The San Raffaele Urologic Oncology Retreat 2022: From Diagnosis to Advanced Stages: An Overview of Prostate Cancer Trials - Giorgio Gandaglia
November 30, 2022
Giorgio Gandaglia explores the ongoing clinical trials in the field of prostate cancer, from diagnosis to advanced stages of the disease. He begins by discussing the implementation of PET/CT and MRI in diagnosing prostate cancer and the potential benefits of these tools, including the reduction in clinically insignificant detections and biopsies. Gandaglia highlights the role of novel biomarkers in aiding diagnosis. He then delves into neoadjuvant therapies, detailing trials such as PROTEUS, assessing the role of ADT + apalutamide versus ADT alone in high-risk patients. Gandaglia sheds light on research probing the efficacy of pembrolizumab in reducing lymph node invasion in prostate cancer patients. He also covers the various trials underway in the metastatic hormone-sensitive setting, like the AMPLITUDE trial, and the castration-resistant setting, such as the CONTACT-02 and KEYNOTE-365 studies. Finally, he outlines the STELLAR-001 and PETRA trials, investigating multi-targeted inhibitors and PARP inhibitors, respectively.
Biography:
Giorgio Gandaglia, MD, FEBU, Unit of Urology/Division of Oncology, IRCCS Ospedale San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
Biography:
Giorgio Gandaglia, MD, FEBU, Unit of Urology/Division of Oncology, IRCCS Ospedale San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
Read the Full Video Transcript
Giorgio Gandaglia: So good morning, and thank you for this kind invitation. I'd like to thank Professor Necchi for inviting me here today to describe the ongoing clinical trials in the field of prostate cancer. And actually it will be a journey starting from a diagnosis to the latest stage of a disease, such as castration-resistant prostate cancer. We have approximately 20 trials, starting again from diagnosis to castration-resistant stages of the disease. We will focus on the main trials which will be discussed, and we will have a look at the study design. This is an issue which has been already discussed today and it's the role of PET/CT in the diagnosis of prostate cancer. And actually this trial has been recently funded by the Italian Ministry of Health, and it's aimed at evaluating the role of fully hybrid PET/MRI system using PSMA to identify patients at the pre-biopsy stage, who should be considered for a prostate biopsy.
So patients with a suspicion of prostate cancer, who should receive a prostate biopsy, and these patients will receive a fully hybrid PET/MRI. The primary endpoint of the study is the predictive value of this approach for the diagnosis of clinically significant prostate cancer, and for the reduction in the detection of clinically insignificant disease, and the number of biopsies spared. This study is waiting for EC approval, it has being just funded, and it will include 167 patients.
Another interesting ongoing study is on the role of MRI targeted biopsy and the systematic biopsy in patients with a suspicion of prostate cancer. This study has the aim to identify the optimal biopsy scheme for men with a positive MRI before prostate cancer diagnosis. These are the initial results of the study, and we can see that the majority of patients actually have a diagnosis in the first MRI targeted core. When we look at the additional role of concomitant systematic biopsies, we can see that a number of 12 cores should be considered in order to diagnose currently, up to 90% of clinically significant diseases.
We have [inaudible 00:02:36] other imaging modalities, such as micro-ultrasound. This is the US-MIRROR trial, it is a prospective single-arm study, aimed to assess the role of micro-ultrasound for the diagnosis of clinically significant disease. This study currently enrolled more than 100 patients and these are the results. You can see that mpMRI, which is compared to micro-ultrasound in patients before prostate biopsies, so patients who are candidates for a prostate biopsy... While in this setting, a mpMRI has a higher sensitivity and specificity compared to micro-ultrasound, but still we have some patients where a clinical significant disease would have been missed by an MRI alone. So it can still play a role in a subset of patients.
This is a study, which has been extensively discussed by Dr. Brembilla, and it is on the role of artificial intelligence in prostate cancer. We plan to start with patient enrollment in December. Finally, for the diagnosis stage, we have a study aimed at assessing the role of novel biomarkers. This is a commercially available biomarker, SelectMDx, and the aim of our study is to assess the role of SelectMDx in men with a negative or... Let's say, equivocal MRI defined as a PIRADS score equal or lower than 3. This man will receive a SelectMDx test and then will be considered for a systematic biopsy approach.
We will assess, in a total of 314 patients, the sensitivity, specificity, and accuracy of SelectMDx for the identification of clinically significant prostate cancer. When we move to neoadjuvant therapies, we have been involved in the PROTEUS trial, this trial is aimed at assessing the role of ADT + apalutamide versus ADT alone, in a perioperative setting, six month ADT before surgery + six month of ADT after surgery, in high-risk prostate cancer patients. We enrolled 10 patients, with total study population is expected to be more than 2000 patients. The study completion date is in April 2027.
This is a spontaneous trial available at our center, where actually we designed the trial aimed at assessing the role of pembrolizumab in the new advanced setting for high-risk prostate cancer patients. We know the role of immunotherapy in several diseases, in several neurological malignancies, data in prostate cancer patients are still lacking. The aim of our study, this is a prospective, single-arm, Phase 2 study, is to assess the role of pembrolizumab in the reduction of the rate of lymph node invasion in prostate cancer patients. This study has been approved by our ethical committee and we are waiting for a final approval by the Italian regulatory agency. Moving to the staging and restaging setting, we have been very active in the field of PSMA, we were able to develop another tracer for PSMA radio-guided surgery.
This is an ongoing study aimed at enrolling approximately 100 patients. We currently enrolled 30 patients. This study is based on the concept that the use of an intraoperative gamma probe in patients who were injected with 99mTc-PSMA-I&S the day before surgery, could allow us to currently identify the [inaudible 00:06:23] of the metastasis in the lymph nodes and to identify additional metastatic sites, as compared to an anatomically defined pelvic lymph node dissection. You can see that the specificity of the risk is extremely high at the per patient analysis, but still when we look at the sensitivity, we're struggling with a low sensitivity... And this is probably related to the special resolution of the probe, which is better compared to preparative PET/MRI or PET/CT, but still can miss micrometastatic disease. We have also available trials comparing the accuracy of PSMA and bombesin for the detection of metastasis in the primary and recurrent prostate cancer stages. These studies are currently enrolling 50 high risk patients in the primary setting and 60 patients with BCR in the recurrent setting.
Moving to salvage therapies, we are a center participating in the PRIMORDIUM study, which is a randomized, Phase 3, controlled, multicenter open-label trial, enrolling patients with PSMA-PET positive recurrence after radical prostatectomy. These patients are men with a high-risk BCR, as defined by the EAU guidelines. Patients are randomized to radiotherapy + ADT versus radiotherapy + ADT + apalutamide. The treatment phase is a six-month treatment phase... You can see that the follow-up is based on repeated PSMA-PET at 6/12 months and at the time of disease progression based on PSA values. We already enrolled five patients in this study.
When we moved to the metastatic hormone-sensitive setting, the AMPLITUDE trial is currently recruiting patients at our center... This is a large Phase 3 randomized, placebo-controlled double-blind study. The aim is to enroll a total of 788 patients with metastatic castration-sensitive prostate cancer based on conventional imaging alone. All these patients, and all patients included in the trial, are patients with germline or somatic homologous recombination repair gene-mutated metastatic castration sensitive disease. Patients will be randomized to niraparib, which is an orally active PARP inhibitor, or abiraterone alone. So niraparib + abiraterone versus abiraterone alone. The primary endpoint is progression-free survival.
Finally, we move to the non-metastatic castration resistant setting. Here we have an observational study which aims to find out in the real world setting whether darolutamide is a safe and effective option for patients with prostate cancer. And this is again in the m0CRPC setting. The primary endpoint is represented by treatment-emergent adverse events. This study aims to enroll approximately 1000 patients. The first intermediate analysis have been published and released at the GU ASCO 22, where the safety and tolerability profile is consistent with what was reported by Phase 3 randomized trials and in particular the ARAMIS trial.
When talking about metastatic castration-resistant prostate cancer patients, we have an ongoing Phase 3, multicenter, randomized, open-label trial, which is the CONTACT-02 trial. This trial aims to evaluate the efficacy of cabozantinib in combination with atezolizumab versus novel hormonal therapies... And actually this study is focused on patients previously treated with novel hormonal therapies such as abi, apalutamide, darolutamide, or enzalutamide, who have progressed on that hormonal treatment. And the previous docetaxel is allowed. The endpoints are oncological endpoints, such as progression-free survival and overall survival. The expected sample size is approximately 580 patients.
The KEYNOTE-365 study is a study in assessing the safety and the efficacy of the administration of pembrolizumab combination in men with metastatic castration-resistant prostate cancer. This is a Phase 1B/2 study, and the primary endpoint is the decrease of 50% in PSA values, adverse events, and an objective response. You can see that the study design is pretty complex, we have approximately nine different cohorts and the inclusion in each cohort is based on the previous treatment received by the single patient. We are currently recruiting patients for this prospective study.
And finally, we move to TROPION trial, which is a phase 2 trial aimed at assessing the safety of adverse events and the objective response rate of an antibody drug conjugate anti-TROP2 IgG1 mAB, conjugated with a tumor-selective cleavable drug linker.
Here patients with prostate cancer are included in the sub-study cohort three, and they are divided in two groups according to combination therapy. 40 patients in group A + another 30 patients in group B. The STELLAR-001 trial is aimed at assessing a multi-targeted inhibitor of a receptor tyrosine kinases. This is a Phase 1, open-label, multicenter trial, and patients with metastatic castration-resistant prostate cancer are included in this study. You can see that the primary endpoints are mainly the same as compared to previous trials.
And finally, we have been involved also in the PETRA trial, which aims at assessing the safety of a novel PARP inhibitor. Again, here we have five different models, and prostate cancer patients represent approximately 16% of patients included in this trial. The primary endpoint is represented by adverse events. So this final slide is an overview of all available trials at our institution in the field of prostate cancer. And with this, I would like to thank you for your attention.
Giorgio Gandaglia: So good morning, and thank you for this kind invitation. I'd like to thank Professor Necchi for inviting me here today to describe the ongoing clinical trials in the field of prostate cancer. And actually it will be a journey starting from a diagnosis to the latest stage of a disease, such as castration-resistant prostate cancer. We have approximately 20 trials, starting again from diagnosis to castration-resistant stages of the disease. We will focus on the main trials which will be discussed, and we will have a look at the study design. This is an issue which has been already discussed today and it's the role of PET/CT in the diagnosis of prostate cancer. And actually this trial has been recently funded by the Italian Ministry of Health, and it's aimed at evaluating the role of fully hybrid PET/MRI system using PSMA to identify patients at the pre-biopsy stage, who should be considered for a prostate biopsy.
So patients with a suspicion of prostate cancer, who should receive a prostate biopsy, and these patients will receive a fully hybrid PET/MRI. The primary endpoint of the study is the predictive value of this approach for the diagnosis of clinically significant prostate cancer, and for the reduction in the detection of clinically insignificant disease, and the number of biopsies spared. This study is waiting for EC approval, it has being just funded, and it will include 167 patients.
Another interesting ongoing study is on the role of MRI targeted biopsy and the systematic biopsy in patients with a suspicion of prostate cancer. This study has the aim to identify the optimal biopsy scheme for men with a positive MRI before prostate cancer diagnosis. These are the initial results of the study, and we can see that the majority of patients actually have a diagnosis in the first MRI targeted core. When we look at the additional role of concomitant systematic biopsies, we can see that a number of 12 cores should be considered in order to diagnose currently, up to 90% of clinically significant diseases.
We have [inaudible 00:02:36] other imaging modalities, such as micro-ultrasound. This is the US-MIRROR trial, it is a prospective single-arm study, aimed to assess the role of micro-ultrasound for the diagnosis of clinically significant disease. This study currently enrolled more than 100 patients and these are the results. You can see that mpMRI, which is compared to micro-ultrasound in patients before prostate biopsies, so patients who are candidates for a prostate biopsy... While in this setting, a mpMRI has a higher sensitivity and specificity compared to micro-ultrasound, but still we have some patients where a clinical significant disease would have been missed by an MRI alone. So it can still play a role in a subset of patients.
This is a study, which has been extensively discussed by Dr. Brembilla, and it is on the role of artificial intelligence in prostate cancer. We plan to start with patient enrollment in December. Finally, for the diagnosis stage, we have a study aimed at assessing the role of novel biomarkers. This is a commercially available biomarker, SelectMDx, and the aim of our study is to assess the role of SelectMDx in men with a negative or... Let's say, equivocal MRI defined as a PIRADS score equal or lower than 3. This man will receive a SelectMDx test and then will be considered for a systematic biopsy approach.
We will assess, in a total of 314 patients, the sensitivity, specificity, and accuracy of SelectMDx for the identification of clinically significant prostate cancer. When we move to neoadjuvant therapies, we have been involved in the PROTEUS trial, this trial is aimed at assessing the role of ADT + apalutamide versus ADT alone, in a perioperative setting, six month ADT before surgery + six month of ADT after surgery, in high-risk prostate cancer patients. We enrolled 10 patients, with total study population is expected to be more than 2000 patients. The study completion date is in April 2027.
This is a spontaneous trial available at our center, where actually we designed the trial aimed at assessing the role of pembrolizumab in the new advanced setting for high-risk prostate cancer patients. We know the role of immunotherapy in several diseases, in several neurological malignancies, data in prostate cancer patients are still lacking. The aim of our study, this is a prospective, single-arm, Phase 2 study, is to assess the role of pembrolizumab in the reduction of the rate of lymph node invasion in prostate cancer patients. This study has been approved by our ethical committee and we are waiting for a final approval by the Italian regulatory agency. Moving to the staging and restaging setting, we have been very active in the field of PSMA, we were able to develop another tracer for PSMA radio-guided surgery.
This is an ongoing study aimed at enrolling approximately 100 patients. We currently enrolled 30 patients. This study is based on the concept that the use of an intraoperative gamma probe in patients who were injected with 99mTc-PSMA-I&S the day before surgery, could allow us to currently identify the [inaudible 00:06:23] of the metastasis in the lymph nodes and to identify additional metastatic sites, as compared to an anatomically defined pelvic lymph node dissection. You can see that the specificity of the risk is extremely high at the per patient analysis, but still when we look at the sensitivity, we're struggling with a low sensitivity... And this is probably related to the special resolution of the probe, which is better compared to preparative PET/MRI or PET/CT, but still can miss micrometastatic disease. We have also available trials comparing the accuracy of PSMA and bombesin for the detection of metastasis in the primary and recurrent prostate cancer stages. These studies are currently enrolling 50 high risk patients in the primary setting and 60 patients with BCR in the recurrent setting.
Moving to salvage therapies, we are a center participating in the PRIMORDIUM study, which is a randomized, Phase 3, controlled, multicenter open-label trial, enrolling patients with PSMA-PET positive recurrence after radical prostatectomy. These patients are men with a high-risk BCR, as defined by the EAU guidelines. Patients are randomized to radiotherapy + ADT versus radiotherapy + ADT + apalutamide. The treatment phase is a six-month treatment phase... You can see that the follow-up is based on repeated PSMA-PET at 6/12 months and at the time of disease progression based on PSA values. We already enrolled five patients in this study.
When we moved to the metastatic hormone-sensitive setting, the AMPLITUDE trial is currently recruiting patients at our center... This is a large Phase 3 randomized, placebo-controlled double-blind study. The aim is to enroll a total of 788 patients with metastatic castration-sensitive prostate cancer based on conventional imaging alone. All these patients, and all patients included in the trial, are patients with germline or somatic homologous recombination repair gene-mutated metastatic castration sensitive disease. Patients will be randomized to niraparib, which is an orally active PARP inhibitor, or abiraterone alone. So niraparib + abiraterone versus abiraterone alone. The primary endpoint is progression-free survival.
Finally, we move to the non-metastatic castration resistant setting. Here we have an observational study which aims to find out in the real world setting whether darolutamide is a safe and effective option for patients with prostate cancer. And this is again in the m0CRPC setting. The primary endpoint is represented by treatment-emergent adverse events. This study aims to enroll approximately 1000 patients. The first intermediate analysis have been published and released at the GU ASCO 22, where the safety and tolerability profile is consistent with what was reported by Phase 3 randomized trials and in particular the ARAMIS trial.
When talking about metastatic castration-resistant prostate cancer patients, we have an ongoing Phase 3, multicenter, randomized, open-label trial, which is the CONTACT-02 trial. This trial aims to evaluate the efficacy of cabozantinib in combination with atezolizumab versus novel hormonal therapies... And actually this study is focused on patients previously treated with novel hormonal therapies such as abi, apalutamide, darolutamide, or enzalutamide, who have progressed on that hormonal treatment. And the previous docetaxel is allowed. The endpoints are oncological endpoints, such as progression-free survival and overall survival. The expected sample size is approximately 580 patients.
The KEYNOTE-365 study is a study in assessing the safety and the efficacy of the administration of pembrolizumab combination in men with metastatic castration-resistant prostate cancer. This is a Phase 1B/2 study, and the primary endpoint is the decrease of 50% in PSA values, adverse events, and an objective response. You can see that the study design is pretty complex, we have approximately nine different cohorts and the inclusion in each cohort is based on the previous treatment received by the single patient. We are currently recruiting patients for this prospective study.
And finally, we move to TROPION trial, which is a phase 2 trial aimed at assessing the safety of adverse events and the objective response rate of an antibody drug conjugate anti-TROP2 IgG1 mAB, conjugated with a tumor-selective cleavable drug linker.
Here patients with prostate cancer are included in the sub-study cohort three, and they are divided in two groups according to combination therapy. 40 patients in group A + another 30 patients in group B. The STELLAR-001 trial is aimed at assessing a multi-targeted inhibitor of a receptor tyrosine kinases. This is a Phase 1, open-label, multicenter trial, and patients with metastatic castration-resistant prostate cancer are included in this study. You can see that the primary endpoints are mainly the same as compared to previous trials.
And finally, we have been involved also in the PETRA trial, which aims at assessing the safety of a novel PARP inhibitor. Again, here we have five different models, and prostate cancer patients represent approximately 16% of patients included in this trial. The primary endpoint is represented by adverse events. So this final slide is an overview of all available trials at our institution in the field of prostate cancer. And with this, I would like to thank you for your attention.