AR Inhibition Advances Progress in Metastatic Castration-Sensitive Prostate Cancer Paradigm

In recent years, findings from multiple pivotal clinical trials have reshaped the treatment paradigm of metastatic castration-sensitive prostate cancer (mCSPC). Three such trials include the phase 3 STAMPEDE (NCT00268476), LATITUDE (NCT01715285), and TITAN (NCT02489318) studies, which brought to light the utility of second-generation androgen receptor (AR) inhibitors.

“De novo metastatic prostate cancer accounts for about 3% of all new prostate cancer [cases] in the United States, said Mary-Ellen Taplin, MD, during a presentation at the 2020 Institutional Perspectives in Cancer webinar on Prostate Cancer. “[That number] appears to be rising.”

Most men with metastatic disease develop mCSPC because of reactivation of AR signaling, according to Taplin, who is the chair of the Executive Committee for Clinical Research, director of clinical research at the Lank Center for Genitourinary Oncology, and an institute physician at Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School.

The STAMPEDE Trial Introduces Abiraterone as a Potential Therapy in mCSPC

After the combination of androgen-deprivation therapy (ADT) and docetaxel became the standard of care for patients with mCSPC, the STAMPEDE trial evaluated the role of abiraterone acetate (Zytiga) in combination with standard therapy compared with standard therapy alone.¹

Eligible patients included those with newly diagnosed locally advanced or metastatic disease with positive lymph nodes and/or those with relapsed disease following initial local therapy, explained Taplin.

The primary end point of the trial was overall survival (OS). Secondary end points included failure-free survival (FFS), toxicity, quality of life (QOL), skeletal-related events, and cost effectiveness.

From November 2011 to January 2014, 957 patients 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.

Patients had a median age of 67 years. Over half (52%) had metastatic disease, 88% of which were bony metastases; 20% had node-positive nonmetastatic disease, and 28% had node-negative nonmetastatic disease.

Arm G of the trial showed that ADT plus abiraterone elicited a 37% improvement in OS compared with ADT alone in patients with newly diagnosed, high-risk mCSPC (HR, 0.63; 95% CI, 0.52-0.76; P < .001).

Moreover, investigators reported a 55% reduction in symptomatic skeletal-related events with the combination versus ADT alone (HR, 0.45; 95% CI, 0.36-0.58). 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 patients 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 standard of care also improved FFS by 71% compared with standard of care alone.

In the nonmetastatic cohort of patients, 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 was a double-blind, randomized study evaluating the use of ADT, abiraterone, and prednisone compared with placebo in men with newly diagnosed, high-risk metastatic mCSPC.² The trial was similar to the STAMPEDE trial; however, LATITUDE did not include patients with locally advanced disease.

Patients 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 end points of the trial were OS and radiographic progression-free survival (rPFS), while key secondary end points included pain progression, prostate-specific antigen (PSA) progression, next symptomatic skeletal event, chemotherapy, and subsequent prostate cancer therapy.

The final OS analysis revealed that patients receiving ADT plus abiraterone had a median OS of 53.3 months compared with 36.5 months with ADT alone (HR, 0.66; 95% CI, 0.56-0.78; P < .0001).

In patients with high-volume disease, OS was 49.7 months with the addition of abiraterone versus 33.3 months with ADT alone (HR, 0.62; 95% CI, 0.52-0.74; P < .0001). In patients with low-volume disease, the OS was not reached in both arms (HR, 0.72; 95% CI, 0.47-1.10; P = .1242).

“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 with regard to all secondary end points.

These findings confirmed the interim analysis of the LATITUDE trial 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

Finally, Taplin presented data from the TITAN trial, which evaluated the second-generation AR inhibitor apalutamide (Erleada) versus placebo in men with mCSPC who were receiving ADT.³

Eligible patients had to have CSPC, distant metastatic disease by 1 or more lesions on bone scan, and an ECOG performance status of 0 or 1. Additionally, patients had to be receiving continuous ADT while on study. Prior treatment with docetaxel was permitted, as was ADT for 6 months or less for metastatic disease or 3 years or less for local disease. Prior local treatment was also permitted if it was completed 1 or more years prior to enrollment.

In the trial, patients were randomized 1:1 to receive 240 mg of apalutamide daily plus ADT (n = 525) or placebo plus ADT (n = 527).

The coprimary end points of the trial were OS and rPFS; secondary end points included time to cytotoxic chemotherapy, time to pain progression, time to chronic opioid use, and time to skeletal-related event. The trial also included exploratory end points 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 (HR, 0.67; 95% CI, 0.51-0.89; P = .0053). 

Additionally, rPFS was not reached in the experimental arm versus 22.1 months with placebo (HR, 0.48; 95% CI, 0.39-0.60; P < .0001); 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 patients remained on treatment with apalutamide compared with 46% of those who were treated with placebo.

Secondary and exploratory end points favored apalutamide versus placebo.

AEs of special interest included rash, fatigue, fall, hypothyroidism, fracture, and seizure. All-grade, as well as grade 3 or higher AEs of special interest, were equally or more frequently observed with apalutamide compared with placebo.

However, the treatment was deemed to be 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 is

evaluating enzalutamide (Xtandi) as a first-line therapy for patients with mCSPC, multiple FDA-approved options are available to treat patients 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

1. 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
2. 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
3. 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
4. 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