An Unmet Need is Met: (The PROSPER Study): Evaluating the Safety and Efficacy Study of Enzalutamide in Patients with Nonmetastatic Castration- Resistant Prostate Cancer

For men with non-metastatic, castration-resistant prostate cancer (nmCRPC), who are invariably at risk of metastasis, the PROSPER trial clearly demonstrated that combining enzalutamide to androgen-deprivation therapy (ADT) resulted in prolonging metastasis-free survival by a median of 22 months compared with ADT plus placebo in a global, double-blind, phase III study (Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer), presented at the plenary session of ASCO GU 2018.1

Metastasis-free survival was 36.6 months with enzalutamide-ADT versus 14.7 months for placebo-ADT, which correlates with a 71% reduction in risk of metastasis or death (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.24 to 0.35; P < .0001). These results have resulted in the U.S. Food and Drug Administration (FDA) designating enzalutamide for breakthrough priority status review for patients with nmCRPC. 

The PROSPER trial also significantly extended time to PSA progression and time to receipt of new antineoplastic therapy, said Mahi Hussain, MD, FACP, FASCO, who presented the findings at the 2018 ASCO Genitourinary Cancers Symposium.

Patients in the enzalutamide treatment arm tolerated enzalutamide well, given their median age of mid-70s, and there were no new safety signals or adverse events not previously detailed in numerous prior phase II/III global trials which evaluated enzalutamide. 

The importance of PSA doubling time 
Non-metastatic, castration-resistant prostate cancer may represent upwards of 16% of prostate cancer cases in an advanced prostate cancer practice; of note, enhanced awareness with additional evaluation may increase the opportunity to identify and optimally treat these patients.3 Prior to the PROSPER trial, there were no approved therapies for nmCRPC patients, also, designated as M0CRPC, or index case 1, per the AUA CRPC guidelines.17 

Now, index case 1 has an approved therapy, as of February 14 ,2018, when the U.S. Food and Drug Administration (FDA) approved a next-generation androgen receptor inhibitor, apa- lutamide, for the treatment of M0 CRPC patients.2 Approval was based on the results of the global phase III SPARTAN trial (A Study of Apalutamide (ARN-509) in Men With Non-Metastatic Castration- Resistant Prostate Cancer), in which men with nmCRPC received apalutamide plus ADT vs ADT pus placebo, and whereby the apalutamide plus ADT arm had a 72% lower risk of progression or death compared with those who received placebo-ADT (median progression-free survival [PFS], 40.5 months vs. 16.2 months; HR, 0.28; 95% CI, 0.23 to 0.35; P < .0001).4 

The approval of apalutamide, and the FDA’s priority review of enzalutamide for nmCRPC marks the importance of clinician awareness to appropriately identify nmCRPC patients. 

With 1 approved therapy and another highly likely to follow very soon, clinicians should be encouraged to improve their diagnostic acumen for identifying these nmCRPC patients, whom are invariable, asymptomatic, except for their ongoing ADT sequelae, and thus discuss with those patients who could benefit from earlier daily oral AR inhibitor treatment.

In both the SPARTAN and PROSPER trials, the nmCRPC accrual population required a PSADT of less than or equal to 10 months, with median PSADT of 4.5 and 4.0 months, respectively.
A recent study consistently linked higher baseline PSA level and faster PSA doubling time with imminent metastasis in men with M0 CRPC.10 The finding confirms PSA as “an important prognostic and an intermediate biomarker for progression”, commented Dr. Hussain. 

Enzalutamide, a novel androgen receptor inhibitor, has been approved for treating metastatic CRPC patients either before or after chemotherapy. 

A large Phase II trial (STRIVE), demonstrated that enzalutamide reduced the risk of progression or death among men with metastatic or non-metastatic CRPC by 76% compared with bicalutamide therapy.

To further evaluate enzalutamide in the M0 CRPC setting, PROSPER enrolled 1,401 such patients whose screening PSA level was at least 2 ng/mL and whose PSA doubling time was 10 months or less, despite having castration levels of testosterone (<50 ng/dL).1 Patients were randomly assigned on a 2:1 basis to receive either enzalutamide (160 mg) or placebo while continuing ADT.1 

Metastasis-free survival: A new trial/regulatory endpoint 
Both SPARTAN and PROSPER used the same enrollment criteria for PSA doubling time,4 and both trials have used MFS as the primary endpoint for evaluation, whereby the FDA has agreed to use metastasis-free survival as a pathway for prostate oncologic drug approval. 

In an earlier FDA Oncologic Drugs Advisory Committee (ODAC) meeting, the panel concluded that relevant endpoints for prostate cancer trials should include quality of life, pain, and overall survival. The committee noted that delaying metastasis was “... meaningful, as long as it’s balanced by [treatment] tolerability and no worsening of overall survival.” 

Delaying time to metastasis may be clinically relevant, with the clinical benefit to delay cancer-related morbidity, additional cancer-related therapies, and ideally, overall survival prolongation. In a meta-analysis of data from nearly 13,000 participants in prostate cancer trials, metastasis-free survival strongly correlated with overall survival (Kendall’s tau correlation, 0.91).9 In addition, metastasis-free survival is a strong surrogate for overall survival
in clinically localized prostate cancer in a patient population with an approximate 15% chance of dying of prostate cancer over 10 years despite potentially curative local therapy. The surrogacy finding was independent of primary local interventions and the type of adjuvant therapy.9 

“But we don’t yet know if this applies to M0 CRPC,” cautioned Philip Kantoff, MD, who was the ASCO GU 2018 review for the plenary presentations of both PROSPER and SPARTAN, given by Maha Hussein and Eric Small, respectively. Additionally, Kantoff noted that both the COU-AA-302 trial of abiraterone acetate12  and the PREVAIL trial of enzalutamide in M1 CRPC,13 offer “hints of a connection between PFS and OS, although it’s an intricate connection.” 

PROSPER investigators defined the primary metastasis-free survival endpoint as time from randomization until radiographic progression or death within 112 days of stopping treatment. Making metastasis-free survival a “conservative endpoint” reflects the need to carefully balance risk with benefit when shifting cancer treatment earlier in the disease course. 

“Treating asymptomatic patients carries a certain burden of proof,” agreed Dr. Kantoff, who chairs the department of medicine at Memorial Sloan Kettering Cancer Center, New York. Data from PROSPER and SPARTAN suggest that patients with M0 CRPC often live more than 5 years – about 2 years longer than patients with metastatic CRPC, he noted. “Thus, treatment at this stage will result in longer drug exposure and its consequences. That’s okay, if the benefit of treatment clearly outweighs the risks.” 

Efficacy 
Secondary efficacy endpoints in the PROSPER trial included safety, overall survival, time to PSA progression, and time to first use of new antineoplastic therapy. Patients in both arms were elderly (median age, 74 years) and the median PSA doubling time was 3.8 months – far less than the 10-month cutoff. “This basically means that their PSA was doubling in between [clinic] visits,” said Dr. Hussain. 

At data cutoff in June 2017 (median follow-up time, 22 months), 634 patients (68%) remained on enzalutamide and 176 patients (38%) remained on placebo, she reported. The enzalutamide-treated patients attained a highly significant metastasis-free survival endpoint benefit and also demonstrated highly statistically benefit for the subgroup of patients stratified by PSA doubling time, geographic region of residence, age, Eastern Cooperative Oncology Group (ECOG) performances status, Gleason score at diagnosis, use of bone-targeting agents, and baseline levels of PSA. The median time to PSA progression 

was approximately 33 months longer with enzalutamide than with placebo, reflecting a 93% risk reduction (median time to PSA progression, 37.2 months vs. 3.9 months; HR, 0.07; 95% CI 0.05 to 0.08; P < .0001). The median time to first use of a new antineoplastic therapy was about 22 months longer with enzalutamide versus placebo, a 79% relative risk reduction (39.6 months vs. 17.7 months; HR, 0.21; 95% CI, 0.17 to 0.26; P < .0001). 

Use of new antineoplastic therapy is a correlate of presumed disease progression. In both arms of PROSPER, most progression events consisted of new soft-tissue metastases, while about a third of events comprised new bone metastases and less than 7% involved metastases of both tissue and bone. 

At interim data cutoff, there were only a very limited number of deaths for both the PROSPER and SPARTAN trials, as the vast majority of MFS events related to imaging progression of the disease, and thus only trends for overall survival were mentioned for both ASCO GU plenary presentations. In PROSPER, median overall survival was not reached in either arm, but the estimated risk of death from any cause was about 20% lower with enzalutamide compared with placebo (HR, 0.80; 95% CI, 0.58 to 1.09; P = 0.152). Final survival analyses for both PROSPER and SPARTAN are planned. 

Safety 
The PROSPER findings reflect that enzalutamide’s safety profile resembles its prior trials in mCRPC (see, AFFIRM/PREVAIL/ STRIVE/TERRAIN trials). All-grade adverse events affected 87% of patients in the enzalutamide-ADT arm and 77% of patients in the control arm, while grade 3 or higher adverse event rates were 31% and 23%, with treatment discontinuation for adverse events, 9% and 3%, respectively. 

The most common single adverse event was hypertension, which affected 12% on enzalutamide versus 5% of patients on placebo. Rates of grade 3 or higher hypertension were 5%
and 2%, respectively. The finding “calls attention to the fact that many of these AR-targeted agents can have effects that we are not expecting,” Dr. Hussain told UroToday. “We need to carefully monitor these patients when they’re starting treatment to make sure their comorbidities are under control.”

Besides hypertension, the most common grade 3 or higher adverse events included fatigue (enzalutamide: 3%; placebo: 1%) and hematuria (2% with enzalutamide; 3% with placebo). Enzalutamide was associated with a risk of all-grades cognitive/ mental impairment (5% vs. 2% for placebo) and major adverse cardiovascular events (5% vs. 3%). 

In both arms, the incidence of major adverse cardiovascular events was higher in patients with a history of cardiovascular disease, hypertension, diabetes mellitus, hyperlipidemia, or age of at least 75 years. 

Enzalutamide’s FDA label also includes warnings on an increased risk of seizure (0.5% overall and 2.2% in patients with predisposing factors) as well as posterior reversible encephalopathy syndrome. In PROSPER, there were three events of convulsions (less than 1% of patients) in the enzalutamide-ADT arm and no events in the placebo-ADT arm. No patients developed posterior reversible encephalopathy syndrome in the PROSPER trial. 

Patients continued enzalutamide for a median of 18.4 months (range, 0 to 41.9 months) versus 11.1 months for placebo (range, 0 to 42.8 months). 

A call to dig deeper 
Interim results from PROSPER and SPARTAN suggest that enzalutamide and apalutamide delay metastases in M0 CRPC “by a very impressive 2 years,” Dr. Kantoff commented at ASCO GU 2018. “These drugs are very biologically active, and it’s not completely surprising to me that they give two options to men with M0 CRPC.” 

He further added, “Patients [with M0 CRPC] fear rising PSA and not doing anything about it. From a physician’s perspective, treatment might delay symptom onset and use of chemotherapy, and it might prolong survival, as it has done in the metastatic, hormone-sensitive setting with CHAARTED, STAMPEDE and LATITUDE.”14, 15,16 

But he also raised questions for investigators from both trials, contending that so far, neither study has fully demonstrated a clinical benefit. “Delaying the onset of disease-related symptoms, as seen in SPARTAN, represents a clinical benefit, although the components of the delay need to be better ascertained. How much of it is the prevention of pain or skeletal-related events as opposed to other endpoints is unclear to me.” 

Furthermore, the results of SPARTAN linked apalutamide therapy to a small increase in the relative risk of falls, fractures, and grade 3 or worse rash, he noted. In PROSPER, there was a death rate discordance of 15% vs 2% for patients coming off of the trial. 

“Was [cause of death] cardiovascular problems or other problems?” Dr. Kantoff asked. “This is a little concerning to me, and I think we need to dissect this a little bit further. If we can understand what’s happening and identify these people in advance, maybe we can minimize this risk.” 

Dr. Kantoff added, “My confidence would be greater with further scrutiny of the toxicities and understanding how care patterns in these studies compare with actual practice. Specifically, how did the timing of the initiation of alternative therapies in these trials compare with what is going on in the community?” 

Take-homes messages and future directions 
If a patient has been initiated with ADT, and has a PSA rise, despite a castrate level of testosterone, and has no positive imaging findings for metastasis, then the option to consider an approved treatment now exists. Reviewing patient performance status, co-morbidities, CRPC disease biology, and other individualized variables will certainly help inform the physician-patient shared decision-making analysis. 

The CHAARTED, STAMPEDE and LATITUDE trials have confirmed the survival benefits of shifting next-generation prostate cancer treatments more proximally within the natural history of earlier diagnosed advanced prostate cancer. Additional combinations, novel sequencing strategies as well as other therapeutics with unique mechanisms of action, approved, or in clinical trials, may significantly change future decision-making treatment options. 

Designing trials with agreed upon endpoints which can both justify clinical utility decision making as well as attain regulatory approval are essential. The FDA’s acceptance of metastasis-free survival as such an endpoint has allowed for the design and completion of two very important global phase III trials for the nmCRPC patient population. There are ongoing phase III trials investigating enzalutamide for treating localized prostate cancer at high risk of recurrence (ENZARAD; NCT02446444), M0 hormone-sensitive prostate cancer (EMBARK; NCT02319837), and metastatic, hormone-sensitive prostate cancer (ARCHES; NCT02677896). Additionally, the ATLAS trial (NCT02531516) is evaluating whether adding apalutamide to ADT and radiation therapy benefits patients with high-risk, localized or locally advanced disease. 

The future holds promise for genomic and molecular profiling of prostate cancer biology which could enhance the precision of our therapeutic choices, which will presumably optimize clinical outcomes and maximize value-based healthcare models.

SPARTAN PROSPER Chart
Written by: Neal Shore, MD, FACS

References: 
  1. Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo (PBO)- controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol 2018;36(6_suppl):3 (abstr 3).
  2. US FDA. FDA approves apalutamide for non-metastatic castration-resistant prostate cancer. https:/ www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm596796.htm Accessed March 20, 2018.
  3. Liede A, Arellano J, Hechmati G, et al. International prevalence of nonmetastatic (M0) castration-resistant prostate cancer (CRPC). J Clin Oncol 2013;31(15_suppl) (abstr e16052).
  4. Small EJ, Saad F, Chowdhury S, et al. SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). Presented at: 2018 Genitourinary Cancers Symposium (ASCO GU); February 8-10, 2018; San Francisco, CA, USA. Abstract 161.
  5. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018 Feb 8. doi: 10.1056/NEJMoa1715546. [Epub ahead of print]
  6. Schalken J, Fitzpatrick JM. Enzalutamide: targeting the androgen signaling pathway in metastaticcastration‐resistant prostate cancer. BJU Int 2016; 117(2): 215-225.
  7. Beer TM, Tombal B. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371(18):1755-1756.
  8. Penson DF, Armstrong AJ, Concepcion R, et al. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J Clin Oncol 2016;34(18):2098-2106.
  9. Xie W, Regan MM, Buyse M, et al. Metastasis-free survival is a strong surrogate of overall survival in localized prostate cancer. J Clin Oncol 2017;35(27):3097-3104.
  10. Smith MR, Saad F, Oudard S, et al. Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol 2013;31(30):3800-3806.
  11. Highlights of prescribing information. XTANDI® (enzalutamide) capsules, for oral use. https:/www. astellas.us/docs/12A005-ENZ-WPI.PDF Accessed March 16, 2018.
  12. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368(2):138-148.
  13. Rathkopf DE, Beer TM, Loriot Y, et al. Radiographic progression-free survival as a clinically meaningful endpoint in metastatic castration-resistant prostate cancer: the PREVAIL randomized clinical trial. JAMA Oncol 2018 Mar 8. doi: 10.1001/jamaoncol.2017.5808. [Epub ahead of print]
  14. James ND, Sydes MR, Clarke NW, et al; STAMPEDE Investigators. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016;387(10024):1163-1177.
  15. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015;373(8):737-746.
  16. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 2017; 377(4):352-360.
  17. Castration-Resistant Prostate Cancer https:/www.auanet.org/guidelines/castration-resistant-prostate-cancer-(2013-amended-2015) Accessed April 4, 2018



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