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*For medical professionals only, the 2022 American Society of Clinical Oncology Symposium on Genitourinary Oncology (ASCO-GU) was successfully held in San Francisco, California, USA from February 17th to 19th
.
As one of the most important academic conferences on urogenital tumors, ASCO-GU aims to provide a platform for academic discussion and cutting-edge knowledge exchange for urologists and other related professionals in the research, diagnosis, and treatment of urologic tumors
.
This conference included a number of research data on the precise diagnosis and treatment of prostate cancer, which has a certain reference value for clinical practice
.
1.
Abstract #186: Comparison of baseline genetic characteristics of newly diagnosed high tumor burden mCSPC patients and non-newly diagnosed high tumor burden mCSPC patients [1] Prognosis of newly diagnosed high tumor burden metastatic castration-sensitive prostate cancer (mCSPC) patients Poor, however, the molecular mechanisms underlying the poor prognosis remain unclear
.
This study aimed to evaluate the genomic characteristics of newly diagnosed high tumor burden mCSPC (dn-hv-mCSPC) and non-newly diagnosed high tumor burden mCSPC (Non-dn-hv-mCSPC)
.
A total of 304 patients with mCSPC were included in the study.
The results showed that 41% and 27% of the newly diagnosed high tumor group and 27% of the non-newly diagnosed high tumor group had ≥2 mutated genes, and the most common mutated genes were TP53, PTEN and SPOP.
(Figure 1)
.
Compared with non-newly diagnosed high tumor patients, newly diagnosed high tumor patients (CHAARTED criteria) had significantly higher TP53 (P=0.
016) and BRCA2 (P=0.
03) mutation rates at baseline (Table 1)
.
Figure 1.
Common Gene Mutations in Newly Diagnosed and Non-Newly Diagnosed MCSPCs Table 1.
Proportions of Common Gene Mutations in Newly Diagnosed and Non-Newly Diagnosed mCSPCs In this real-world patient study, new Patients diagnosed with high tumor had a higher proportion of gene mutation, and the correlation between the difference in baseline characteristics and gene mutation between the two groups needs to be further analyzed
.
Expert comment: With the continuous enrichment of prostate cancer treatment options, patients with metastatic hormone-sensitive prostate cancer (mHSPC) have more treatment options, but the prognosis of newly diagnosed mHSPC patients with high tumor burden is still poor, and the poor prognosis The molecular mechanism behind it is unclear
.
In this study published by ASCO-GU, the genetic characteristics of newly diagnosed patients with high tumor burden were analyzed.
The results of the study showed that the most commonly mutated genes in patients with newly diagnosed high tumor and non-newly diagnosed high tumor were TP53 and PTEN.
and SPOP, and newly diagnosed high tumor patients had a higher proportion of gene mutation than non-newly diagnosed high tumor patients
.
The results of this study provide a certain reference for the future targeted therapy of mHSPC
.
2.
Abstract #267: Transcriptome identification of prostate cancer patients with active surveillance of apalutamide therapy [2] A report at the 2020 SUO Congress on limited-stage very low-risk, low-risk and Preliminary results from a phase II study evaluating efficacy in low- and intermediate-risk prostate cancer patients showed that a significant proportion (59%) of patients had a positive re-biopsy pathology result after 90 days of apalutamide treatment.
was negative (Schweizer et al, SUO Annual Meeting 2020)
.
To assess biomarkers of response to apalutamide treatment in patients with localized early-stage prostate cancer, we performed transcriptomic analysis of tumor tissue from enrolled patients
.
The study included 23 patients, 22 of whom completed 3 months of apalutamide treatment and underwent post-treatment biopsies
.
The results of the study showed that the transcriptome features of ductal (Luminal) and basal (Basal) were mixed at baseline, but the transcriptome of basal (Basal) was more dominant after treatment (Figure 2); Figure 2.
Different Differences in gene expression at time points on day 91 (D91) after initiation of treatment, androgen receptor signaling (P=0.
02) (Figure 3) and estrogen receptor signaling (P<0.
01) (Figure 4 ) were significantly decreased; at D365, only the gene transcription levels of the estrogen receptor signaling pathway were continuously inhibited (P=0.
03); Figure 3.
The gene transcription levels of the androgen signaling pathwayFigure 4.
The estrogen signaling pathway The gene transcription level signaling pathway analysis showed that compared with baseline, the gene transcription level of angiogenic signaling pathway was significantly up-regulated at D91 (P<0.
01) and D365 (P=0.
10) (Fig.
5)
.
At D91, the transcription levels of inflammation-related genes were also significantly up-regulated (Fig.
6); Fig.
5.
The transcriptional levels of genes in angiogenesis signaling pathwaysFig.
6.
The transcriptional levels of inflammation-related genes Among the Gleason grading groups, responders and non-responders: GG1: 8/15 (53%), GG2: 5/7 (71%) (Fisher's exact test P=0.
65); Patients with higher Decipher scores had better responses; higher Cuzick cell cycle progression scores were associated with better responses (P=0.
14); higher rates of nucleotide excision repair (P=0.
07) and TP53 mutations at baseline (P=0.
07) 0.
03) had better responses; this study observed significant transcriptomic changes after 90 days of apalutamide treatment in actively monitored prostate cancer patients, suggesting persistent differences within one year of patient enrollment, with higher Baseline Decipher risk score and other prognostic scores were associated with better response to apalutamide treatment
.
Subsequent prospective studies are warranted to evaluate the benefit of apalutamide in high-risk prostate cancer (PC) patients undergoing active surveillance
.
Expert comment: The research program of apalutamide, a novel androgen receptor inhibitor, covers all stages of prostate cancer, including mHSPC, NM-CRPC, neoadjuvant and adjuvant therapy for limited-stage prostate cancer, among which TITAN research and The SPARTAN study has demonstrated a significant survival benefit with apalutamide in patients with mHSPC and NM-CRPC
.
The congress reported on the genetic signature of active surveillance of apalutamide therapy in localized early-stage prostate cancer.
The results of this phase II study showed that 59% of patients after 90 days of apalutamide treatment, the pathological results of re-biopsy were determined by Positive turned negative, and at the same time, significant transcriptomic changes were observed before and after treatment
.
This result provides a very meaningful reference for the early intervention of prostate cancer, allowing clinicians to see the effect of early intervention.
Of course, the long-term survival benefit of this study needs further research
.
3.
Abstract #279: Safety and preliminary antitumor activity evaluation of a PSMA/CD3 bispecific antibody (JNJ-081) for the treatment of mCRPC[3] PSMA progressively increases after antiandrogen therapy in prostate cancer , so PSMA is a potential therapeutic target
.
JNJ-081 is a dual-antibody drug in which one arm binds PSMA on tumor cells and the other arm binds CD3 on T cells
.
The study disclosed the safety and preliminary efficacy profile of JNJ-081
.
As of May 10, 2021, a total of 39 patients with metastatic castration-resistant prostate cancer (mCRPC) who had received multiple lines of therapy were enrolled in the study.
The patients received JNJ-081 intravenously and subcutaneously.
Dosage escalation
.
The study results showed that subjects were safe and well-tolerated, with grade 2 cytokine release syndrome (CRS) observed in patients given high-dose intravenously, but reduced with subcutaneous administration and dose escalation Incidence of CRS
.
PSA reductions were observed in subjects at doses ≥30 μg/kg, with 2 subjects receiving 55 μg/kg subcutaneously with >50% reductions in PSA (Figure 7)
.
Figure 7.
PSA response in end-line mCRPC after subcutaneous injection of JNJ-081.
PSMA-CD3 dual antibody (JNJ-081) as a novel drug to mediate T cell targeting to PSMA shows therapeutic potential in mCRPC
.
4.
Abstract #17: ARDENT study: A phase I/II study of proteolytic targeting chimera targeting androgen receptor (PROTAC) ARV-110 in mCRPC [4] Bavdegalutamide (ARV-110) is a proteolytic target An innovative oral AR degrader developed towards chimera (PROTAC) technology
.
In a phase I/II study [4], ARV-110 showed targeting of wild-type AR and AR variants and preliminary efficacy in patients
.
As of August 26, 2021, a total of 173 mCRPC patients were enrolled in the study
.
Results of the study showed that of 140 patients with evaluable biomarker data, of whom 26 had AR T878A/S and/or H875Y mutations, PSA decreased by ≥50% (PSA 50) and ≥30% ( PSA 30) were 46% and 58%, respectively, while those without these mutations had PSA 50 and PSA 30 rates of 10% and 23%, respectively (Figure 8)
.
Figure 8.
Patient PSA Response Among 7 patients with AR T878A/S and/or H875Y mutations evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), 6 had tumor shrinkage (2 of which were partial responses).
(Fig.
9)
.
Figure 9.
Changes in Tumor Volume in Patients The results of this study suggest that ARV-110 has antitumor activity in mCRPC patients after previous intensive therapy, including novel endocrine therapy; AR T878X/H875Y mutant patients may be ARV-110-treated Potential advantage population; further validation of ARV-110 for the treatment of mCRPC is warranted
.
Expert comments: Prostate cancer is a progressive disease.
After treatment, the vast majority of mHSPC patients may still develop into mCRPC and require further treatment
.
With the continuous development of targeted therapy research, it has brought hope to the majority of patients, indicating that the diagnosis and treatment of prostate cancer has entered the era of precision
.
Targeted therapy is gradually becoming a new direction for the treatment of prostate cancer in the future due to its precise and remarkable curative effect
.
At the same time, finding new therapeutic targets will also become a hot spot in the research and development of prostate cancer drugs
.
At this ASCO-GU conference, the preliminary evaluation results of two targeted therapy drugs, JNJ-081 and ARV-110, were reported
.
JNJ-081 is a PSMA/CD3 bispecific antibody, and the study reported this time preliminarily demonstrated the safety and efficacy of JNJ-081
.
ARV-110 is an innovative oral AR degrader developed using Protein Degradation Targeted Chimera (PROTAC) technology
.
In the Phase I/II study reported here, ARV-110 demonstrated targeting of wild-type AR and AR variants and initial efficacy in patients
.
We look forward to the results of further validation of these two drugs in future large-scale clinical studies, hoping to become a new option for mCRPC treatment
.
Expert Profile Professor Zhou Wenquan Deputy Director, Professor, Chief Physician, Doctoral Supervisor of Urology Department of Eastern Theater General Hospital Professor of Nanjing Medical University, Nanjing University School of Medicine, Southeast University School of Medicine, and Southern Medical University Standing Committee Member of the Urology Branch of Jiangsu Medical Association Standing Committee Member of the Urology Branch of Jiangsu Integrated Traditional Chinese and Western Medicine Editorial Board of the Chinese Journal of Andrology Won 1 second prize and 1 third prize for military medical achievements, and the second prize of the Military Science and Technology Progress Award 1 project, 1 second prize of Jiangsu Province Science and Technology Progress Award, hosted and participated in 4 national natural topics, and cooperated in 1 national 973 project branch project.
The first or corresponding author published nearly 50 papers (more than 10 SCI papers, the highest IF 17.
8) Reference: [1].
Nicolas S et al.
Genomic characterization of patients (pts) with de-novo high-volume metastatic castration-sensitive prostate cancer (dn-hv-mCSPC) compared to those without dn-hvmCSPC.
2022 ASCO-GU abstr 189[2].
Schweizer MT.
Transcriptomic discriminators of response to apalutamide in patients with prostate cancer (PC) on active surveillance (AS).
J Clin Oncol 40, 2022 (suppl 6; abstr 267)[3] .
Lim EA, et al.
Safety and preliminary clinical activity of JNJ-63898081 (JNJ-081), a PSMA and CD3 bispecific antibody, for the treatment of metastatic castrate-resistant prostate cancer (mCRPC).
J Clin Oncol 40,2022 (suppl 6; abstr 279)[4].
Gao X, et al.
Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC).
J Clin Oncol 40, 2022 (suppl 6; abstr 17)*This article is for the purpose of providing scientific information to medical professionals only and does not represent the views of this platform
.
As one of the most important academic conferences on urogenital tumors, ASCO-GU aims to provide a platform for academic discussion and cutting-edge knowledge exchange for urologists and other related professionals in the research, diagnosis, and treatment of urologic tumors
.
This conference included a number of research data on the precise diagnosis and treatment of prostate cancer, which has a certain reference value for clinical practice
.
1.
Abstract #186: Comparison of baseline genetic characteristics of newly diagnosed high tumor burden mCSPC patients and non-newly diagnosed high tumor burden mCSPC patients [1] Prognosis of newly diagnosed high tumor burden metastatic castration-sensitive prostate cancer (mCSPC) patients Poor, however, the molecular mechanisms underlying the poor prognosis remain unclear
.
This study aimed to evaluate the genomic characteristics of newly diagnosed high tumor burden mCSPC (dn-hv-mCSPC) and non-newly diagnosed high tumor burden mCSPC (Non-dn-hv-mCSPC)
.
A total of 304 patients with mCSPC were included in the study.
The results showed that 41% and 27% of the newly diagnosed high tumor group and 27% of the non-newly diagnosed high tumor group had ≥2 mutated genes, and the most common mutated genes were TP53, PTEN and SPOP.
(Figure 1)
.
Compared with non-newly diagnosed high tumor patients, newly diagnosed high tumor patients (CHAARTED criteria) had significantly higher TP53 (P=0.
016) and BRCA2 (P=0.
03) mutation rates at baseline (Table 1)
.
Figure 1.
Common Gene Mutations in Newly Diagnosed and Non-Newly Diagnosed MCSPCs Table 1.
Proportions of Common Gene Mutations in Newly Diagnosed and Non-Newly Diagnosed mCSPCs In this real-world patient study, new Patients diagnosed with high tumor had a higher proportion of gene mutation, and the correlation between the difference in baseline characteristics and gene mutation between the two groups needs to be further analyzed
.
Expert comment: With the continuous enrichment of prostate cancer treatment options, patients with metastatic hormone-sensitive prostate cancer (mHSPC) have more treatment options, but the prognosis of newly diagnosed mHSPC patients with high tumor burden is still poor, and the poor prognosis The molecular mechanism behind it is unclear
.
In this study published by ASCO-GU, the genetic characteristics of newly diagnosed patients with high tumor burden were analyzed.
The results of the study showed that the most commonly mutated genes in patients with newly diagnosed high tumor and non-newly diagnosed high tumor were TP53 and PTEN.
and SPOP, and newly diagnosed high tumor patients had a higher proportion of gene mutation than non-newly diagnosed high tumor patients
.
The results of this study provide a certain reference for the future targeted therapy of mHSPC
.
2.
Abstract #267: Transcriptome identification of prostate cancer patients with active surveillance of apalutamide therapy [2] A report at the 2020 SUO Congress on limited-stage very low-risk, low-risk and Preliminary results from a phase II study evaluating efficacy in low- and intermediate-risk prostate cancer patients showed that a significant proportion (59%) of patients had a positive re-biopsy pathology result after 90 days of apalutamide treatment.
was negative (Schweizer et al, SUO Annual Meeting 2020)
.
To assess biomarkers of response to apalutamide treatment in patients with localized early-stage prostate cancer, we performed transcriptomic analysis of tumor tissue from enrolled patients
.
The study included 23 patients, 22 of whom completed 3 months of apalutamide treatment and underwent post-treatment biopsies
.
The results of the study showed that the transcriptome features of ductal (Luminal) and basal (Basal) were mixed at baseline, but the transcriptome of basal (Basal) was more dominant after treatment (Figure 2); Figure 2.
Different Differences in gene expression at time points on day 91 (D91) after initiation of treatment, androgen receptor signaling (P=0.
02) (Figure 3) and estrogen receptor signaling (P<0.
01) (Figure 4 ) were significantly decreased; at D365, only the gene transcription levels of the estrogen receptor signaling pathway were continuously inhibited (P=0.
03); Figure 3.
The gene transcription levels of the androgen signaling pathwayFigure 4.
The estrogen signaling pathway The gene transcription level signaling pathway analysis showed that compared with baseline, the gene transcription level of angiogenic signaling pathway was significantly up-regulated at D91 (P<0.
01) and D365 (P=0.
10) (Fig.
5)
.
At D91, the transcription levels of inflammation-related genes were also significantly up-regulated (Fig.
6); Fig.
5.
The transcriptional levels of genes in angiogenesis signaling pathwaysFig.
6.
The transcriptional levels of inflammation-related genes Among the Gleason grading groups, responders and non-responders: GG1: 8/15 (53%), GG2: 5/7 (71%) (Fisher's exact test P=0.
65); Patients with higher Decipher scores had better responses; higher Cuzick cell cycle progression scores were associated with better responses (P=0.
14); higher rates of nucleotide excision repair (P=0.
07) and TP53 mutations at baseline (P=0.
07) 0.
03) had better responses; this study observed significant transcriptomic changes after 90 days of apalutamide treatment in actively monitored prostate cancer patients, suggesting persistent differences within one year of patient enrollment, with higher Baseline Decipher risk score and other prognostic scores were associated with better response to apalutamide treatment
.
Subsequent prospective studies are warranted to evaluate the benefit of apalutamide in high-risk prostate cancer (PC) patients undergoing active surveillance
.
Expert comment: The research program of apalutamide, a novel androgen receptor inhibitor, covers all stages of prostate cancer, including mHSPC, NM-CRPC, neoadjuvant and adjuvant therapy for limited-stage prostate cancer, among which TITAN research and The SPARTAN study has demonstrated a significant survival benefit with apalutamide in patients with mHSPC and NM-CRPC
.
The congress reported on the genetic signature of active surveillance of apalutamide therapy in localized early-stage prostate cancer.
The results of this phase II study showed that 59% of patients after 90 days of apalutamide treatment, the pathological results of re-biopsy were determined by Positive turned negative, and at the same time, significant transcriptomic changes were observed before and after treatment
.
This result provides a very meaningful reference for the early intervention of prostate cancer, allowing clinicians to see the effect of early intervention.
Of course, the long-term survival benefit of this study needs further research
.
3.
Abstract #279: Safety and preliminary antitumor activity evaluation of a PSMA/CD3 bispecific antibody (JNJ-081) for the treatment of mCRPC[3] PSMA progressively increases after antiandrogen therapy in prostate cancer , so PSMA is a potential therapeutic target
.
JNJ-081 is a dual-antibody drug in which one arm binds PSMA on tumor cells and the other arm binds CD3 on T cells
.
The study disclosed the safety and preliminary efficacy profile of JNJ-081
.
As of May 10, 2021, a total of 39 patients with metastatic castration-resistant prostate cancer (mCRPC) who had received multiple lines of therapy were enrolled in the study.
The patients received JNJ-081 intravenously and subcutaneously.
Dosage escalation
.
The study results showed that subjects were safe and well-tolerated, with grade 2 cytokine release syndrome (CRS) observed in patients given high-dose intravenously, but reduced with subcutaneous administration and dose escalation Incidence of CRS
.
PSA reductions were observed in subjects at doses ≥30 μg/kg, with 2 subjects receiving 55 μg/kg subcutaneously with >50% reductions in PSA (Figure 7)
.
Figure 7.
PSA response in end-line mCRPC after subcutaneous injection of JNJ-081.
PSMA-CD3 dual antibody (JNJ-081) as a novel drug to mediate T cell targeting to PSMA shows therapeutic potential in mCRPC
.
4.
Abstract #17: ARDENT study: A phase I/II study of proteolytic targeting chimera targeting androgen receptor (PROTAC) ARV-110 in mCRPC [4] Bavdegalutamide (ARV-110) is a proteolytic target An innovative oral AR degrader developed towards chimera (PROTAC) technology
.
In a phase I/II study [4], ARV-110 showed targeting of wild-type AR and AR variants and preliminary efficacy in patients
.
As of August 26, 2021, a total of 173 mCRPC patients were enrolled in the study
.
Results of the study showed that of 140 patients with evaluable biomarker data, of whom 26 had AR T878A/S and/or H875Y mutations, PSA decreased by ≥50% (PSA 50) and ≥30% ( PSA 30) were 46% and 58%, respectively, while those without these mutations had PSA 50 and PSA 30 rates of 10% and 23%, respectively (Figure 8)
.
Figure 8.
Patient PSA Response Among 7 patients with AR T878A/S and/or H875Y mutations evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), 6 had tumor shrinkage (2 of which were partial responses).
(Fig.
9)
.
Figure 9.
Changes in Tumor Volume in Patients The results of this study suggest that ARV-110 has antitumor activity in mCRPC patients after previous intensive therapy, including novel endocrine therapy; AR T878X/H875Y mutant patients may be ARV-110-treated Potential advantage population; further validation of ARV-110 for the treatment of mCRPC is warranted
.
Expert comments: Prostate cancer is a progressive disease.
After treatment, the vast majority of mHSPC patients may still develop into mCRPC and require further treatment
.
With the continuous development of targeted therapy research, it has brought hope to the majority of patients, indicating that the diagnosis and treatment of prostate cancer has entered the era of precision
.
Targeted therapy is gradually becoming a new direction for the treatment of prostate cancer in the future due to its precise and remarkable curative effect
.
At the same time, finding new therapeutic targets will also become a hot spot in the research and development of prostate cancer drugs
.
At this ASCO-GU conference, the preliminary evaluation results of two targeted therapy drugs, JNJ-081 and ARV-110, were reported
.
JNJ-081 is a PSMA/CD3 bispecific antibody, and the study reported this time preliminarily demonstrated the safety and efficacy of JNJ-081
.
ARV-110 is an innovative oral AR degrader developed using Protein Degradation Targeted Chimera (PROTAC) technology
.
In the Phase I/II study reported here, ARV-110 demonstrated targeting of wild-type AR and AR variants and initial efficacy in patients
.
We look forward to the results of further validation of these two drugs in future large-scale clinical studies, hoping to become a new option for mCRPC treatment
.
Expert Profile Professor Zhou Wenquan Deputy Director, Professor, Chief Physician, Doctoral Supervisor of Urology Department of Eastern Theater General Hospital Professor of Nanjing Medical University, Nanjing University School of Medicine, Southeast University School of Medicine, and Southern Medical University Standing Committee Member of the Urology Branch of Jiangsu Medical Association Standing Committee Member of the Urology Branch of Jiangsu Integrated Traditional Chinese and Western Medicine Editorial Board of the Chinese Journal of Andrology Won 1 second prize and 1 third prize for military medical achievements, and the second prize of the Military Science and Technology Progress Award 1 project, 1 second prize of Jiangsu Province Science and Technology Progress Award, hosted and participated in 4 national natural topics, and cooperated in 1 national 973 project branch project.
The first or corresponding author published nearly 50 papers (more than 10 SCI papers, the highest IF 17.
8) Reference: [1].
Nicolas S et al.
Genomic characterization of patients (pts) with de-novo high-volume metastatic castration-sensitive prostate cancer (dn-hv-mCSPC) compared to those without dn-hvmCSPC.
2022 ASCO-GU abstr 189[2].
Schweizer MT.
Transcriptomic discriminators of response to apalutamide in patients with prostate cancer (PC) on active surveillance (AS).
J Clin Oncol 40, 2022 (suppl 6; abstr 267)[3] .
Lim EA, et al.
Safety and preliminary clinical activity of JNJ-63898081 (JNJ-081), a PSMA and CD3 bispecific antibody, for the treatment of metastatic castrate-resistant prostate cancer (mCRPC).
J Clin Oncol 40,2022 (suppl 6; abstr 279)[4].
Gao X, et al.
Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC).
J Clin Oncol 40, 2022 (suppl 6; abstr 17)*This article is for the purpose of providing scientific information to medical professionals only and does not represent the views of this platform
