esophagus and, finally, out of the patient’s mouth.

As it makes its way up, the sponge comes into contact with the entire length and breadth of the esophagus, collecting genetic material all along the way. Then, as the sponge nears the top, the screener gives a final gentle tug, popping the sponge past the organ’s upper sphincter muscle. The sponge emerges loaded with genetic material that holds the key to the patient’s esophageal health.

The sponge is then sent to a company that performs simple genetic tests on the material to determine the patient’s risk for esophageal cancer.

In previous research, Meltzer has performed rigorous testing on the set of genetic biomarkers he uses to diagnose Barrett’s esophagus. The gene combination of p16, NELL1, AKAP12 and TAC1 has yielded a sensitivity of nearly 92 percent and has offered reliable diagnoses.

Medicine has never had routine screening methods for the disease. Both endoscopy and biopsy are less-than-ideal, since they’re inexact, expensive and rely on random tissue samples, rather than material from the whole esophagus lining.

“It’s actually possible to miss early cancerous cells using endoscopy with biopsy and most patients with Barrett’s don’t ever undergo endoscopy,” said Meltzer. “Right now, we’re confident that we have the tools to identify this type of cancer. But we previously lacked a way to collect enough genetic material to confidently determine a patient’s diagnosis. We believe that EsophaCap now provides a solution to this serious problem.”

Meltzer administered the EsophaCap test to 94 people over the course of the study. Eighty-five percent of subjects were able to swallow the capsule, with 100 percent successful sponge retrieval.

Endoscopic evaluation of the patients after EsophaCap administration, Meltzer reported, showed no evidence of bleeding, pain, trauma or other adverse reactions to the test.

In the journal article, Meltzer reports that of the patients able to swallow the capsule, nearly half would be diagnosed with Barrett’s esophagus—a rate far higher than that of the general U.S. population. He notes that most patients enrolled in the study were being treated for gastrointestinal symptoms.

This work was supported by NIH (Grants CA211457 and DK118250), the Emerson Cancer Research Fund and a Discovery Award from The Johns Hopkins University School of Medicine. Stephen Meltzer is the Harry and Betty Myerberg-Thomas R. Hendrix Professor and an American Cancer Society Clinical Research Professor. Zhixiong Wang was supported by a Scholarship from the China Scholarship Council (CSC) and the 3-3 Fund from the First Affiliated Hospital of Sun Yat-sen University.


AbbVie’s Imbruvica fails late-stage pancreatic cancer study

AbbVie announced an update on the phase III RESOLVE trial (PCYC-1137) of ibrutinib (Imbruvica) in combination with chemotherapy agents nab-paclitaxel and gemcitabine versus placebo in combination with these chemotherapy agents in patients with metastatic pancreatic adenocarcinoma.

PCYC-1137 evaluated the efficacy of ibrutinib in combination with nab-paclitaxel and gemcitabine for the first-line treatment of patients with metastatic pancreatic cancer.

Patients were randomized 1:1 to receive ibrutinib and nab-paclitaxel and gemcitabine combination treatment arm (n=211 study patients) versus the placebo and nab-paclitaxel and gemcitabine combination treatment arm (n=213 study patients).

At conclusion, the study did not meet its primary endpoint of improving progression-free survival or overall survival benefit among the study population. Safety data collected from the study were consistent with the existing safety information for the study therapies.

The full results from this trial will be submitted for publication to a future scientific conference and/or a peer-reviewed medical journal.

PCYC-1137 is a Pharmacyclics sponsored randomized, multicenter, double-blind, placebo-controlled, phase III study of the Bruton’s tyrosine kinase inhibitor ibrutinib in combination with nab-paclitaxel and gemcitabine versus placebo in combination with nab-paclitaxel and gemcitabine, in the first-line treatment of patients with metastatic pancreatic adenocarcinoma.

Imbruvica is a first-in-class Bruton’s tyrosine kinase inhibitor jointly developed and commercialized by Pharmacyclics LLC. Imbruvica has been available in the U.S. since 2013 and is FDA-approved for use in five B-cell blood cancers, as well as in chronic graft-versus-host-disease for a total of nine FDA-approved indications.

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