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Rana R. McKay, MD, discusses the benefit of intense neoadjuvant hormone therapy prior to radical prostatectomy in men with high-risk prostate cancer and next steps for research.
Intense neoadjuvant hormone therapy followed by radical prostatectomy resulted in favorable pathologic complete responses (pCRs) in men with high-risk prostate cancer, according to Rana R. McKay, MD, who added that follow-up is necessary to determine the significance of these responses on recurrence rates.
In the randomized phase 2 analysis, 119 patients with high-risk prostate cancer, who also displayed a Gleason score of 4+3=7, a prostate-specific antigen (PSA) value of over 20 ng/mL, T3 disease, or a lymph node of less than 20 mm, were enrolled. During part 1 of the study, patients were randomized 1:1 to receive abiraterone acetate (Zytiga),prednisone, apalutamide (Erleada), and leuprolide (APAL; n = 59 or abiraterone, prednisone and leuprolide (APL; n = 59), followed by radical prostatectomy. The primary end point of the trial was the rate of pCR and minimum residual disease (MRD) by central review.
Results showed that the combined pCR and MRD rate was 20% in the APAL arm and 22% in the APL arm. With regard to safety, a total of 13 patients, or 11% experienced grade 3 treatment-related adverse effects (TRAEs); 8 were reported in the APAL arm and 5 reported in the APL arm. No grade 4 or 5 TRAEs were reported.
“In a very high-risk population with aggressive disease, we observed early declines in PSA with this approach. The majority of patients had dramatic declines in their PSA and the median PSA values pre–radical prostatectomy was 0.03 in both arms,” said McKay. “Ultimately, we’re learning that PSA does not correlate with pCR because, while PSA dropped in the majority of patients, there was variability with regard to pCR.”
Next, investigators will focus their efforts on determining intermediate pathologic end points in prostate cancer to see whether pCRs correlate with improved long-term outcomes. Additionally, efforts will be focused on defining exceptional responders to see whether a subset of patients may not require radical prostatectomy, as well as defining nonresponders to understand which patients might benefit more from chemotherapy, according to McKay.
In an interview with OncLive, McKay, an assistant professor of medicine and medical oncologist at the University of California, San Diego, further discussed the benefit of intense neoadjuvant hormone therapy in men with high-risk prostate cancer and next steps for research.
OncLive: Could you provide background on the phase 2 trial of intense androgen deprivation therapy (ADT) prior to radical prostatectomy in men with high-risk localized prostate cancer?
McKay: In the United States, prostate cancer is the most common cancer in men and a majority of patients present with localized disease. Of those who present with localized disease, approximately 15% have high-risk features, which is based on PSA, Gleason score, or stage. When looking at the 15-year prostate cancer–specific mortality for those individuals who are high risk, it can be over 38%. There's clearly an unmet need in this space; we need to improve outcomes for patients.
The treatment paradigm for patients with high-risk prostate cancer has changed very little over the past several decades. [Our approach] basically includes either up-front radical prostatectomy, followed by adjuvant or salvage radiation and ADT or definitive up-front radiation therapy with ADT. A neoadjuvant approach has been investigated in prostate cancer, but it's certainly not yet the standard of care; this is still under investigation.
With regard to other solid tumor malignancies, such as breast, rectal, bladder, and other cancers, neoadjuvant therapy is a standard of care and has been associated with improved long-term survival. It facilitates downstaging of local disease, which would enable surgical resection. It reduces and delays the need for post-surgery treatment, and it can actually provide an in vivo assessment of response to treatment. For patients with breast, bladder, and rectal cancer, pCR has been correlated with long-term outcomes.
I alluded to the fact that the neoadjuvant approach, prior to radical prostatectomy, has been previously tested in prostate cancer. In the early 1990s, a series of trials were conducted with LHRH agonists, with or without first-generation antiandrogens, prior to radical prostatectomy. These trials were primarily conducted in low-risk patients; they were not designed to systematically assess pCR. No central pathology review [was done] in the context of these studies because they were designed to look at the rates of positive surgical margins.
The studies were limited in terms of long-term follow-up and, after a flurry of these neoadjuvant trials, the approach fell by the wayside. However, the advent of more potent androgen-targeting agents, such as abiraterone, enzalutamide (Xtandi), and apalutamide (Erleada)—which have demonstrated efficacy for patients with advanced disease—has really opened up an opportunity to investigate these drugs in the neoadjuvant setting.
We've conducted a series of contemporary trials in the neoadjuvant space. The majority of these trials were done in high-risk patients, as opposed to those former trials that were done in low-risk patients. We included systematic central pathology review to tease out the pCR and we have ongoing, long-term follow-up. We’ve conducted these trials over the past 10 years and sequentially built upon our understanding of disease biology.
Acknowledging the limitations of these phase 2 studies, we are demonstrating a signal that pCR are observed with more potent therapy in a subset of patients. On the heels of these trials, we also did a pooled analysis of 3 former neoadjuvant trials to assess the correlation between pCR and PSA recurrence. While longer follow-up is certainly needed, in our initial analysis, none of the patients with a pCR or MRD had disease recurrence.
From these initial studies, we were also understanding the constraints of the phase 2 space. However, this did provide us with an opportunity for rich correlative analyses to be conducted in the context of these historic trials. We wanted to determine who the responders were versus [which patients were not responding]. There does appear to be a molecular signature that seems to be associated with response and resistance. For example, patients who had SPOP alterations in their tumors seemed to respond better to hormonal therapy, whereas those with TP53 [mutations or] PTEN loss seemed to be associated with resistance.
Ultimately, all of this led to the design of our current trial, which is exploring more potent neoadjuvant treatment with abiraterone, apalutamide and leuprolide, and asking the question of whether this triple therapy will improve pCR, along with rates of biochemical recurrence, in men with high-risk localized prostate cancer.
What was the design of this study?
This was a multicenter, randomized phase 2 trial that enrolled patients with Gleason score 4+3=7 prostate cancer, a PSA greater than 20, or T3 disease shown on an MRI. Patients were required to have lymph nodes that were less than 20 mm and they needed to have a good performance status.
Patients were randomized 1:1 to receive treatment with APAL for 6 months followed by radical prostatectomy, or APL for 6 months followed by radical prostatectomy; that was part 1 of the study. Part 2 of the study, which I'm not going to discuss today because it’s still ongoing, randomized patients after radical prostatectomy to additional therapy or observation. Seventy percent of the patients who had a radical prostatectomy went on to be randomized to part 2 of the trial. The trial enrolled a total of 119 patients.
In line with the eligibility criteria for this trial, we enrolled a very high-risk patient population. The majority of patients had T3 disease, 42% of patients had Gleason 9/10 disease, and 94% had National Comprehensive Cancer Center high-risk disease.
The key message in terms of the pCR was that with APL, the pCR rate and MRD rate was 20%. As such, it seemed like a subset of patients benefited from this approach. With the triple therapy of APAL, the pCR was 33%. Although there wasn't really a difference between the 2 arms, a subset of patients seemed to have dramatic pCRs with this therapy. Rates of nodal involvement ranged from 7% to 17% between the arms, while positive surgical margins ranged from 7% to 12%. [The rate of] seminal vesicle invasion was around 27% in both arms.
All patients underwent a baseline multiparametric MRI, and a subset of patients underwent a pre–radical prostatectomy MRI. We're analyzing the data from the 71 patients with paired MRI samples and are also analyzing the residual tumors in the radical prostatectomy specimens to define markers of response and resistance.
What did the safety profile of this approach look like?
With regard to toxicity, 13 patients, so 11%, experienced grade 3 TRAEs. In the overall study, no grade 4 or 5 TRAEs were reported. Also, no new safety signals were reported. Perioperative and postoperative complications were low overall and low at 28 days and 3 months, post radical prostatectomy. To really summarize these data, intense neoadjuvant hormone therapy appears to benefit a subset of patients with high-risk prostate cancer. The combination of APAL did not appear better than APL, and this supports the design of the current phase 3 trial.
Could you expand on the ongoing phase 3 trial?
The current phase 3 trial is called PROTEUS, and it is a randomized, double-blinded study investigating perioperative apalutamide for men with high-risk prostate cancer. This is really going to be a landmark study that will define pCR to neoadjuvant therapy, and it will also validate pCR as a surrogate for metastasis-free survival. We're also going to look at biomarkers of response and resistance.
We’re excited about being able to define those intermediate end points for prostate cancer so we can develop therapies for patients with localized disease. We’re also excited about integration of imaging and tissue correlative so we can guide selection for patients. Can some patients undergo therapy de-escalation while others may need therapy escalation?
We’re also really looking at defining those exceptional responders. Some of the provocative questions in the field are: Is there a subset of patients who may not require a radical prostatectomy, and can we define who those patients are using our imaging and tissue-based biomarkers? We also need to define non-responders. Is there a subset of patients who may be better served with docetaxel-based treatment as opposed to hormonally-based therapies?
McKay RR, Xie W, Fennessy F, et al. Results of a phase II trial of intense androgen deprivation therapy prior to radical prostatectomy in men with high-risk localized prostate cancer. J Clin Oncol. 2020;38(suppl 15):5503. doi: 10.1200/JCO.2020.38.15_suppl.550