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Data on apalutamide, enzalutamide offer new insights into treatment of nonmetastatic castration-resistant prostate cancer

NEW YORK — Data presented earlier this year on two therapies offered new insights into the treatment of men with nonmetastatic castration-resistant prostate cancer, according to a presenter at HemOnc Today New York.

Patients with M0 disease have rising PSA despite castrate levels of testosterone, and they have no evidence of metastasis on conventional imaging such as CT or bone scan.

Until several weeks ago, the standard approach for these patients included androgen deprivation therapy, with the option for sequential anti-androgens.

However, data presented in February at Genitourinary Cancers Symposium showed the potential benefit that apalutamide (Erleada, Janssen) and enzalutamide (Xtandi; Astellas, Medivation) may offer for this patient population, according to Ravi A. Madan, MD, clinical director of the genitourinary malignancies branch at NCI.

Apalutamide is a nonsteroidal antiandrogen that inhibits the action of testosterone in prostate cancer cells and prevents androgen from binding to the androgen receptor.

The phase 3 SPARTAN trial included 1,207 men with nonmetastatic, castration-resistant prostate cancer who had stopped responding to ADT and were at high risk for metastasis based on PSA doubling time. Researchers randomly assigned men 2:1 to apalutamide 240 mg daily plus ADT or placebo plus ADT.

As HemOnc Today previously reported, the apalutamide regimen significantly prolonged the time to metastasis or death, the study’s primary endpoint (HR = 0.28; 95% CI, 0.23-0.35). Median metastasis-free survival was 40.5 months among men assigned apalutamide plus ADT and 16.2 months for those assigned ADT alone.

Apalutamide also extended time to symptomatic progression (HR = 0.45; 95% CI, 0.32-0.63), and researchers observed a trend toward improved OS (HR = 0.7; 95% CI, 0.47-1.04).

“What this study doesn’t answer perfectly is whether it is better to have apalutamide in the M0 state or should you wait until the patient has metastatic disease,” Madan said.

At the time of development of metastases, patients received standard second therapies at their physician’s discretion and had an option to receive on-study abiraterone acetate (Zytiga, Janssen) and prednisone.

“There are cross-resistant mechanisms you would expect with antiandrogen therapies, yet for reasons that still need to be further elucidated, apalutamide-treated patients who went on to get abiraterone seemed to do better than placebo patients,” Madan said. “If this is real data, this is certainly interesting and it quells the concern that if you give these treatments too early, you drive a resistant subset of cancer cells. But again, I think there are some caveats with this data until we understand it better.”

Adverse event analysis showed higher rates of fatigue, along with risk for falls/fractures and dizziness in the apalutamide group.

“We have to take this into account as part of the consideration of using this treatment,” Madan said.

On Feb. 14, the FDA approved apalutamide for treatment of nonmetastatic, castration-resistant prostate cancer.

Madan also provided an overview of the randomized, phase 3 PROSPER trial, presented at Genitourinary Cancers Symposium.

The trial included 1,401 men with nonmetastatic castration-resistant prostate cancer that progressed as determined by rising PSA. The men had no symptoms and no evidence of metastatic disease.

Researchers assigned men 2:1 to ADT plus 160-mg once-daily enzalutamide, an androgen receptor inhibitor, or ADT plus placebo. Metastasis-free survival served as the primary objective.

As HemOnc Today previously reported, patients assigned enzalutamide plus ADT achieved significantly longer median metastasis-free survival (36.6 months vs. 14.7 months; HR = 0.29; 95% CI, 0.24-0.35). Results also showed a trend toward improved OS (HR = 0.8; 95% CI, 0.58-1.09).

A higher percentage of enzalutamide-treated patients experienced any-grade hypertension (12% vs. 5%), major adverse cardiovascular event (5% vs. 3%) and mental impairment disorders (5% vs. 2%).

The most common grade 3 or higher adverse events were hypertension (5% for enzalutamide plus ADT vs. 2% for ADT alone) and fatigue (3% vs. 1%).

“As I mentioned, one concern is are you breeding resistant cancer cells quicker with earlier exposure to these agents,” Madan said. “That concern was somewhat quelled by time to new antineoplastic therapy, which did not appear to be quicker among patients who received enzalutamide earlier.”

Of note, 32 men (15%) assigned enzalutamide and four men (2%) assigned placebo died without documented radiographic progression within 112 days of treatment discontinuation.

“There are concerns about whether these deaths were cardiac related or disease related,” Madan said. “It needs to be flushed out further, and we definitely must take that into account when thinking about using these therapies earlier.”

Madan encouraged clinicians to be cautious when deciding what to do for a patient with castration-resistant disease with rising PSA but no evidence of metastatic disease.

“I think we should consider the patients enrolled on the study who had a benefit,” Madan said. “These were patients with rapid PSA doubling times and PSAs generally greater than 2. If you have a patient whose PSA goes from 0.3 to 0.4 on ADT, I would not favor putting them on one of these therapies right now. I don’t know they would need something that aggressive in the context of some of the toxicities we’re still trying to understand.” – by Mark Leiser

Reference:

Madan RA. What’s new in prostate cancer? Presented at: HemOnc Today New York; March 8-10, 2018; New York.

Disclosure: Madan reports no relevant financial disclosures.

NEW YORK — Data presented earlier this year on two therapies offered new insights into the treatment of men with nonmetastatic castration-resistant prostate cancer, according to a presenter at HemOnc Today New York.

Patients with M0 disease have rising PSA despite castrate levels of testosterone, and they have no evidence of metastasis on conventional imaging such as CT or bone scan.

Until several weeks ago, the standard approach for these patients included androgen deprivation therapy, with the option for sequential anti-androgens.

However, data presented in February at Genitourinary Cancers Symposium showed the potential benefit that apalutamide (Erleada, Janssen) and enzalutamide (Xtandi; Astellas, Medivation) may offer for this patient population, according to Ravi A. Madan, MD, clinical director of the genitourinary malignancies branch at NCI.

Apalutamide is a nonsteroidal antiandrogen that inhibits the action of testosterone in prostate cancer cells and prevents androgen from binding to the androgen receptor.

The phase 3 SPARTAN trial included 1,207 men with nonmetastatic, castration-resistant prostate cancer who had stopped responding to ADT and were at high risk for metastasis based on PSA doubling time. Researchers randomly assigned men 2:1 to apalutamide 240 mg daily plus ADT or placebo plus ADT.

As HemOnc Today previously reported, the apalutamide regimen significantly prolonged the time to metastasis or death, the study’s primary endpoint (HR = 0.28; 95% CI, 0.23-0.35). Median metastasis-free survival was 40.5 months among men assigned apalutamide plus ADT and 16.2 months for those assigned ADT alone.

Apalutamide also extended time to symptomatic progression (HR = 0.45; 95% CI, 0.32-0.63), and researchers observed a trend toward improved OS (HR = 0.7; 95% CI, 0.47-1.04).

“What this study doesn’t answer perfectly is whether it is better to have apalutamide in the M0 state or should you wait until the patient has metastatic disease,” Madan said.

At the time of development of metastases, patients received standard second therapies at their physician’s discretion and had an option to receive on-study abiraterone acetate (Zytiga, Janssen) and prednisone.

“There are cross-resistant mechanisms you would expect with antiandrogen therapies, yet for reasons that still need to be further elucidated, apalutamide-treated patients who went on to get abiraterone seemed to do better than placebo patients,” Madan said. “If this is real data, this is certainly interesting and it quells the concern that if you give these treatments too early, you drive a resistant subset of cancer cells. But again, I think there are some caveats with this data until we understand it better.”

Adverse event analysis showed higher rates of fatigue, along with risk for falls/fractures and dizziness in the apalutamide group.

“We have to take this into account as part of the consideration of using this treatment,” Madan said.

On Feb. 14, the FDA approved apalutamide for treatment of nonmetastatic, castration-resistant prostate cancer.

Madan also provided an overview of the randomized, phase 3 PROSPER trial, presented at Genitourinary Cancers Symposium.

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The trial included 1,401 men with nonmetastatic castration-resistant prostate cancer that progressed as determined by rising PSA. The men had no symptoms and no evidence of metastatic disease.

Researchers assigned men 2:1 to ADT plus 160-mg once-daily enzalutamide, an androgen receptor inhibitor, or ADT plus placebo. Metastasis-free survival served as the primary objective.

As HemOnc Today previously reported, patients assigned enzalutamide plus ADT achieved significantly longer median metastasis-free survival (36.6 months vs. 14.7 months; HR = 0.29; 95% CI, 0.24-0.35). Results also showed a trend toward improved OS (HR = 0.8; 95% CI, 0.58-1.09).

A higher percentage of enzalutamide-treated patients experienced any-grade hypertension (12% vs. 5%), major adverse cardiovascular event (5% vs. 3%) and mental impairment disorders (5% vs. 2%).

The most common grade 3 or higher adverse events were hypertension (5% for enzalutamide plus ADT vs. 2% for ADT alone) and fatigue (3% vs. 1%).

“As I mentioned, one concern is are you breeding resistant cancer cells quicker with earlier exposure to these agents,” Madan said. “That concern was somewhat quelled by time to new antineoplastic therapy, which did not appear to be quicker among patients who received enzalutamide earlier.”

Of note, 32 men (15%) assigned enzalutamide and four men (2%) assigned placebo died without documented radiographic progression within 112 days of treatment discontinuation.

“There are concerns about whether these deaths were cardiac related or disease related,” Madan said. “It needs to be flushed out further, and we definitely must take that into account when thinking about using these therapies earlier.”

Madan encouraged clinicians to be cautious when deciding what to do for a patient with castration-resistant disease with rising PSA but no evidence of metastatic disease.

“I think we should consider the patients enrolled on the study who had a benefit,” Madan said. “These were patients with rapid PSA doubling times and PSAs generally greater than 2. If you have a patient whose PSA goes from 0.3 to 0.4 on ADT, I would not favor putting them on one of these therapies right now. I don’t know they would need something that aggressive in the context of some of the toxicities we’re still trying to understand.” – by Mark Leiser

Reference:

Madan RA. What’s new in prostate cancer? Presented at: HemOnc Today New York; March 8-10, 2018; New York.

Disclosure: Madan reports no relevant financial disclosures.

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