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Ipatasertib/Abiraterone Combination Shows Potential in Metastatic Castration-Resistant Prostate Cancer With PTEN Loss


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Ipatasertib plus abiraterone plus prednisone achieved significantly superior radiographic progression–free survival and antitumor activity compared with placebo plus abiraterone plus prednisonein patients with metastatic castration-resistant prostate cancer and PTEN loss, according to the results of a primary analysis of the phase III IPATential150 trial presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.1

With a median follow-up of 19 months, median radiographic progression–free survival was 18.5 months with the experimental combination vs 16.5 months with placebo plus abiraterone in the PTEN-loss subgroup of patients with metastatic castration-resistant prostate cancer (P = .0335), representing a 23% reduction in the risk of radiographic disease progression. Estimated 1-year event-free rates for the two treatment arms were 64.4% and 63.3%, respectively.

In an intent-to-treat analysis of all patients in the trial, median radiographic progression–free survival was 19.2 months for the experimental arm compared with 16.6 months for the control arm, a 16% difference that failed to meet the requirement for statistical significance. In the intent-to-treat population, 1-year event-free rates were 65.3% and 63%, respectively.

Improved Outcomes for Subset of Patients

“Combined androgen receptor and AKT blockade with ipatasertib plus abiraterone improves clinical outcomes over androgen receptor blockade alone for patients with PTEN-loss metastatic castration-resistant prostate cancer. This is a subset with poor prognosis,” said lead author Johann de Bono, MD, of The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London.

Johann de Bono, MD

Johann de Bono, MD

Metastatic castration-resistant prostate cancer is a heterogeneous disease. Anywhere from 40% to 50% of patients have PTEN loss, which is associated with worse prognosis and reduced benefit from androgen receptor blockade compared with other prostate cancer subtypes. A preliminary study suggested that dual androgen receptor inhibition and PI3K/AKT inhibition would prolong progression-free survival in patients with PTEN-loss tumors. The phase III IPATential150 trial was designed to evaluate this strategy in patients with previously untreated metastatic castration-resistant prostate cancer.

Ipatasertib is an investigational oral potent small molecule that binds to the ATP pocket of all three isoforms of AKT. In preclinical prostate cancer models, this agent improved the antitumor activity of androgen receptor blockade.

Study Details

IPATential150 enrolled 1,101 men with asymptomatic or mildly symptomatic, previously untreated metastatic castration-resistant prostate cancer and tumor PTEN loss documented by immunohistochemistry, defined as a minimum of specimen tumor cells with no detectable PTEN staining. Patients were randomly assigned 1:1 to ipatasertib at 400 mg/d plus abiraterone at 1,000 mg/d plus prednisone at 5 mg/d vs placebo plus the same dose of abiraterone and prednisone.

Patients were stratified according to tumor PTEN loss, prior docetaxel in the hormone-sensitive setting, prostate-specific antigen (PSA) progression alone, presence of liver or lung metastases, and geographic region.

Baseline characteristics were well balanced between the two treatment arms and also between the intent-to-treat population (n = 1,101 patients) and the PTEN-loss subgroup (n = 521). Median age was about 70, and about 70% were White. About 18% had prior taxane therapy and about 50% had PSA progression alone. About 84% had bone metastasis, about 38% had positive lymph nodes, and about 12% had lung or liver metastasis.

KEY POINTS

  • The strategy of combining an AKT inhibitor (ipatasertib) plus an androgen receptor inhibitor (abiraterone) appears to have promise for the treatment of metastatic castration-resistant prostate cancer characterized by PTEN loss.
  • Prophylactic medications may be able to avoid the side effects of diarrhea and skin rash encountered with the investigational combination.
  • Further study and longer follow-up are needed before this combination is incorporated into clinical practice.
  • Next-generation sequencing appears to be a more accurate method of defining PTEN loss than immunohistochemistry.

At the time of study cutoff, 367 patients in the ipatasertib-plus-abiraterone arm and 377 patients in the placebo-plus-abiraterone arm were still on study. In the experimental arm, 180 patients discontinued the study compared with 177 in the control arm. Deaths were 121 (22%) and 139 (25%), respectively.

PTEN-Loss Analysis

In the PTEN-loss population, radiographic progression–free survival was 18.5 months for the investigational arm vs 16.5 months for controls (P = .0335). In the intent-to-treat population, median radiographic progression–free survival was 19.2 months and 16.6 months, respectively.

In a prespecified analysis of radiographic progression–free survival in the PTEN-loss population, the experimental combination did better in almost all subgroups except for those with prior taxane therapy.

In the PTEN-loss population, objective response rate was 61% in the experimental arm vs 39% for controls. In the intent-to-treat analysis, objective response rates were 61% and 44%, respectively. Median duration of response was 15.9 months compared with 16.2 months, respectively. These results were not statistically significant.

PSA response rates in the PTEN-loss group were 84% for the combination of ipatasertib plus abiraterone and 72% for placebo plus abiraterone. In the intent-to-treat population, PSA response rates were 81% and 76%, respectively. Time to PSA progression favored the combination in both the PTEN-loss subgroup and in the intent-to-treat analysis, but again, these findings were not significant.

All of these data were reported on the PTEN-loss population as defined by immunohistochemistry. In an exploratory analysis using PTEN loss as defined by next-generation sequencing, radiographic progression–free survival rates in the next-generation sequencing–defined PTEN-loss population were 68% for the combination and 45% for placebo. Median radiographic progression–free survival was 19.1 months for the combination and 14.2 months for placebo (P = .0206).

Ipatasertib combined with abiraterone prolonged the time to pain progression and the time to initiation of cytotoxic chemotherapy in both the PTEN-loss and intent-to-treat populations.Overall survival data are still immature, but an early look suggests a trend toward improved survival with the investigational combination.

More grades 3 and 4 adverse events were reported in the ipatasertib-containing arms, and there were more treatment discontinuations in that arm. The main adverse events related to ipatasertib were diarrhea and skin rash. Dr. de Bono said that prophylactic use of loperamide and antihistamines could reduce the risk of those side effects. 

DISCLOSURE: The IPATential150 study was supported by F. Hoffmann–LaRoche. Dr. de Bono has received honoraria from Astellas Pharma, AstraZeneca, BioXcel Therapeutics, Daiichi Sankyo, Genentech/Roche, Janssen Oncology, Menarini Silicon Biosystems, Pfizer, Sanofi, and Sierra Oncology; has served in a consulting or advisory role for Astellas Pharma, AstraZeneca, Bayer, BioXcel Therapeutics, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, Genentech/Roche, Genmab, GlaxoSmithKline, Janssen Oncology, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma GmbH, Pfizer, Sanofi, Sierra Oncology, and Taiho Pharmaceutical; has received institutional research funding from Astex Pharmaceuticals, AstraZeneca, Bayer, Celgene, CellCentric, Daiichi Sankyo, Genentech, GlaxoSmithKline, MedImmune, Medivation, Merck Serono, Merck Sharp & Dohme, Orion Pharma GmbH, Sanofi, Sierra Oncology, and Taiho Pharmaceutical; holds institutional intellectual property in “Abiraterone rewards to inventors,” “CHK1 inhibitor,” “PARP inhibitors and DNA repair defects,” and “Targeting of IL23 in prostate cancer”; and has been reimbursed for travel, accommodations, or other expenses by Astellas Pharma, AstraZeneca, Genmab, GlaxoSmithKline, Orion Pharma GmbH, Sanofi, Taiho Pharmaceutical, Qiagen, and Vertex.

REFERENCE

1. de Bono JS, Bracarda S, Sternberg CN, et al: IPATential150: Phase III study of ipatasertib plus abiraterone vs placebo plus abiraterone in metastatic castration-resistant prostate cancer. ESMO Virtual Congress 2020. Abstract LBA4. Presented September 20, 2020.


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Formal discussant of the -IPATential150 trial, Henrik Grönberg, MD, Professor at Karolinska Institute, Stockholm, found the study results intriguing, especially in the PTEN-loss patients. “Biomarkers are the wave of the future,” he said.

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