The landscape for the treatment of castrate sensitive prostate cancer has had several significant changes in the recent past. Results from three phase 3 trials, STAMPEDE, LATITUDE, and TITAN, have demonstrated the utility of using the newer second-generation androgen receptor inhibitors.
According to a presentation at the 2020 Institutional Perspectives in Cancer webinar on Prostate Cancer, Mary-Ellen Taplin, MD stated that "De novo metastatic prostate cancer accounts for about 3% of all new prostate cancer [cases] in the United States and [That number] appears to be rising."
The STAMPEDE Trial Introduces Abiraterone as a Potential Therapy in mCSPC
One of the first changes cited by Dr. Taplin was the use of abiraterone (Zytiga) after the combination of androgen-deprivation therapy (ADT) and docetaxel became the standard of care for men with metastatic castrate sensitive prostate cancer (mCSPC). The STAMPEDE trial evaluated the role of abiraterone acetate (Zytiga) in combination with standard therapy compared with standard therapy alone.1
In the trial, men included those with newly diagnosed locally advanced or metastatic disease with positive lymph nodes and/or those with relapsed disease following initial local therapy. The primary endpoint of the trial was overall survival (OS). Secondary endpoints included failure-free survival (FFS), toxicity, quality of life (QOL), skeletal-related events, and cost-effectiveness.
From November 2011 to January 2014, 957 men were accrued to the control arm (arm A), and 960 patients were accrued to Arm G to receive standard of care plus abiraterone acetate and prednisolone (Zytiga + P).
The subject men had a median age of 67 years. Over half (52%) had metastatic disease, 88% of which were bony metastases, 20% had node-positive non-metastatic disease, and 28% had node-negative non-metastatic disease.
Arm G of the trial showed that ADT plus abiraterone elicited a 37% improvement in overall survival (OS) compared with ADT alone in men with newly diagnosed, high-risk mCSPC. The trial also showed a 55% reduction in symptomatic skeletal-related events with the combination of ADT and Zytiga versus ADT alone.
According to Taplin, these findings are significant as skeletal-related events are associated with pain, a need for radiation, and an increased risk of bone metastases and compression fractures. "This was one of the first trials to demonstrate the benefit of a non-chemotherapy agent, in this case, abiraterone, in men with metastatic prostate cancer," said Taplin. "It gave us a new tool to use in the clinic for these patients."
The addition of abiraterone to the standard of care also improved FFS by 71% compared with standard of care alone. In the non-metastatic cohort of men, long-term OS outcomes have not yet been reached, added Taplin.
In terms of safety, grade 3 or higher adverse effects included a 10% incidence rate of cardiovascular disorder, including hypertension, myocardial infarction, and cardiac dysrhythmia in the experimental arm versus 4% in the control arm. Additionally, hepatic disorder was increased in the investigational arm, at 7%, versus 1% in the control arm.
LATITUDE Study Confirms Abiraterone as an Effective Agent
The LATITUDE trial, a double-blind, randomized study evaluating the use of ADT, abiraterone, and prednisone (Zytiga + P) compared with placebo men with newly diagnosed, high-risk metastatic mCSPC.2 The trial was similar to the STAMPEDE trial; however, LATITUDE did not include men with locally advanced disease.
Men were randomized 1:1 to receive ADT plus 1000 mg of abiraterone once daily and 5 mg of prednisone once daily (n = 597) or ADT plus placebo (n = 602).
The primary endpoints of the trial were OS and radiographic progression-free survival (rPFS). In contrast, critical secondary endpoints included pain progression, prostate-specific antigen (PSA) progression, next symptomatic skeletal event, chemotherapy, and subsequent prostate cancer therapy.
The final OS analysis revealed that men receiving ADT plus abiraterone had a median OS of 53.3 months compared with 36.5 months with ADT alone.
In men with high-volume disease, OS was 49.7 months with the addition of abiraterone versus 33.3 months with ADT alone. In men with low-volume disease, the OS was not reached in both arms.
"The benefit [with this approach] was seen in patients with high- and low-volume disease," said Taplin. "There is no need to consider or start counting the number of metastases your patients have when you are considering this treatment."
High-risk disease was defined as meeting 2 of the following 3 criteria: a Gleason score of 8 or greater, the presence of 3 or more lesions on bone scan, and the presence of measurable visceral metastasis.
The experimental regimen compared favorably with the control regimen concerning all secondary endpoints.
These findings confirmed the LATITUDE trial's interim analysis and solidified the role of abiraterone plus standard of care in men with newly diagnosed high-risk mCSPC, explained Taplin.
Apalutamide Enters the Space in the TITAN Study
Taplin also presented data from the third trial, TITAN. TITAN evaluated newer second-generation AR inhibitor apalutamide (Erleada) versus placebo in men with mCSPC who were receiving ADT.3
Eligible men had to have castrate sensitive prostate cancer (CSPC), distant metastatic disease by one or more lesions on bone scan, and an ECOG performance status of 0 or 1. Additionally, men had to be receiving continuous ADT while on the study.
Prior treatment with docetaxel was permitted, as was ADT for six months or less for metastatic disease or three years or less for local disease. Previous local treatment was also allowed if it was completed one or more years before enrollment.
In TITAN, men were randomized 1:1 to receive 240 mg of apalutamide daily plus ADT (n = 525) or placebo plus ADT (n = 527).
The trial's co-primary endpoints were OS and rPFS; secondary endpoints included time to use cytotoxic chemotherapy, time to pain progression, time to chronic opioid use, and time to askeletal-related event. The trial also included exploratory endpoints such as time to PSA progression, second PFS (PFS2), and time to symptomatic progression.
At a median follow-up of 22.9 months for apalutamide and 22.4 months for placebo, apalutamide reduced the risk of death by 33% compared with placebo.
Additionally, rPFS was not reached in the experimental arm versus 22.1 months with placebo. This translated to a 52% reduction in the risk of radiographic progression or death with apalutamide versus placebo.
The median treatment duration was 20.5 months, with apalutamide compared with 18.3 months with ADT alone. Additionally, 66% of the subject men remained on treatment with apalutamide compared with 46% of those treated with a placebo. Secondary and exploratory endpoints favored apalutamide versus placebo.
AEs of particular interest included rash, fatigue, fall, hypothyroidism, fracture, and seizure. All-grade and grade 3 or higher AEs of particular interest were equally or more frequently observed with apalutamide compared with placebo.
However, the treatment was deemed tolerable as the safety profile was consistent with the expected AEs of apalutamide. Additionally, health-related QOL was maintained with apalutamide and did not differ from placebo.
Current FDA-Approved Treatment Options in mCSPC
With positive OS data also coming out of the phase 3 ENZAMET trial (NCT02446405), which evaluated enzalutamide (Xtandi) as a first-line therapy for patients with mCSPC, multiple FDA-approved options are available to treat men with this disease.4
Abiraterone, enzalutamide, apalutamide, and docetaxel could be considered for this patient population, noted Taplin. "None of us can [confirm] that one [option] is better than the other; [the treatment decision] needs to be individualized [by weighing the] pros and cons [with each agent] for each patient," Taplin concluded.
References
James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Eng J Med. 2017;377(4):338-351. doi:10.1056/NEJMoa1702900
Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. N Eng J Med.2019;20(5):686-700. doi:10.1016/S1470-2045(19)30082-8
Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Eng J Med. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307
Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Eng J Med. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835
