Metastatic PCa: Studies point to new standard of care

New findings from two large-scale, international studies support the use of upfront treatment with abiraterone acetate (ZYTIGA) in men with metastatic prostate cancer.

The phase III international LATITUDE trial met its co-primary endpoints, demonstrating that adding abiraterone acetate plus prednisone (AA+P) to androgen deprivation therapy (ADT) significantly improved overall survival (OS) and significantly prolonged radiographic progression-free (rPFS) survival in men newly diagnosed with high-risk, metastatic castration-sensitive prostate cancer (mCRPC).

The second trial, STAMPEDE, found that abiraterone added to standard initial treatment reduced the risk of death by 37% over 3 years compared with standard of care alone in men with locally advanced or metastatic prostate cancer.

Both studies’ results were reported at the American Society of Clinical Oncology annual meeting in Chicago and published in the New England Journal of Medicine (June 4, 2017) and (June 3, 2017).

LATITUDE randomized 1,199 men 1:1 to ADT plus AA, 1,000 mg/day, and prednisone, 5 mg/day, or ADT plus placebos for both medications. Lead author Karim Fizazi, MD, PhD, from Gustave Roussy, Villejuif, France, presented findings from a first interim analysis that was planned to be done when about 50% of expected death events had occurred. It was conducted at a median follow-up of 30.4 months after 406 deaths.

Next: Compared with the control group, men treated with AA+P in addition to ADT had a 38% reduction in the risk of death (p<.001)

The results showed that compared with the control group, men treated with AA+P in addition to ADT had a 38% reduction in the risk of death (p<.001) and a 53% reduction in risk of radiographic progression or death (p<.001). Median OS was 34.7 months in the control arm and not yet reached in the AA+P group. Median length of rPFS was 33.0 months in the AA+P group and 14.8 months in the control group. The OS rate at 3 years was 66% for the AA+P arm and 49% for controls.

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“The study hypothesis was that AA+P would improve rPFS with a risk reduction of about 30% and improve OS with a risk reduction of about 20%. Due to the positive findings, the interim analysis is now the final analysis, and I believe that the addition of AA+P to ADT can be considered a new standard of care for patients newly diagnosed with high-risk metastatic castration-sensitive prostate cancer,” Dr. Fizazi said.

Eric J. Small, MD, of the University of California, San Francisco, discussed the study after Dr. Fizazi’s presentation. He concurred with Dr. Fizazi’s statement on the role of abiraterone for newly diagnosed metastatic prostate cancer and went a step further, suggesting AA+P together with ADT should be a new standard of care for all men with untreated metastatic prostate cancer.

“The LATITUDE report is of great importance because prostate cancer is the second leading cause of cancer deaths of men in the world, and in the United States, there appears to be a rising incidence of metastatic prostate cancer as the first presentation of this disease,” said Dr. Small, who was not involved with the study.

“There is no biologically plausible reason to believe that the impact of adding abiraterone to ADT will be volume or risk dependent.”

Dr. Fizazi said that since the first data from phase II trials of AA+P for men with mCRPC became available, it was hypothesized that the best place for the treatment was much earlier in the disease; ie, in the castration-sensitive patient.

“The reasons are that mechanisms of resistance to ADT may develop very early in men with metastatic disease. In addition, ADT alone does not inhibit androgen synthesis by adrenal and prostate cancer cells. And abiraterone not only improves OS in mCRPC, but it is also active in the neoadjuvant setting in men with high-risk localized prostate cancer,” he explained.

In LATITUDE, the definition of high-risk disease required that men meet at least two of the following three criteria: Gleason score ≥8, three or more lesions on bone scan, and presence of measurable visceral lesion. Patients were stratified at baseline by presence of visceral disease and Eastern Cooperative Oncology Group (ECOG) performance status. The study population was typical of men newly diagnosed with metastatic prostate cancer, and the two treatment arms were similar in their baseline characteristics.

Dr. Fizazi reported that the OS benefit of abiraterone was consistently favorable across subgroups defined by ECOG performance status, presence of visceral disease, Gleason score, bone lesion burden, and geographic region. All secondary endpoints, which included time to PSA progression, time to pain progression, time to next symptomatic skeletal event, time to chemotherapy, and time to subsequent prostate cancer therapy, were also significantly improved in the AA+P group (p≤.0086 for all comparisons).

A total of 314 (53%) of the 597 men in the AA+P arm and 469 (78%) of the 602 men in the control group discontinued study treatment and were eligible for subsequent life-prolonging therapy. Of those eligible men, 40% who had received AA+P and 52% of those in the control group received subsequent life-prolonging therapy.

Also see: Is focal therapy the future of treatment for localized PCa?

“In terms of absolute numbers, twice as many controls compared with abiraterone-treated patients (246 vs. 125) received life-prolonging therapy. This suggests that the OS benefit observed in the experimental arm is truly related to upfront AA+P treatment and not to receipt of active drugs beyond progression,” Dr. Fizazi said.

Next: Overall safety profile of treatment with AA+P with ADT consistent with that seen in prior studies of men with mCRPC

The overall safety profile of treatment with AA+P with ADT was consistent with that seen in prior studies of men with mCRPC.

Related: Urologists positive about abiraterone integration

The incidence of grade 3 or 4 adverse events was 63% in the abiraterone arm and 48% in the control group. Rates of Grade 3 adverse events of interest in the abiraterone and control arms were: hypertension, 20% versus 10%; hypokalemia, 10% versus 1%; cardiac disorders, 3% versus 1%. Two patients in each group died of cerebrovascular events, and there were 10 cardiac-related deaths in the abiraterone group and six in the control arm.

“Hypertension and hyperkalemia rarely required treatment discontinuation and none of the deaths due to cardiac disorders were linked to presence of Grade 3 hypertension or hypokalemia,” Dr. Fizazi said.

Placebo rather than docetaxel (Taxotere) was given to men in the control arm in LATITUDE because LATITUDE was designed and fully enrolled before studies establishing a role for docetaxel in men with metastatic hormone-sensitive prostate cancer were completed.

Acknowledging that cross-study comparisons are fraught with hazard and need to be cautiously interpreted, Dr. Small compared OS, rPFS, and 3-year OS survival data from the LATITUDE study and for men with high-volume disease in the CHAARTED study evaluating docetaxel.

The data he presented showed that the benefits obtained from adding abiraterone to ADT were the same as those seen with docetaxel.

Also see: Prostate Ca test influences decision-making post RP

“However, use of abiraterone avoids chemotherapy and its rare, but potentially life-threatening complications. In addition, abiraterone replaces short-term intravenous treatment with long-term oral treatment and may be more appropriate in elderly or debilitated patients,” Dr. Small said.

Next: STAMPEDE - Reduced risks of relapse, bone complications

In the STAMPEDE trial, in addition to the 37% reduced risk of death, men randomized to abiraterone, 1,000 mg/day, plus prednisolone, 5 mg/day, also had reduced risks of relapse and bone complications, reported Nicholas James, BSc, MBBS, PhD.

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The findings should prompt a change in the upfront care of patients with newly diagnosed advanced prostate cancer to include abiraterone, said Dr. James, of Queen Elizabeth Hospital, Birmingham, United Kingdom.

Abiraterone was already known to prolong survival in men relapsing after first-line hormone therapy. The STAMPEDE investigators hypothesized that its use at inception of therapy may result in a larger absolute benefit in OS. STAMPEDE is a unique multi-arm, multi-stage randomized trial conducted in the United Kingdom and Switzerland. It was started in 2005 and an abiraterone arm was opened in 2011, closing in 2014. The analysis presented at the ASCO annual meeting compared standard therapy with standard therapy plus abiraterone in 1,917 men with high-risk prostate cancer who were starting androgen deprivation therapy (ADT). Standard therapy involved ADT for at least 2 years; radiation therapy was also mandated for men with N0M0 disease and encouraged for those with N+M0 disease.

The median age of the cohort was 67 years. Fifty-two percent of participants had distant metastases; of these, 88% had bone metastases. Newly diagnosed patients constituted 95% of the study population. The median follow-up was 40 months.

The 3-year OS rate was 76% with standard therapy alone compared with 83% in the men randomized to standard therapy plus abiraterone (HR 0.63; p=.00000012).

Also see: Why is AS for prostate Ca not used more?

“Our projections are that in the experimental arm, in the metastatic part of the comparison, the median survival will be around 3.5 years in our population to 6.5 years for the abiraterone [arm], so we think this is one of the biggest survival gains ever reported in a trial of an adult solid tumor,” said Dr. James.

Next: “We think these survival data apply to the whole trial population, not just to the metastatic subpopulation"

The effect on OS was similar in men with metastatic and non-metastatic disease.

“We think these survival data apply to the whole trial population, not just to the metastatic subpopulation,” he said.

The rates of failure-free survival at 3 years were 75% versus 45% in the standard therapy and abiraterone plus standard therapy arms, respectively, corresponding to a 71% relative improvement in risk with abiraterone (HR: 0.29; p=.377 x 10^-61). The relative risk of skeletal-related outcomes was also reduced by 55% in the abiraterone group.

Adverse events in the abiraterone arm were similar to those seen with abiraterone used in the relapse setting, Dr. James said. The rate of grade 3 to grade 5 adverse events was similar in both arms. There were more cardiovascular adverse events in the abiraterone arm compared with the control arm (10% vs. 4%), and these were mostly hypertension. Hepatic events were also more common in the abiraterone group (7% vs. 1%).

Also on PCa: RRP plus castration linked to improved survival

“Several years ago, the STAMPEDE trial actually showed benefit associated with chemotherapy added to conventional hormone therapy for metastatic prostate cancer. Here, the same study backbone is used to show the benefit of abiraterone,” said ASCO expert Sumanta Kumar Pal, MD, of City of Hope, Duarte, CA, who was not involved in the study. “Abiraterone should change the treatment paradigm for patients with newly diagnosed metastatic prostate cancer and largely displaces chemotherapy from the current paradigm,” Dr. Pal said.

The combination of abiraterone plus docetaxel should be considered for future study, Dr. James and Dr. Pal agreed.

Dr. Fizazi has received personal fees from Janssen and several other pharmaceutical companies. For the full list of disclosures from LATITUDE, click here.

Dr. James has received grant funding, personal fees, and/or non-financial support from Janssen and other pharmaceutical companies, and his institution has received research funding from Janssen. For the full list of disclosures from STAMPEDE, click here.

Dr. Small’s institution has received research funding from Janssen.

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