PROSPER Trial TE Articles

Articles

  • ASCO 2018: Results from the PROSPER Study: HRQoL Deterioration and Pain Progression in Men with Non-Metastatic Castration-Resistant Prostate Cancer

    Chicago, IL (UroToday.com) At the 2018 GU ASCO meeting in San Francisco, Maha Hussain, MD presented the results of PROSPER, a phase III randomized controlled trial assigning 1,401 men with non-metastatic CRPC (M0 CRPC) 2:1 to enzalutamide (160 mg) or placebo [1]. With a primary endpoint of metastasis-free survival (MFS), enzalutamide had a significantly longer time to metastasis (36.6 months, 95%CI 33.1-NR) compared to placebo (14.7 months, 95%CI 14.2-15.0; HR 0.29, 95%CI 0.24-0.35).  Secondary endpoints also favored enzalutamide including:
    • Time to first use of new antineoplastic therapy (39.6 months vs 17.7 months; HR 0.21, 95%CI 0.17-0.26)
    • Time to PSA progression (37.2 months vs 3.9 months; HR 0.07, 95%CI 0.05-0.08)
    During this year's 2018 ASCO annual meeting, Gerhardt Attard, MD, and colleagues presented results of the Health-related quality of life (HRQoL) and pain evaluations among men in the PROSPER trial.
    Published June 3, 2018
  • ASCO 2020: Phase 3 PROSPER Trial Results: Enzalutamide Demonstrates Significant Improvement in OS in Patients with nmCRPC

    (UroToday.com) Enzalutamide is an FDA approved androgen receptor antagonist used in the treatment of essentially every phase of advanced prostate cancer, from metastatic hormone-sensitive prostate cancer to metastatic and non-metastatic castration-resistant prostate cancer. The approval of enzalutamide for non-metastatic castration-resistant prostate cancer (nmCRPC) was based on PROSPER1, a double-blind, phase III study that randomly assigned patients with nmCRPC and a PSA doubling time of 10 months or less to ADT + placebo or ADT+ enzalutamide 160 mg daily. Initial data showed that enzalutamide led to 71% lower risk of metastasis or death compared with placebo and was FDA approved for nmCRPC In July 2018. This abstract provides the final overall survival analysis for PROSPER.
    Published May 29, 2020
  • ASCO GU 2018: First Presentation - PROSPER: Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC)

    San Francisco, CA (UroToday.com) Dr. Maha Hussain provided the first presentation of the phase III randomized double-blind controlled trial, the following men were eligible for inclusion:
    Published February 9, 2018
  • ASCO GU 2018: Review of First Presentation: SPARTAN and PROSPER

    San Francisco, CA (UroToday.com) The management of metastatic prostate cancer (PCa) continues to change in rapid succession. While we were once reliant on androgen deprivation therapy (ADT) for hormone-sensitive prostate cancer (hsPCa) and docetaxel alone for the treatment of metastatic castration-resistant PCa (mCRPC), the landscape of PCa treatment has drastically changed. The introduction of androgen axis targeting agents, specifically enzalutamide (ENZA) and abiraterone (ABI), have revolutionized the field. 
    Published February 9, 2018
  • AUA 2018: PROSPER Study Results: Impact of Enzalutamide on Pain and Health-Related Quality of Life in Men with nmCRCP

    San Francisco, CA (UroToday.com) The PROSPER trial (NCT02003924) compared the efficacy and safety of enzalutamide (ENZA) 160 mg/day vs placebo (PBO) in asymptomatic men with non-metastatic castration-resistant prostate cancer with prostate-specific antigen doubling time of 10 months. Patients were randomized 2:1. The study showed a statistically significant improvement in metastasis-free survival (MFS) with ENZA vs PBO. PROSPER also prospectively evaluated health-related quality of life (HRQoL) and pain.
    Published May 24, 2018
  • AUA 2018: The PROSPER Trial: Chemotherapy-related Endpoints in Patients with Nonmetastatic Castration-resistant Prostate Cancer Treated with Enzalutamide

    San Francisco, CA USA (UroToday.com) Earlier this year, at the 2018 GU ASCO conference, the results of two major clinical trials assessing androgen-targeted therapies (ART) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC or M0 CRPC) were released with much interest – with both demonstrating >70% metastasis-free surviva (MFS)l benefit, the results of both studies indicated a drastic shift in the medical management of advanced prostate cancer.
    Published May 18, 2018
  • EAU 2018: Patient-Reported Outcome Measures in Men with Non-Metastatic Castration-Resistant Prostate Cancer: Baseline Data from the PROSPER Trial

    Copenhagen, Denmark (UroToday.com) At GU ASCO 2018, Dr. Maha Hussain presented the data from the PROSPER study, which was an incredibly important study looking at the role for enzalutamide (ENZA) in the setting of non-metastatic castration-resistant prostate cancer (nmCRPC). There was a 71% risk reduction of metastases; MFS was 36.6 months in the ENZA arm compared to just 14.7 months in the placebo arm.
    Published March 19, 2018
  • EAU 2018: Prostate-Specific Antigen Response in Men with Nonmetastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide: Results from PROSPER

    Copenhagen, Denmark (UroToday.com)  Androgen deprivation therapy (ADT) is the standard treatment recommended for hormone-sensitive prostate cancer. Since their initial introduction as alternatives to docetaxel for metastatic castrate resistant prostate cancer (mCRPC), abiraterone and enzalutamide have been standard of care, and docetaxel itself was promoted to first-line therapy for metastatic hormone sensitive prostate cancer (MHSPC), especially in the setting of high-volume disease. LATITUDE [1] and STAMPEDE [2], which demonstrated significant survival benefit with the use of abiraterone in conjunction with ADT for MHSPC, have caused abiraterone to be regarded as standard of care in this disease stage as well.
    Published March 18, 2018
  • Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer

    Preliminary trial results showed that enzalutamide significantly improved metastasis-free survival among men who had nonmetastatic, castration-resistant prostate cancer and rapidly increasing prostate-specific antigen (PSA) levels while taking androgen-deprivation therapy. Results from the final analysis of overall survival have not yet been reported.
    Published May 29, 2020
  • Enzalutamide Demonstrates Significant Improvement in Overall Survival in Phase 3 PROSPER Trial of Patients with nmCRPC

    San Francisco, CA (UroToday.com) -- Astellas Pharma Inc. and Pfizer Inc. announced the results of the final overall survival (OS) analysis from the Phase 3 PROSPER trial, which evaluated XTANDI® (enzalutamide) plus androgen deprivation therapy (ADT) versus placebo plus ADT in men with non-metastatic castration-resistant prostate cancer (nmCRPC).
    Published February 11, 2020
  • Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer.

    Men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising prostate-specific antigen (PSA) level are at high risk for metastasis. We hypothesized that enzalutamide, which prolongs overall survival among patients with metastatic, castration-resistant prostate cancer, would delay metastasis in men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level.

    Published April 5, 2019
  • ESMO 2018: Results of PROSPER by Age and Region - A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Enzalutamide in Men with nmCRPC

    Munich, Germany (UroToday.com) During GU ASCO 2018, Dr. Hussain presented the results of PROSPER (NCT02003924), a phase III randomized, double-blind, placebo-controlled study of enzalutamide in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC)1. Prior to this study, there were no approved therapies for men with M0 CRPC, and in particular men with high-risk disease with PSA doubling times less than 10 months. In this study, the authors hypothesized that enzalutamide would be able to delay the development of metastases in men with M0 CRPC in this high-risk population and thus the primary endpoint was metastases-free survival, defined as the time from randomization to radiographic progression or death within 112 days of treatment discontinuation.
    Published October 23, 2018
  • PROSPER Trial Journal Club: Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer - Zachary Klaassen and Christopher J.D. Wallis

    In this Journal Club, Zachary Klaassen and  Christopher Wallis review the recently published New England Journal of Medicine article Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer, the double-blind, phase 3 PROSPER trial. Men with nonmetastatic, castration-resistant prostate cancer (defined on the basis of conventional imaging and a PSA doubling time of ≤10 months) who were continuing to receive androgen-deprivation therapy were randomly assigned (in a 2:1 ratio) to receive enzalutamide at a dose of 160 mg or placebo once daily.

    Biographies:

    Christopher J.D. Wallis, MD, Ph.D., Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee

    Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center


    Read the Full Video Transcript

    Zachary Klaassen: Welcome to this UroToday Journal Club. We'll be discussing enzalutamide and survival in non-metastatic castration-resistant prostate cancer. My name is Zach Klaassen. I'm an Assistant Professor in the Division of Urology at the Medical College of Georgia, and joining me is Chris Wallis, he's a Fellow in Urological Oncology at Vanderbilt University in Nashville.

    As I mentioned, we'll be discussing this paper that was recently published in the New England Journal of Medicine following presentation at the 2020 ASCO Virtual Meeting. The first author is Cora Sternberg for the PROSPER investigators.

    By way of background, enzalutamide is an oral androgen receptor inhibitor, and it's been approved in men with metastatic castration-resistant prostate cancer in both the pre-chemo and post-chemo state based on the AFFIRM and PREVAIL trials. It was also recently approved in men with metastatic castration-sensitive prostate cancer based on ENZAMET and the ARCHES trial.

    Enzalutamide was first approved by the FDA in 2018 in this disease space of non-metastatic CRPC on the basis of improved metastasis-free survival compared to ADT alone. You can see here that the hazard ratio for metastasis or death was 0.29 with a 95% confidence interval of .24 to .35, and this was published by Hussain and colleagues in the New England Journal of Medicine in 2018.

    Subsequent to this publication was a quality of life study from this data, which was published in Lancet Oncology in 2019, looking at several factors that showed that enzalutamide compared to ADT alone improved health-related quality of life, including the BPI-sf item 3 tool, the EORTC QLQ-PR25 urinary symptoms metric, as well as that same metric for bowel symptoms, the FACT-P total score, and finally the European quality of life visual analog scale. So, you can see an early separation of the curves for all of these quality of life metrics favoring enzalutamide.

    In the initial publication in 2018, which was the primary analysis of PROSPER, there were 23 months of follow-up, but the OS data was immature and the median OS was not reached. At this point in time, they had 165 deaths, which was 28% of the pre-specified survival events for the final analysis. The publication that was published in June of 2020 is the survival analysis with longer follow-up in the PROSPER trial, which we'll be discussing today.

    This was a multinational, double-blind, randomized, placebo-controlled, Phase III trial of 300 sites and 32 countries. The key inclusion criteria were confirmed prostate adenocarcinoma with an increasing PSA despite a castrate level of testosterone, a baseline PSA level of greater than two nanograms per milliliter, a PSA doubling time of less than 10 months, and no evidence of metastatic disease.

    In terms of their methods, stratification was based on PSA doubling time of less than or greater than six months. They also stratified based on previous or current use of bone-targeting agents, and randomization was two to one for ADT plus enzalutamide versus ADT plus placebo. Their primary endpoint was MFS or death, which, as I mentioned before, was reported in their 2018 New England Journal of Medicine article, and there were several secondary endpoints as you can see here, one of which was overall survival, which was the key endpoint discussed in their 2020 update.

    Their efficacy endpoint was in the ITT population. They evaluated safety, which was described as time from the first dose to 30 days after the last dose or to the day before initiation of a new antineoplastic therapy. For their final analysis of overall survival, they needed 590 deaths to provide 85% power to detect a hazard ratio of 0.77 with a two-sided significance level of 0.05. This was the third preplan analysis for overall survival. After adjusting for multiplicity, they detected if there was a P value of less than or equal to 0.021, this indicated statistical significance.

    Christopher Wallis: Thanks for the setup, Zach. I'll talk now about the results of the updated overall survival analysis and help put these in a little bit of context.

    The original publication of the PROSPER trial described some of these initial background features, but we'll just review them quickly. Patients were screened and accrued between 2013 and 2017, with enrollment stopped after about 450 MFS events, giving adequate power for the primary outcome. There was two to one randomization schema to enzalutamide versus placebo and, as Zach described before, this was stratified on the basis of receipt of prior bone-targeting agents and PSA doubling time. As we might expect from the fact that enzalutamide prolonged metastasis-free survival, the median duration of treatment was longer for patients who were on therapy than on placebo.

    Now, these baseline characteristics come from the initial publication, but as we would expect, they ought to be the same in the updated analysis, and so we see a fairly typical prostate cancer population, the median age in the mid-70s, good performance status, median PSAs in the range of 10, and a doubling time in the range of four months. Bone-targeted therapy was used infrequently in only about 10% of the population at baseline.

    Now, following primary analysis of the metastasis-free survival endpoint, trial data were unblinded. And at that time, given that it demonstrated benefits of enzalutamide in prolonging metastasis-free survival, patients who were receiving placebo who hadn't yet progressed, that is who were still nmCRPC, were allowed to cross over. So, among 114 eligible patients randomized to placebo who had not progressed, 87 of those crossed over to enzalutamide. And this, as you might imagine, affects our ability to detect overall survival differences in an ITT analysis.

    Despite the crossover, as we see here, overall survival was significantly improved for patients receiving enzalutamide compared to placebo. With a median follow-up of 48 months, we see a median survival of 67 months in those patients on therapy and 56 months in those initially randomized to placebo. As a result, the hazard ratio is 0.73 and a P-value of 0.001. As Zach alluded to before, due to multiplicity, the threshold for statistical significance here was 0.021, so this reaches statistical significance.

    In subgroup analyses, we see a relatively consistent effect across subgroups defined based on geographic region, patient age, performance status, PSA doubling time, as well as absolute PSA values, the use of bone-targeting agents, Gleason Score, LDH values, and hemoglobin values, indicating that there are no specific subgroups for whom a greater or lesser benefit would be expected.

    As of the data cutoff of October 15, 2019, about 60% of patients who were randomized to enzalutamide had subsequently stopped therapy, and a reasonable portion of those who had crossed over later had also stopped. Treatment was stopped for both disease progression and adverse events, and we'll talk about that a little bit here.

    So, the next lines of therapy, following progression or discontinuation for toxicity, subsequent therapy was used in about one-third of the patients randomized to enzalutamide and about two-thirds of those randomized to placebo. Abiraterone was the most commonly used agent in patients who were initially randomized to placebo, where docetaxel was the most commonly used agent in those initially randomized to enzalutamide. And this makes sense given what we know from other work from Kim Chi's group as well as the CARD study, suggesting that failure on one androgen receptor-targeting agent should lead us to consider cytotoxic chemotherapy rather than an androgen receptor-targeting switch.

    In terms of adverse events, this is a summary of overall any adverse events and serious adverse events. We see that these are quite common in both groups, although somewhat higher in the enzalutamide-treated population with a 94% rate of any adverse events versus 82% in the placebo group. Serious events, again, were more common in the enzalutamide group at 48% as compared to 27% in the placebo group, and adverse events leading to treatment discontinuation occurred in 17% of those in the enzalutamide group and only nine in the placebo group. Deaths were uncommon in both, but slightly more prevalent in the enzalutamide group.

    Based on data from the use of enzalutamide in other disease states, including metastatic castration-resistant prostate cancer, there are specific adverse events of interest, including fatigue or asthenia and seizures, and these are summarized here. Fatigue is somewhat more common in the enzalutamide group with a proportion of 46% as compared to 22 in the placebo group. However, very few seizures were noted in the study population.

    Now, despite the fact that we've been able to demonstrate a statistically significant difference in overall survival, these data are still relatively immature. And as we see from data on the use of enzalutamide in early metastatic castration-resistant prostate cancer, as data matures, we may expect changing effect estimates. And so, these show that from the initial analysis in 2014, 22 months through extended analysis published in 2017 of 31 months, and now onto 70-month median follow-up, the hazard ratio of the benefit of enzalutamide in early metastatic disease has moved towards one, although remains statistically significant, so Dr. Beer highlighted that this may occur in the non-metastatic space as well when he was discussing this paper at the ASCO 2020 virtual meeting.

    In conclusion, an updated analysis of the PROSPER trial shows improved overall survival for patients with nmCRPC who receive enzalutamide as compared to placebo. There are now three agents approved for non-metastatic CRPC on the basis of metastasis-free survival improvements, and each of these has now demonstrated subsequent proven benefits in overall survival. The specific magnitude of benefit is likely to change as the data matures, but these data provide encouraging information for our patients, suggesting that early use of androgen-targeting agents in patients with castration-resistant disease is likely to provide a survival benefit.

    I'd like to thank you for your time and hope that this session has proved both interesting and informative for you.

    Published June 19, 2020
  • PROSPER Trial Results of Enzalutamide in Non-Metastatic Castration-Resistant Prostate Cancer

    Truckee, CA (UroToday.com) - Pfizer Inc. and Astellas Pharma Inc. announced that the Phase 3 PROSPER trial evaluating XTANDI (enzalutamide) plus androgen deprivation therapy (ADT) versus ADT alone in patients with non-metastatic (M0) Castration-Resistant Prostate Cancer (CRPC) met its primary endpoint of improved metastasis-free survival (MFS). The preliminary safety analysis of the PROSPER trial appears consistent with the safety profile of XTANDI in previous clinical trials.
    Published October 9, 2017