publication date: Mar. 27, 2020

Clinical Roundup

Venclexta combination improves OS in previously untreated AML

The phase III VIALE-A study demonstrated that Venclexta in combination with azacitidine, a hypomethylating agent, showed a statistically significant improvement in overall survival in people with previously untreated acute myeloid leukemia who were ineligible for intensive induction chemotherapy, compared to azacitidine alone.

The trial, sponsored by Genentech, a member of the Roche Group, met its dual primary endpoints of overall survival and composite complete remission rate.

FDA previously granted Venclexta accelerated approval in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of people with newly-diagnosed AML who are 75 years or older, or for those ineligible for intensive induction chemotherapy due to coexisting medical conditions, based on response rates from the M14-358 and M14-387 studies.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory studies. Venclexta has also been granted five Breakthrough Therapy Designations by the FDA, including two for previously untreated AML. 

Venclexta is being developed by AbbVie and Genentech. It is jointly commercialized by the companies in the United States and commercialized by AbbVie outside of the United States.


Intense form of radiation slows disease progression in some men with prostate cancer

Highly focused, intense doses of radiation called stereotactic ablative radiation may slow progression of disease in a subset of men with hormone-sensitive prostate cancers that have spread to a few separate sites in the body, according to results of a phase II clinical trial of the therapy.

The trial, called ORIOLE and led by Johns Hopkins Kimmel Cancer Center researchers since 2016, compared the effectiveness of SABR versus “wait and watch” observation in recurrent cases of oligometastatic prostate cancer.

“It has been a longstanding question, especially important now in the era of immunotherapy, whether any type of radiation, and SABR specifically, can stimulate the immune system,” study leader Phuoc Tran, professor of radiation oncology and molecular radiation sciences at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center, said in a statement. “Our trial offers the best data to date to suggest that SABR can cause a systemic immune response.”

Metastatic prostate cancer is incurable, and men with recurrent hormone-sensitive cancers may prefer to delay one of the standard treatments, an antihormone therapy called androgen deprivation therapy.

A report on the study is available in the journal JAMA Oncology.

Among the 54 men enrolled in the trial, the disease progressed within six months in seven out of 36 (19%) of participants treated with SABR, compared to 11 out of 18 participants (61%) undergoing observation alone. The risk of new cancers at six months was also lower, occurring in 16% of those receiving SABR compared to 63% of those under observation.

There were no significant differences in clinically meaningful side effects or in reports of pain related to the treatment between the two groups, the study found. The average age of the men on the ORIOLE trial were 68-years old, and most participants were Caucasian.

Analysis of immune system white cells in blood drawn from the patients indicated that SABR treatment was associated with an expanded population of T cells, suggesting that the treatment stimulated a full-body immune system response to their cancers, Tran said.

Tran co-directs the Kimmel Cancer Center’s Cancer Invasion and Metastasis program with Andrew Ewald and Ashani Weeraratna, aimed at studying the process by which cancers spread, to expand and develop better treatments for patients with advanced cancers.

The findings suggest SABR might be usefully paired with other immunotherapies to treat recurrent oligometastatic prostate cancers, but Tran cautioned that any potential benefits of such combined therapy will need to be tested in future clinical trials.

The research team also detected a set of tumor mutations in genes known to be important for suppressing cancer development in some patients that correlated with a higher risk of cancer progression even among those undergoing SABR.

“This may be a molecular signature which is indicative of the underlying biology of the patient’s cancer,” Tran said.

The biomarker could help clinicians know “which patients are going to benefit the most from a metastasis-directed therapy like SABR” compared to a systemic treatment such as chemotherapy,” Tran said.

The ORIOLE results also suggest that SABR treatment may remove or affect signals that promote the development of micrometastases in recurrent oligometastatic prostate cancer, rather than just “resetting” the clock on the disease until metastases grow large again, said Tran.

Tran and team will continue with phase II studies to determine if they can increase the number of participants with slower disease progression. In the ORIOLE trial, patients with metastatic lesions in the bone were most likely to have their cancers recur in a new bone site. To target these new metastatic bone lesions, Tran and colleagues have another clinical trial called RAVENS that combines SABR with radium-223 (Xofigo) that targets metastatic cancer in the bones.


Repurposed antidepressant may be a treatment option when prostate cancer comes back, USC study finds

An antidepressant in use for decades, repurposed to fight prostate cancer, shows promise in helping patients whose disease has returned following surgery or radiation, a pilot study at USC shows.

Phenelzine, a MAO inhibitor, represents a potential new treatment direction with fewer side effects for men with recurrent prostate cancer, researchers said.

“To our knowledge, this study is the first clinical trial of an MAO inhibitor in cancer patients,” senior author Jean Shih, a University Professor in USC’s School of Pharmacy who has studied the enzyme MAO, or monoamine oxidase, for four decades, said in as statement. .

The research appears in Prostate Cancer and Prostatic Diseases.

“If our findings are confirmed, this could be part of a new avenue for patients that could avoid undesirable side effects of standard therapies,” first author Mitchell Gross, a medical oncologist and research director at the Lawrence J. Ellison Institute for Transformative Medicine of USC, said in a statement. Gross and Shih have been collaborating for several years to bring her research out of the lab and into the clinic.

In the study, 11 of 20 participants had a measurable decline in their PSA levels after 12 weeks of twice-a-day treatment, with the greatest decline in PSA being a 74% drop.

In prostate cancer, MAO inhibitors disrupt androgen receptor signaling — the main growth pathway for prostate cancer. Previous studies with animals and human prostate cancer cell lines showed that MAO inhibitors decreased the growth and spread of prostate cancer, the researchers found.

Because the MAO inhibitor phenelzine is already FDA-approved, the researchers were able to rapidly design and implement a pilot study to test the drug’s ability to fight cancer.

For this study, researchers enrolled 20 participants who had been treated for prostate cancer and who had elevated PSA levels. Patients received the MAO inhibitor phenelzine twice a day for 12 weeks. Fifty-five percent of the men experienced PSA declines; five of them saw PSA level declines of 30% or more; two participants saw decreases of 50% or more.

Three patients had to drop out due to dizziness or hypertension.

The main limitations of the study include the lack of a placebo comparison group and the small sample size, researchers said. Additional studies are planned.

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