【Explanation】From simple taste to ascendant: Analysis of the development trend of prostate cancer immunotherapy

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.

Foreword According to the latest data from Globocan 2020, prostate cancer is the second most common type of cancer in men worldwide and the fifth leading cause of death from cancer in men
.

There will be approximately 1.
4 million new cases and 375,000 deaths worldwide in 2020
.

In recent years, the incidence and mortality of prostate cancer in China have been increasing year by year, ranking sixth among men1, which is one of the main challenges faced by urinary oncologists
.

Expert profile Professor Xing Nianzeng Chief physician, doctoral student and post-doctoral tutor, Hebei Hospital, Chinese Academy of Medical Sciences Tumor Hospital-Vice President, National Cancer Center, Chinese Academy of Medical Sciences Tumor Hospital-Urology Director, Chinese Physician Association Urology Branch Chairman, National Committee of the Chinese People's Political Consultative Conference Talent Project-National Talents, National "Young and Middle-aged Experts with Outstanding Contributions", "National Famous Doctors" Enjoy the Special Allowance of the State Council, Director and Member of the Urological Oncology Committee of China Human Health Promotion Committee A number of technologies are at the domestic or international advanced level.
Published more than 300 academic papers at home and abroad, and won more than 10 scientific and technological awards at or above the provincial and ministerial level.
Physician, Youth Committee of the Urological Oncology Committee of the Chinese Anti-Cancer Association Member of the Beijing Cancer Society Member and Secretary of the Urinary Oncology Committee of the Beijing Cancer Society Member and Secretary General of the Urological Oncology Committee of the Beijing Cancer Society Association Youth Director, Beijing Anti-Cancer Association Urinary Male Reproductive Tumor Professional Committee, Youth Committee Member and Secretary, Beijing Association of Integrated Traditional Chinese and Western Medicine Urology Professional Committee Member, Beijing Medical Association Urology Branch Digital Urology Group Member, Chinese Anti-Cancer Association Photodynamic Committee Member Limited Patients with prostate cancer have a longer survival period, but when the disease progresses to an advanced or metastatic stage, the overall survival (OS) declines in a precipitous manner
.

Data from the US SEER database from 2004 to 2010 show that the 5-year survival rate for localized prostate cancer is 100%, while that for metastatic prostate cancer is only 28%2
.

The staging of prostate cancer in China is later than that in the United States, and 70% of the first diagnosed patients are in the advanced stage or metastatic stage
.

Although the 5-year survival rate of prostate cancer in China has steadily increased to 69.
2%, it is still significantly lower than that of Asian countries such as the United States (97.
4%) and Japan (93%)3
.

Since Charles Huggins invented androgen deprivation therapy (ADT) in 1941, endocrine therapy has been the cornerstone of prostate cancer
.

When the disease progresses to the stage of metastatic castration-resistant prostate cancer (mCRPC), the patient has limited treatment options and the prognosis is extremely poor
.

Since 2011, new endocrine drugs targeting androgen receptors such as abiraterone and enzalutamide have been approved to enter the clinic, bringing significant survival benefits to patients with mCRPC; in addition, docetaxel and cabazitaxel With the definite efficacy of chemotherapeutics, a treatment model based on new endocrine therapy and taxane chemotherapy has gradually formed in the clinic
.

2021NCCN.
V2 version of prostate cancer guidelines: treatment of mCRPC4 However, standard treatment is not all inevitable
.

In the COU-AA-301 and AFFIRM studies, 1/3 and 1/4 of the mCRPC patients receiving abiraterone and enzalutamide showed imaging progression after 3 months of treatment, and all patients were treating 24 Disease progression and drug resistance occurred 5,6 months later
.

Therefore, continuous exploration of new and effective treatment options is a problem faced in clinical work
.

PD-1/PD-L1 inhibitors are currently a hot spot in tumor therapy, and many attempts have been made in the field of prostate cancer
.

However, compared with the outstanding efficacy in lung cancer, esophageal cancer and other cancers, the immunotherapy of prostate cancer appears to be very lonely
.

On the one hand, due to the strong position of new endocrine therapy in mCRPC, on the other hand, the "cold" tumor characteristics of prostate cancer have caused the initial attempts of immunotherapy to be repeatedly frustrated
.

As people’s understanding of the immune microenvironment has deepened, a variety of combined solutions containing PD-1/PD-L1 inhibitors have achieved breakthroughs in the past two years, and immunotherapy has become a prairie fire
.

Immunotherapy breaks the traditional treatment model of mCRPC and reappears opportunities.
This article summarizes the prostate cancer immunotherapy data and ongoing research
.

PD-1/PD-L1 inhibitor single-agent therapy: The key researches on PD-1 inhibitor single-agent therapy include KEYNOTE-199 and KEYNOTE-028
.

In KEYNOTE-199, mCRPC patients who failed the standard treatment had an objective response rate (ORR) of only 5% even if PD-L1 was positive; the survival period of 7.
9-14.
1 months was unsatisfactory
.

Obviously, monotherapy cannot overcome the "cold" tumor characteristics and immune resistance mechanisms of prostate cancer
.

1.
KEYNOTE-199 Cohort 1-37 The KEYNOTE-199 study is an open-label, 5-cohort phase II study.
The 1-3 cohorts are classified into measurable lesions (cohorts 1 and 2) or bone metastases and no bone metastases according to RECIST v1.
1.
RECIST can measure the lesion (cohort 3), and the patient has previously received ≥1 new endocrine therapy and 1-2 chemotherapy regimens (one of which is docetaxel)
.

The results showed that the ORR of cohort 1, cohort 2, and cohort 1+2 were 5%, 3%, and 5%, respectively; PSA remission rate: cohort 1+2+3 was 6%
.

The median duration of response (DOR) for cohort 1 was not reached, and cohort 2 was 10.
6 months
.

The median imaging progression-free survival (rPFS) of cohort 1 and cohort 2 were both 2.
1 months, and the median OS was 9.
5 months and 7.
9 months, respectively
.

2.
The KEYNOTE-0288 study included 23 patients with advanced prostate cancer who had failed standard treatments, and 73.
9% of the patients had received at least two treatment options
.

The main study endpoint is ORR
.

The results showed that 4 patients had partial remission, with an ORR of 17.
4%
.

The median DOR was 13.
5 months
.

The median rPFS and median OS were 3.
5 months and 7.
9 months, respectively
.

Immune combination therapy: in the ascendant In recent years, researches on immunotherapy combined with different mechanisms of drug therapy for mCRPC have been published successively, allowing people to see the determination of PD-1/PD-L1 inhibitors to enter prostate cancer and the dawn of this determination
.

Among them, PD-1 inhibitors combined with chemotherapy, new endocrine therapy, anti-vascular drugs, PARP inhibitors and other attempts have achieved good results
.

PD-1/PD-L1 inhibitor combined with chemotherapy 1.
KEYNOTE-365 Cohort B99KEYNOTE-365 is a phase Ib/II study designed to evaluate pembrolizumab in combination with 4 different drugs (A, B, C, D Cohort) for the efficacy and safety of mCRPC patients
.

Cohort B included patients with mCRPC who had progressed after receiving abiraterone acetate/enzalutamide treatment for ≥4 weeks
.

The patient received pembrolizumab + docetaxel + prednisone treatment
.

The final overall ORR was 23.
1%, and the PSA remission rate was 34.
0%
.

The median rPFS was 8.
5 months, and the median OS was 20.
2 months
.

2.
CheckMate 9KD cohort B10 CheckMate 9KD is a multi-cohort, open-label phase II study
.

Cohort B included mCRPC patients who had not undergone chemotherapy, were undergoing androgen deprivation treatment, and had received up to two new anti-androgen therapies in the past to evaluate the efficacy and safety of nivolumab + docetaxel
.

At a median follow-up of 15.
2 months, the ORRs of patients who received or did not receive new anti-androgen therapy were 38.
7% and 42.
9%, respectively, the median rPFS was 8.
5 months and 12 months, and the median OS was 16.
2 months, respectively.
And not reached
.

From an overall point of view, the combination of nivolumab combined with docetaxel chemotherapy in mCRPC patients who have not undergone chemotherapy has a significant efficacy and reliable safety
.

PD-1/PD-L1 inhibitor combined with new endocrine therapy 1.
KEYNOTE-365 Cohort C11KEYNOTE-365 Study Cohort C cohort observed the efficacy of pembrolizumab combined with enzalutamide in patients after abiraterone resistance
.

The overall patient's PSA remission rate was 21.
8%; among measurable lesions, the ORR was 12%, and the disease control rate (DCR) was 32.
0%; the DCR of non-measurable lesions was 36.
4%
.

The rPFS of the entire group of patients was 6.
1 months, and the OS was 20.
4 months
.

2.
KEYNOTE-199 Cohort 4+512KEYNOTE-199 study cohort 4 and cohort 5 are for patients who have previously failed enzalutamide treatment and have not received docetaxel chemotherapy
.

Cohort4 is a patient with measurable lesions, and cohort5 is a patient with simple bone metastases.
Both received pembrolizumab combined with enzalutamide
.

The primary study endpoint was the ORR of cohort 4
.

The results showed that the ORR of cohort 4 was 12%, the PSA remission rates of cohorts 4 and 5 were 16% and 9%, respectively, the median rPFS was 4.
2 months and 4.
4 months, and the median OS was 17.
6 months and 20.
8 months, respectively.
Month
.

PD-1/PD-L1 inhibitor combined with PARP inhibitor 1.
KEYNOTE-365 Cohort A14 cohort A enrolled 82 patients with mCRPC who had progressed within 6 months (increased PSA or bone or soft tissue imaging)
.

The patient was previously treated with docetaxel and was allowed to receive 1 other chemotherapy or ≤2 second-generation hormone therapy
.

The enrolled patients received pembrolizumab + olaparib
.

Among patients with measurable lesions, the PSA remission rate was 8.
5%, and the ORR was 8.
3%
.

The median rPFS of the overall patient was 4.
3 months, and the median OS was 14.
4 months
.

2.
CheckMate 9KD cohort A115 and cohort A2A1 cohort are included in the 1-2 line of taxane chemotherapy, and at most mCRPC patients who have received 2 times of NHA in the past are allowed to be treated with nivolumab combined with PARP inhibitor rucaparib
.

The results showed that the overall ORR was 10.
3%, the PSA remission rate was 11.
9%, and the median rPFS and median OS were 4.
9 months and 13.
9 months, respectively
.

Distinguishing HRD status for analysis, the ORR of HRD+ and HRD- patients were 17.
2% vs.
3.
4%, and the PSA remission rate was 18.
2% vs.
5.
0%
.

The median rPFS of HRD+ and HRD- patients was 5.
8 months vs.
3.
7 months, and the median OS was 15.
4 months vs.
9.
4 months.
HRD+ patients were more likely to benefit from the treatment of immune combined with PARP inhibitors
.

The ESMO conference in 2021 will soon announce the final follow-up data of the A2 cohort
.

The A2 cohort included patients who had failed NHT treatment but had not undergone chemotherapy, and received vouliumab combined with PARP inhibitor rucaparib
.

PD-1/PD-L1 inhibitors combined with anti-angiogenesis drugs 1.
COSMIC-021 cohort 616COSMIC-021 study is a phase 1b study, cohort 6 aims to evaluate cabotinib combined with atilizumab in the treatment of advanced entities Efficacy and safety of tumors
.

Cohort 6 included 44 CRPC patients who had previously received enzalutamide and/or abiraterone.
The primary endpoint was ORR, and the secondary endpoints were adverse events (AE) and immune-related AEs
.

The results showed that the ORR reached 32%, and the median duration of treatment was 8.
3 months
.

As a major LBA study of ESMO in 2021, the final survival follow-up data of COSMIC-021 cohort 6 will be announced soon
.

Dual immune combination therapy 1.
CheckMate 650 cohort 1+217 CheckMate 650 study enrolled mCRPC patients who had progressed after new endocrine therapy but did not receive chemotherapy and who had progressed after failing to receive taxane chemotherapy, entered Cohort 1 and 2, respectively, and received 4 navole Nivolumab was maintained until the disease progressed after the combination of yumab and ipilimumab
.

The common primary endpoints are ORR and rPFS
.

The confirmed ORRs in cohort 1 (n = 45) and cohort 2 (n = 45) were 25% and 10%, the confirmed PSA response rates were 17.
6% and 10%, respectively, and the median OS was 19.
0 and 15.
2 months
.

Ongoing Phase III studies of PD-1 inhibitors There are 9 phase III studies of PD-1 inhibitor-containing regimens registered on the Clinicaltrial website for the treatment of prostate cancer, including 2 foreign phase III extended studies in China
.

These studies are not limited to the mCRPC population, but also extend to the mHSPC population; the treatment options are all combination treatments, including combined NHA, docetaxel, PARP inhibitors, and antivascular drugs
.

These combination treatments have obtained encouraging data in the above-mentioned phase II study
.

Part of the Phase III study has been recruited and is under follow-up
.

Summary and prospects The efficacy of PD-1 inhibitor single-agent therapy is limited; how to choose an immunological combination therapy mode, give full play to the synergy between different anti-tumor drug mechanisms, and obtain the best tumor control has become the goal of current immunotherapy exploration
.

In recent years, with the publication of multiple research results of immunotherapy combined with chemotherapy, new endocrine therapy, anti-vascular targeted drugs, PARP inhibitors, etc.
, immunotherapy is breaking through the bottleneck of "cold tumor" treatment and opening up a prosperous situation
.

Although these studies are mostly early phase I or phase II clinical studies with small sample sizes, they still show good expected clinical effects
.

A number of Phase III studies are underway, and the results are very much to look forward to
.

With the deepening of research, how to determine the timing, order of use, and optimization of the population of immunotherapy is the next challenge for prostate cancer immunotherapy
.

The research on predicting the efficacy of immunotherapy is still being explored.
With the continuous in-depth exploration of biomarkers, detection techniques and analysis methods, it will also bring new hopes for the immunotherapy of prostate cancer
.

In short, the immunotherapy of prostate cancer has undergone a transition from a simple one to an ascendant.
Although it is not enough to change the overall treatment pattern of prostate cancer at this stage, it can be expected in the future
.

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