ADXS-PSA/Keytruda Combo Prolongs Survival in mCRPC, Early Trial Results Suggest

Adding ADXS-PSA, an investigational cancer vaccine, to Keytruda (pembrolizumab) is showing positive signs of safety and efficacy in patients with metastatic, castration-resistant prostate cancer (mCRPC), and appears to prolong survival compared with standard-of-care therapy, early results from an ongoing Phase 1/2 trial show.

The results were announced by Advaxis, the company developing ADXS-PSA, and presented in a poster at the recent American Association for Cancer Research (AACR) Annual Meeting 2019 in Atlanta.

Its title was “Effects of ADXS-PSA With or Without Pembrolizumab on Survival and Antigen Spreading in Metastatic, Castration-Resistant Prostate Cancer Patients.”

ADXS-PSA is a potential immunotherapy targeting PSA, a protein overproduced in prostate cancers. It contains live attenuated bacteria (Listeria monocytogenes, Lm) bioengineered to release a hybrid protein that combines a bacterial immune-stimulating molecule (tLLO), and human PSA.

The product was designed to work as a cancer vaccine that helps boost the immune system’s ability to specifically recognize and attack prostate tumors.

In animal models, combining ADXS Lm-based immunotherapies with PD-1 blocking antibodies, such as Keytruda, has been shown to improve efficacy.

Keytruda is a checkpoint inhibitor immunotherapy that blocks a cellular pathway known as PD-1/PD-L1, which helps cancer cells evade the immune system. The medicine is approved for several cancer types, including prostate cancers with a specific genetic marker, referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

A two-part Phase 1/2 trial, called KEYNOTE-046 (NCT02325557), is underway to evaluate the safety, tolerability, and recommended doses of ADXS-PSA alone (part A), and in combination with Merck’s Keytruda (pembrolizumab) (part B).

The trial is being conducted by Advaxis in collaboration with Merck (known as MSD outside the U.S. and Canada) at several centers in the U.S. Target patients are men with mCRPC, including those who have failed chemotherapy and heavily treated previously.

One of the most important findings to date is a good safety profile of the combo. So far, 50 patients have tolerated the treatment well, with the most common treatment-related adverse events being low-grade and temporary (e.g. chills, fever, low blood pressure, nausea, and fatigue).

No additive toxicity, apart from the one expected, was observed.

In light of this data, “the combination of ADXS-PSA and [Keytruda] appeared safe and tolerable in this heavily pretreated, unselected population of patients with bone-predominant mCRPC,” the study states.

The other significant result in patients treated with the combo was a median overall survival of 21.1 months, which is superior to ADXS-PSA alone or standard treatment.

“These results compare favorably to standard-of-care therapy and to study results from similar unselected patient populations with bone-predominant disease, which indicates that this combination warrants further investigation,” said Mark N. Stein, MD, FACS, professor at Columbia University Medical Center and lead author of the study.

Although this is a single-arm study, the combo “appears to show activity and to be associated with prolonged [overall survival] in this population,” researchers said.

Exploratory analysis also showed the dual treatment favored anti-tumor specific immune responses, as evidenced by a T-cell reactivity specific for prostate-specific antigen (PSA) in 75% of the patients taking the combo.

“These data show the clinical potential of ADXS-PSA both alone and in combination with Keytruda. It is meaningful that the combination has been well-tolerated in the study population because dose-related toxicities can present challenges for cancer patients, and an additive therapy with a favorable safety and tolerability profile may offer an attractive option for clinicians if developed further in this indication,” Kenneth A. Berlin, Advaxis’ president and chief executive officer, said in a press release.

“Based on the prolonged survival data and strong safety profile to date, we believe that continued clinical development of ADXS-PSA in combination with Keytruda is warranted and represents a potentially significant opportunity for Advaxis,” he said.