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96.5% Adverse Events reported in mCRPC patients with Tecentriq + Xtandi Combination therapy

Researchers speculated that enzalutamide (Xtandi) could be a candidate for combination with anti-PD-1 or anti-PD-L1 agents such as Tecentriq (atezolizumab) as it “can improve IFNɣ signaling and sensitize cancer cells immune-mediated cell killing “.

In a randomized phase 3 trial IMbassador250 to compare overall survival in patients with metastatic castration resistant prostate cancer (mCRPC) in an advanced stage study has failed tremendously. Overall survival was the main goal of this study, but on the other hand, comparing the results of Tecentriq + Xtandi and Xtandi monotherpay, the median overall survival for the combination of two drugs was drastically shorter at 15.3 months compared to 16.6 months of the Xtandi alone.

Literally all patients in each group had an adverse event, 96.5% of the combined group (Tecentriq + Xtandi) and 91.8% of the monotherapy group (Xtandi). Researchers noted treatment-related adverse effects among 77.8% (28.8% grade 3 to grade 4; 1.9% grade 5) of patients in the combination group compared to 51.1% (9, 6% grade 3 to grade 4; 0.3% grade 5) of patients in the monotherapy group.

The overall result from subgroup analysis also showed that the combination of the drug Tecentriz plus Xtandi had no benefit in terms of overall patient survival. Therefore, the non-beneficial results of the IMbassador250 study led to the early termination of this study.

KOL Comments

“This study is the first phase 3 study to investigate a combination of checkpoint immunotherapy in this disease and has not shown any evidence of differences in cancer control between the two groups” said, Medical Oncologist at the Dana-Farber Cancer Institute & member of American Society of Clinical Oncology

“Despite the current availability of [treatments for] castration-resistant metastatic prostate cancer, most men still die from the disease” said, Medical Oncologist at the Dana-Farber Cancer Institute & member of American Society of Clinical Oncology

Others PARP Inhibitors Combination Studies for Prostate Cancer

To date, PARPs have shown success only in phase 3 in patients with a genetic mutation. In addition, Lynparza (AstraZeneca, Merck) and Rubraca (Clovis) are a PARP candidate for BRCA and ATM mutations. These inhibitors drew all the attention of immuno-oncology or drug manufacturers, who used to be a quick partner in the studies.

In 2017 BMS (Bristol-Myers Squibb) collaborated with Clovis to start a Phase 2 study in combination with Opdivo and Rubraca for prostate cancer. The study started in August 2018 and has a primary completion date in October 2020.

“We are very excited to study Rubraca and Opdivo in combination and the potential to create new therapeutic options for patients with multiple tumor types as well as for patients in addition to those with BRCA mutations.” said, President and Chief Executive Officer, Clovis Oncology.

Along with a serious failure of the Roche combination study, Merck will also test its Keytruda with Xtandi in a Phase 2 study similar to that of Tecentriq. Keytruda has lost the extent of overall survival, which is the standard class for evaluating the effectiveness of cancer therapy. Compared to the 30% cut in global risk of death for Roche Tecentriq and AstraZeneca Imfinzi in 27% in their separate study, both are substantially higher than 20% of Keytruda.

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