Dr Ravi on the Investigation of RCB Following ARPI Treatment in High-Risk Prostate Cancer

Praful K. Ravi, MB, BChir, MRCP, medical oncologist, Lank Center for Genitourinary Oncology, medical director, GU Theranostics, Dana-Farber Cancer Institute, instructor, medicine, Harvard Medical School, discusses the rationale for a study evaluating the prognostic impact of residual cancer burden (RCB) on long-term outcomes after neoadjuvant androgen receptor pathway inhibitor (ARPI) and radical prostatectomy (RP) in patients with high-risk localized prostate cancer (HRLPC).

This study focused on patients receiving neoadjuvant therapy before surgery for high-risk prostate cancer, a practice not yet considered standard of care, Ravi begins. Multiple trials have been conducted using ARPI as neoadjuvant treatment for patients with high-risk disease. Investigators pooled data from patients across 5 of these trials to assess their long-term outcomes, particularly focusing on metastasis-free survival (MFS), which is a known surrogate for overall survival in this context, according to Ravi. Previous reports have primarily concentrated on early end points, such as pathologic outcomes, so this analysis aimed to provide insight into the long-term effects of residual disease after surgery and its potential prognostic significance, he reports.

The study included 218 patients from these 5 randomized neoadjuvant trials, with a median follow-up period of approximately 5 years, Ravi continues. The patients received treatment for 6 months prior to undergoing surgery. All patients underwent a central pathology review to assess the extent of residual disease post-surgery, he states. The key focus of this study was on evaluating the pathological response and the amount of residual disease, leading to the calculation of RCB, Ravi explains. This metric is similar to what is used in patients with breast cancer after neoadjuvant chemotherapy, Ravi notes. Investigators correlated RCB with long-term outcomes, specifically looking at MFS—defined as the time until patients developed metastasis or died from the disease post-surgery, Ravi emphasizes.

This analysis sheds light on the potential prognostic value of measuring residual disease following neoadjuvant therapy, offering insights that could influence future treatment strategies for HRLPC, he concludes.

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Praful K. Ravi, MB, BChir, MRCP, discusses the prognostic impact of residual cancer burden on long-term outcomes in high-risk localized prostate cancer.

Dr Ravi on Neoadjuvant ARPIs Prior to Radical Prostatectomy in Prostate Cancer

Praful K. Ravi, MB, BChir, MRCP, medical oncologist, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, instructor, medicine, Harvard Medical School, discusses findings from a pooled analysis of 5 phase 2 trials conducted between 2006 to 2018 that evaluated the use of neoadjuvant androgen receptor pathway inhibitors (ARPIs) prior to radical prostatectomy in patients with high-risk, localized prostate cancer.

Ravi and colleagues presented findings from this pooled analysis at the 

 Metastasis-free survival (MFS) and residual cancer burden (RCB), which was defined as tumor volume multiplied by tumor cellularity, were both evaluated in the study. Investigators showed that RCB was highly prognostic for MFS with this treatment approach, Ravi begins. The 5-year MFS rate for patients treated with ARPIs prior to surgery was 83% (95% CI, 77%-88%). This rate compares favorably with 5-year MFS rates observed in similar high-risk patient populations treated with radiotherapy and androgen deprivation therapy. The study also highlighted the prognostic significance of RCB, showing that the extent of residual disease following neoadjuvant therapy and surgery had a strong correlation with patient outcomes, he reports.

One key finding was that 11% of the patients achieved a pathologic complete response (pCR), defined as RCB-0, and an additional 11% had minimal residual disease, defined as up to 5 mm of residual cancer (RCB-1), Ravi continues. Patients who achieved pCR had a 5-year MFS rate of 100%, meaning none of these patients experienced metastasis or death within the 5-year period, he notes.

Patients with minimal residual disease (RCB-1) also had favorable outcomes, with a 5-year MFS rate of 90%. However, the majority of patients had more extensive residual disease categorized as RCB-2 or RCB-3. These patients demonstrated poorer outcomes, with 5-year MFS rates ranging from 82% to 63%, he explains. The findings suggest that patients with higher residual disease burden after neoadjuvant therapy and surgery are more likely to experience metastasis and poorer long-term outcomes.

This study underscores the importance of RCB as a prognostic marker in high-risk, localized prostate cancer, and it highlights the potential benefit of neoadjuvant ARPIs in improving MFS in this patient population, Ravi concludes.

Praful K. Ravi, MB, BChir, MRCP, discusses the use of neoadjuvant androgen receptor pathway inhibitors prior to radical prostatectomy in high-risk, localized prostate cancer.
 

Dr Ravi on the Potential Use of RCB to Inform Neoadjuvant Strategies in High-Risk Prostate Cancer  

Praful K. Ravi, MB, BChir, MRCP, medical oncologist, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, instructor, medicine, Harvard Medical School, discusses the prognostic value and potential use of residual cancer burden (RCB) to guide intensified neoadjuvant treatment strategies for patients with high-risk localized prostate cancer.

Data from patients treated in 5 neoadjuvant trials at Dana-Farber Cancer Institute between 2006 and 2018 were pooled to evaluate the efficacy of 6 months of neoadjuvant androgen receptor pathway inhibitor (ARPI) therapy, specifically abiraterone acetate (Zytiga), enzalutamide (Xtandi), and abiraterone plus apalutamide (Erleada), combined with androgen deprivation therapy (ADT).

Results presented at the 2024 Kidney Cancer Research Summit demonstrated that the 5-year metastasis-free survival rate for patients with high-risk localized prostate cancer who received this neoadjuvant therapy before radical prostatectomy was over 80%. Moreover, the depth of pathologic response was strongly prognostic for metastasis-free survival, with a 100% 5-year metastasis-free survival rate in patients who achieved a pathologic complete response.

Ravi discusses the implications of these data, noting that neoadjuvant therapy is not yet a standard of care. However, the ongoing phase 3 PROTEUS trial (NCT03767244) aims to determine if treatment with apalutamide plus ADT before and after radical prostatectomy in patients with localized high-risk or locally advanced prostate cancer improves pathologic complete response. If results from PROTEUS prove positive, RCB may become a critical factor in guiding post-neoadjuvant therapy strategies, Ravi states.

Ravi envisions a scenario where patients receive 6 months of neoadjuvant therapy with hormone therapy, ADT, and an ARPI. Patients who achieve an excellent pathological response could be observed post-surgery, he explains. Conversely, patients with significant residual disease (classified as RCB2 or RCB3) could be candidates for trials exploring intensified post-neoadjuvant adjuvant strategies, such as chemotherapy or other agents, he says. However, Ravi notes the need to validate RCB as a prognostic tool within larger cohorts, including the PROTEUS study and other trials, to ensure its robustness across different patient populations.

If future studies confirm the benefits of neoadjuvant therapy and validate the use of RCB, these findings could significantly influence clinical practice, Ravi emphasizes. The ability to stratify patients based on their pathological response to neoadjuvant therapy would allow for more personalized and potentially more effective treatment strategies, he concludes.

Praful K. Ravi, MB, BChir, MRCP, discusses the use of residual cancer burden to guide intensified neoadjuvant treatment in high-risk prostate cancer.

Praful K. Ravi, MB, BChir, MRCP, medical oncologist, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, instructor, medicine, Harvard Medical School, discusses the use of prostate-specific membrane antigen (PSMA)-targeted therapies in metastatic castration-resistant prostate cancer (mCRPC), highlighting the use of the targeted radioligand lutetium Lu 177 vipivotide tetraxetan (formerly 177Lu-PSMA-617; Pluvicto).

® State of the Science Summit™, Ravi and colleagues each gave presentations on topics spanning prostate cancer treatment. Ravi highlighted PSMA-targeted therapies in prostate cancer, specifically focusing on lutetium Lu 177 vipivotide tetraxetan, an FDA-approved targeted radioligand therapy for patients with mCRPC. Ravi shares some of the data that 

 in March 2022, including outcomes from the phase 3 VISION trial (NCT03511664). This international, prospective, open-label, multicenter, randomized study demonstrated an overall survival benefit with the use of lutetium Lu 177 vipivotide tetraxetan compared with standard supportive care, Ravi explains. Notably, the smaller phase 2 TheraP trial (NCT03392428) compared lutetium Lu 177 vipivotide tetraxetan with cabazitaxel (Jevtana) in the same patient population, Ravi notes.

Researchers in the prostate cancer treatment landscape have known about PSMA for a long time, and the biomarker was discovered the 1990s, Ravi expands, adding that in the early 2000s, there was an initial effort to utilize PSMA-targeted agents. Over the past 10 years, investigators revived this effort, which led to the development of agents such as lutetium Lu 177 vipivotide tetraxetan, Ravi explains. Once lutetium Lu 177 vipivotide tetraxetan was developed, it showed very encouraging activity in initial trials, which is what led to the phase 3 confirmatory trial, Ravi says.

Lutetium Lu 177 vipivotide tetraxetan has been the front-runner of PSMA-targeted therapies for many years, Ravi continues. However, other agents are now entering the mix and are under investigation in clinical trials, such as other radioligands, monoclonal antibodies, and PSMA-targeted antibodies, Ravi concludes.

Praful K. Ravi, MB, BChir, MRCP, discusses the use of prostate-specific membrane antigen-targeted therapies in metastatic castration-resistant prostate cancer, highlighting the use of the targeted radioligand lutetium Lu 177 vipivotide tetraxetan.

Dr Ravi on the Use of Lutetium Lu 177 Vipivotide Tetraxetan in mCRPC

Praful K. Ravi, MB, BChir, MRCP, medical oncologist, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, instructor in medicine, Harvard Medical School, discusses ongoing and future clinical trials investigating the use of prostate-specific membrane antigen (PSMA)-targeted therapies in metastatic castration-resistant prostate cancer (mCRPC).

Lu-PSMA-617) was previously studied in the phase 3 VISION trial (NCT03511664), Ravi begins. The trial evaluated PSMA-positive patients who were previously treated with at least one androgen receptor (AR) inhibitor and 1 or 2 taxane regimens. Results from the trial demonstrated that 

Lu-PSMA-617 prolonged both median radiographic progression-free survival (rPFS) and overall survival when added to standard-of-care (SOC) treatment options in mCRPC.

There are 2 main trials currently evaluating the use of this agent in earlier stages of mCRPC, Ravi continues. The phase 3 PSMAfore trial (NCT04689828) is comparing the effect of 

Lu-PSMA-617 vs changing AR-directed therapy (ARDT), on the risk of radiographic progression or death, he explains. The trial population consists of patients with mCRPC or metastatic hormone-sensitive prostate cancer (mHSPC) who were previously treated with an alternate ARDT and not exposed to a taxane-containing regimen. A recent press release stated that the trial had met its primary end point of a clinically meaningful improvement in rPFS, but initial data are still forthcoming, Ravi notes.

Additionally, the phase 3 PSMAddition trial (NCT04720157) aims to investigate the efficacy and safety of 

Lu-PSMA-617 in combination with SOC androgen deprivation therapy (ADT) plus ARDT compared with ARDT and ADT alone in patients with mHSPC, Ravi says.

Aside from these large-scale efforts, several smaller trials have been designed to investigate

Lu-PSMA-617 in combination with PARP inhibitors or immunotherapies, Ravi says. Future research will likely continue the development of these novel combination regimens and focus on implementing PSMA-targeted strategies in earlier stages of disease, he concludes.

Praful K. Ravi, MB, BChir, MRCP, discusses ongoing and future clinical trials investigating the use of prostate-specific membrane antigen-targeted therapies in metastatic castration-resistant prostate cancer.
 

Dr. Ravi on Ongoing Investigation of PSMA-targeted Therapies in mCRPC

Praful K. Ravi, MD, oncology fellow at Dana-Farber Cancer Institute, discusses the evolving treatment landscape of advanced bladder cancer.

Five years ago, the treatment of patients with advanced bladder cancer consisted only of chemotherapy options, Ravi says. Now, the paradigm includes a multitude of therapies including immunotherapy. 

Pembrolizumab (Keytruda) and atezolizumab (Tecentriq) are approved for use in patients with locally advanced or metastatic bladder cancer, says Ravi. Moreover, pembrolizumab has demonstrated an overall survival benefit compared with chemotherapy in patients who have received platinum-based chemotherapy. 

Additionally, targeted therapies with FGFR inhibitors and antibody-drug conjugates have been instrumental in expanding the landscape, Ravi explains.

In the future, personalization of therapy, as well as optimization of sequencing will be critical areas of research, concludes Ravi.

Praful K. Ravi, MD, discusses the evolving treatment landscape of advanced bladder cancer.  



Praful K. Ravi, MD

Articles

Dr Ravi on the Investigation of RCB Following ARPI Treatment in High-Risk Prostate Cancer

Dr Ravi on Neoadjuvant ARPIs Prior to Radical Prostatectomy in Prostate Cancer

Dr Ravi on the Potential Use of RCB to Inform Neoadjuvant Strategies in High-Risk Prostate Cancer

Dr Ravi on the Use of Lutetium Lu 177 Vipivotide Tetraxetan in mCRPC

Dr. Ravi on Ongoing Investigation of PSMA-targeted Therapies in mCRPC

Dr. Ravi on the Evolving Treatment Landscape of Advanced Bladder Cancer