Residual Cancer Burden May Prognosticate Outcomes With Neoadjuvant Therapy in Prostate Cancer

Measuring residual cancer burden (RCB) in clinical trials may guide post-neoadjuvant and adjuvant treatment decisions for patients with high-risk, localized prostate cancer, according to Praful Ravi, MB, BChir, MRCP.

At the 2024 ASCO Annual Meeting, Ravi and colleagues presented findings from a pooled analysis of 5 phase 2 trials conducted between 2006 to 2018 that evaluated neoadjuvant androgen receptor pathway inhibitors (ARPIs) prior to radical prostatectomy in patients with high-risk, localized prostate cancer. This analysis measured metastasis-free survival (MFS), as well as RCB, which was defined as tumor volume multiplied by tumor cellularity. Investigators observed a 5-year MFS rate of 83% (95% CI, 77%-88%) with this treatment approach and found that RCB was highly prognostic for MFS.

“Validation of these findings is going to be important,” Ravi said in an interview with OncLive^® during the meeting.

In the interview, Ravi discussed the rationale for measuring RCB in patients with high-risk, localized prostate cancer who receive neoadjuvant therapy followed by radical prostatectomy; how the administration of ARPIs prior to surgery affected patient outcomes in the pooled analysis; and the importance of validating this study’s findings in future analyses.

Ravi is the medical director of Genitourinary (GU) Theranostics at Dana-Farber Cancer Institute (DFCI), as well as an assistant professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

OncLive: What was the rationale for conducting this pooled analysis?

Ravi: We evaluated patients receiving neoadjuvant therapy prior to surgery for high-risk prostate cancer, which is not a standard of care [(SOC) for these patients] at this time. We have done many trials led at DFCI by one of my mentors, Mary-Ellen Taplin, MD, investigating neoadjuvant therapy with drugs such as ARPIs prior to surgery in high-risk disease. Five of these trials had been [previously conducted], and we pooled the 218 patients to assess their long-term outcomes from this series of trials. [We evaluated] MFS, which is a surrogate for overall survival in this situation, because so far we’ve only reported early end points, such as pathologic outcomes. The second rationale was to see whether residual disease at surgery was prognostic for long-term outcomes.

What patient data were included in this analysis?

The median follow-up was 5.1 years [after radical prostatectomy]. These patients had received drugs such as abiraterone [Zytiga], enzalutamide [Xtandi], apalutamide [Erleada], or combinations of these [agents] for approximately 6 months prior to surgery. All patients underwent central pathology review to determine the extent of residual disease, if any, [and whether they achieved] a pathologic complete response [pCR]. We computed an RCB, which is similar to what is computed for patients with breast cancer after neoadjuvant chemotherapy. We evaluated RCB in these patients, and then we followed them [to see] their long-term MFS, i.e., [whether] they developed metastases or died of disease after surgery.

What were the key findings from this analysis?

The overall 5-year MFS rate in these patients with high-risk, localized prostate cancer [who received] 6 months of neoadjuvant treatment prior to surgery was 83%, which compares relatively favorably with similar 5-year MFS rates seen with radiotherapy and androgen deprivation, for example, in a similar patient population. A second finding was that 11% of patients had a pCR, and a further 11% of patients had minimal residual disease, [defined as] up to 5 mm of residual cancer.

The other key finding was that the 5-year MFS rates were clearly differentiated amongst patients based on the extent of residual disease present after neoadjuvant therapy and surgery. For example, patients [who achieved a] pCR, [defined as] RCB-0, had a 5-year MFS rate of 100%. No patients died, and none developed metastasis. [They had] an outstanding prognosis. Patients with a bit of residual disease, what we called RCB-1, had a 5-year MFS rate of 90%, which was still good. The patients who had poorer outcomes were those with more extensive residual disease—RCB-2 or RCB-3—which constituted approximately 70% of patients. These patients had 5-year MFS rates between 82% and 63%. These are the patients in whom there is more residual disease present, so naturally it would follow that they’re the ones who are likely to experience poorer outcomes after surgery.

How might these findings inform the future use of RCB in guiding intensified adjuvant treatment strategies for patients with high-risk, localized prostate cancer?

Firstly, neoadjuvant therapy is not a SOC yet [for this patient population]. An ongoing phase 3 trial called the PROTEUS trial [NCT03767244] is evaluating androgen deprivation plus apalutamide, which is an ARPI, [in patients with high-risk, localized or locally advanced prostate cancer who are candidates for radical prostatectomy]. Should that trial read out to be positive, [a marker such as] RCB would come to the forefront of guiding strategies after neoadjuvant therapy.

You could envision a situation where patients get 6 months of neoadjuvant therapy with hormone therapy, androgen deprivation, and an ARPI. If they have an outstanding pathological response, classified as RCB-0 or RCB-1, they could probably be observed. The patients with more significant residual disease, defined as RCB-2 and RCB-3, could then be potential candidates for trials exploring post-neoadjuvant adjuvant strategies with intensified treatments, [such as] chemotherapy or other agents.

However, first we need to validate [a marker such as] RCB within a bigger cohort. We’ve done it in our trials, but we need to validate it perhaps within the PROTEUS study, as well as in other studies, to see: Does [this marker] stand up across the board? If it does, then it becomes ready for primetime to guide the next trial, should studies like PROTEUS be positive and show that there is a benefit with neoadjuvant therapy.

What is the importance of collaborating with pathologists when determining optimal treatment strategies for patients with prostate cancer?

Pathology review is paramount. When you’re looking for [a marker such as] residual disease at surgery [to see if there is] a pCR or no residual cancer, you need an expert pathologist to know what they’re looking at and quantify how much residual disease there is. One of the strengths of our analysis in this study was that every single patient had expert pathology reviewed by a GU pathologist.

If [RCB] is going to be rolled out [as a prognostic marker], pending the results of studies like PROTEUS, pathology collaboration with expert pathology review in all these patients is going to be key. We have to think about that, because globally, there’s not necessarily an expert pathologist in every part of the world. We [also] have to think about how we could roll this out.

What are the next steps for this research?

Our pooled analysis of these trials had a follow-up of 5 years, so we could evaluate outcomes like 5-year MFS rate. Some of the other phase 2 neoadjuvant trials have had shorter follow-up. As their data mature, we can validate our findings in their cohorts. Additionally, validation in a cohort like the PROTEUS study, which is a 2,000-patient trial, would be interesting to look at [so we can] see whether [our findings] hold up in a large, global study.

Reference

Ravi P, Kwak L, Acosta A, et al. Prognostic impact of residual cancer burden (RCB) on long-term outcomes after neoadjuvant (neo) androgen receptor pathway inhibitor (ARPI) and radical prostatectomy (RP) for high-risk localized prostate cancer (HRLPC): a pooled analysis of phase 2 trials. J Clin Oncol. 2024;42(suppl 16):5099. doi:10.1200/JCO.2024.42.16_suppl.5099