Hit the wall again!

*Read only for medical professionals Reference Negative=nothing? Immunotherapy has limited efficacy in most prostate cancer patients, but those who respond often show longer-lasting responses
.

The OS results of the IMbassador 250 study were presented at the 2020 American Association for Cancer Research (AACR) virtual meeting.
to survive
.

Because the likelihood of the trial hitting its primary endpoint was extremely low and it was not deemed to be in the best interests of patients to continue, the study was stopped early following a planned Independent Data Monitoring Committee (IDMC) meeting to assess safety
.

The findings were published in Nature Medicine in January 2022
.

Screenshot of the study IMbassador 250 is an international large-scale open-label randomized phase III clinical study to evaluate the efficacy and safety of atezolizumab combined with enzalutamide versus enzalutamide alone in mCRPC
.

The final study results showed that the addition of checkpoint inhibitors did not further improve overall survival (OS) in patients with mCRPC compared to endocrine therapy with androgen receptor blockers alone, but the broad biomarker analysis relevant to this study was Further exploration of predictive biomarkers of ICIs in mCRPC brings new thinking.
Let us take a closer look at the specific research content
.

A phase Ia clinical trial of mCRPC (NCT01375842) demonstrated clinical activity of atezolizumab, and multiple previous studies have shown that enzalutamide may enhance IFNɣ signaling and sensitize tumor cells to immune-mediated cell killing
.

To further expand the above data, the researchers designed this clinical trial
.

A total of 759 patients with mCRPC who had failed prior abiraterone and docetaxel, or who were ineligible for taxane therapy (without androgen deprivation therapy) were randomized to receive enzalutamide alone or in combination with Tilizumab treatment
.

Primary endpoint was OS, key secondary endpoints were 12-month OS rate, 24-month OS rate, radiographic progression-free survival (rPFS), objective response rate (ORR), time to PSA response, time to PSA progression, and safety
.

At the same time, this study further explored the relationship between biomarkers and treatment efficacy
.

Study results showed that the addition of atezolizumab to enzalutamide did not meet the primary endpoint and did not improve overall survival in the unselected population (stratified HR 1.
12, 95% CI 0.
91-1.
37, P=0.
28)
.

Median OS follow-up was 15.
2 months (95%CI 14.
0-17.
0) in the combination arm and 16.
6 months (95%CI 14.
7-18.
4) in the monotherapy arm
.

In the ITT population, no significant difference in OS was observed between the two groups (stratified hazard ratio = 1.
12, 95% CI 0.
91-1.
37; P = 0.
28)
.

In the key secondary endpoint, the 12-month OS rate in the combination group was slightly better (64.
7% vs.
60.
6%)
.

Subgroup analyses also did not find a benefit of combination therapy over monotherapy
.

The median time to PSA progression in both groups was 2.
8 months
.

The ORR was 13.
7% (95%CI 8.
4%-20.
7%) in the combination arm and 7.
4% (95%CI 3.
7%-13.
0%) in the monotherapy arm
.

In the combination group, 12.
2% (16/131) of patients experienced a partial response (PR), compared with 6.
7% (9/135) in the single-agent group
.

The median duration of response (DOR) was 12.
4 months (95% CI 7.
0-NE) in the combination arm and NE (95% CI 5.
4-NE) in the single-agent arm
.

In terms of safety, almost all patients had adverse events, of which 78% and 51% in the combination group and single-agent group, respectively, were considered to be treatment-related; the incidence of grade 3-4 adverse events was 54% and 35%, of which Treatment-related were 28% and 10%, respectively
.

Serious adverse events and treatment-related serious adverse events were 36% and 14%, respectively, in the combination arm and 22% and 3%, respectively, in the monotherapy arm; discontinuation rates due to adverse events were 14% and 6%, respectively, in the two groups
.

Although there was no significant difference in OS in this study, further analysis of the PFS data revealed that fewer PFS events (HR 0.
28; 95% CI 0.
12-0.
66) and CD8 infiltration were observed in patients with IC2/3 tumors in the combination arm above-average tumors (HR 0.
72; 95% CI 0.
54-0.
96), for which we further explored relevant predictive biomarkers
.

Among the archived tumor samples, prostate tumors showed relatively low expression of key immune biomarkers
.

Altered DNA damage response, phosphatase and tensin homolog status, and PD-L1 expression levels were similar between hormone-sensitive and castration-resistant prostate cancers
.

In a planned biomarker analysis, progression-free survival was longer with atezolizumab in patients with higher PD-L1 IC2/3, CD8 expression, and an established immune gene signature
.

Exploratory analyses linked progression-free survival in the atezolizumab-treated group with immune genes such as CXCL9 and TAP1, and other potentially relevant biomarkers, including phosphatase and tensin homolog alterations, showing immune Increased gene expression in related pathways, including IFN and PD-1 signaling, was associated with longer PFS in the combination group
.

Expert Comments The Phase III IMbassador 250 trial was the first to study the clinical efficacy of the immunotherapy combination of atezolizumab combined with enzalutamide and enzalutamide alone in 759 patients with mCRPC.
Today, with the development of immunotherapy in full swing, The negative result of this study is undoubtedly a pot of "cold water" for us who are full of expectations
.

However, we should find a way forward from the negative results.
In the future, we should provide immunotherapy for prostate cancer patients in a more comprehensive, prudent and open manner
.

In our specific clinical practice, the lack of effective biomarkers hinders clinicians from selecting patients potentially benefiting from immunotherapy
.

Biomarker analysis using 750 patient tissue specimens available in IMbassador 250 showed atezolizumab in patients with PD-L1 IC2/3, higher CD8 expression, and an established immune gene signature.
The progression-free survival of monoclonal antibodies is longer, and the genetic characteristics of these patients are more important in the context of the overall negative results.
The search for more effective prostate cancer-related immune markers is a point we need to focus on in the future
.

We have also seen that some clinical trials are specifically studying the efficacy of ICI in patients selected by mCRPC biomarkers, such as HRD-positive tumors, CDK12-inactivated tumors, MSI-high tumors, etc.
We look forward to the release of relevant research results to help us in the future More comprehensive considerations apply to the prostate cancer patient population with immune checkpoint inhibitors, and prudently select patients from the perspective of biomarkers to provide them with a more precise treatment plan
.

At the same time, we should see that due to the characteristics of prostate cancer with few infiltrating lymphocytes and low tumor mutation load, the exploration of immune checkpoint inhibitor single drugs in prostate cancer has repeatedly hit a wall
.

For example, from the analysis of KEYNOTE-028 results, PD-1 single agent has poor response in CRPC, ORR is about 5%, even in PD-L1 positive patients, it is only 17%
.

But combination therapy has brought us the light, and some studies have evaluated the combination of ICI and standard therapy (anti-androgen, chemotherapy, PARP inhibitor, radium-223, etc.
), and obtained promising results, suggesting that we should use more An open eye is designing a combination regimen to promote the transition from "cold" to "hot" prostate cancer
.

In the past decade, immunotherapy has greatly changed the treatment pattern of malignant tumors, but immune checkpoint inhibitors are by no means a panacea.
Prostate cancer also has hormone dependence, low tumor mutation load and immunosuppressive microenvironment, which is different from other malignant tumors.
characteristics of the tumor
.

Therefore, in the future, it is necessary to have a deep understanding of the immune microenvironment of prostate cancer, comprehensively evaluate the impact of previous treatments on the immune system of patients, prudently select more accurate patient groups, optimize patient selection strategies, and follow the guidelines.
Sequence therapy and other methods overcome the immunosuppression and immune escape of prostate cancer, so that more prostate cancer patients can benefit from immunotherapy
.

Expert Profile Professor Li Xiaojiang Director, Chief Physician, Doctoral Supervisor of Oncology Department of the First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine Chairman of Tianjin Anti-Cancer Association Oncology Traditional Medicine Committee Chairman of Tianjin Traditional Chinese Medicine Association Oncology Professional Committee Chairman of China Anti-Cancer Association Oncology Traditional Standing Member and Secretary General of the Medical Professional Committee Deputy Secretary General and Member of the Oncology Branch of the Chinese Association of Traditional Chinese Medicine Member of the First Youth Council of the China Anti-Cancer Association Member of the Standing Committee of the Joint Oncology Committee