Ipatasertib plus abiraterone improves PFS in men with mCRPC and PTEN loss

The addition of the AKT inhibitor ipatasertib to abiraterone acetate (Zytiga) and prednisone delayed disease progression and induced superior antitumor activity in patients with metastatic castration-resistant prostate cancer (mCRPC) whose tumors had PTEN loss, according to findings published in the Lancet.1

The results showed that at a median follow-up of 19 months, the median radiographic progression-free survival (rPFS) was 18.5 months with ipatasertib plus abiraterone/prednisone compared to 16.5 months with placebo plus abiraterone/prednisone (HR, 0.77; P = .0335) in a subgroup of patients with mCRPC and PTEN loss. The estimated 1-year event-free survival rates were 64.4% versus 63.3%, respectively.

While there was a numerical benefit in median rPFS with ipatasertib in the study’s intent-to-treat (ITT) population (HR, 0.84; 19.2 vs 16.6 months), the difference did not meet the statistical threshold for superiority established in the study design. The 1-year event-free survival rates in the ITT population were 65.3% and 63.0% in the ipatasertib and control arms, respectively.

Also of note, ipatasertib was associated with improved prostate-specific antigen (PSA) progression and PSA response rates.

“We have shown that combining an existing and a new drug to attack cancer on two different fronts can keep men with prostate cancer healthier for longer. The findings offer a promising new treatment option for patients with a common and aggressive type of prostate cancer and could eventually change clinical practice for these men,” lead study author Johann de Bono, MB CHB, PhD, MSC, professor of Experimental Cancer Medicine at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, stated in a press release.2 “PTEN is one of the most commonly deleted genes in prostate cancer, so this study offers hope to many patients.”

Between 40% and 50% of patients with mCRPC have loss in PTEN, which is associated with worse prognosis and reduced benefit from AR blockade. Reciprocal cross talk has been demonstrated between AR and PI3K/AKT signaling, as AR blockade can activate PI3K/AKT signaling and enable prostate cancer cell survival.

The phase 3 IPATential150 study randomized 1101 patients with asymptomatic or mildly symptomatic previously untreated mCRPC (ITT population) in a 1:1 ratio to ipatasertib or placebo plus abiraterone and prednisone. Patient characteristics at baseline were well balanced between the 2 study arms, as well as between the ITT population and the PTEN-loss subgroup (n = 521). Overall, the median age was 69.5 years, and 69.2% of patients were white. A total 17.9% of patients had previously received a taxane, and about half of patients had a PSA-only progression factor. Most patients had site of metastatic disease in the bone (84.2%), followed by the lymph nodes (39.1%), lung or liver (11.9%), and other (6.5%).

At the time of the data analysis, 377 patients on the placebo/abiraterone arm were still on the study compared with 367 on the ipatasertib arm, with 33% and 36%, respectively, were on treatment. In the placebo arm, 177 patients discontinued the study compared with 180 on the ipatasertib arm, with 25% of placebo-treated patients and 22% of ipatasertib-treated patients discontinuing due to death.

The ipatasertib regimen was associated with an rPFS benefit across several patient subgroups: ECOG performance status of 0 (HR, 0.76); at least 75 years old (HR, 0.67); lactate dehydrogenase levels that are the upper limit of normal and higher (HR, 0.77); no prior taxane-based treatments (HR, 0.74); and the presence of liver/lung metastases (HR, 0.66).

rPFS was also measured in a PTEN-loss population defined by next-generation sequencing (NGS; n = 208). Here, the median rPFS was 19.1 months with ipatasertib compared with 14.2 months with placebo (HR, 0.65; P = .0206).

The confirmed ORR in the PTEN-loss subgroup, was 61% with ipatasertib/abiraterone, with a 19% complete response (CR) rate and a 41% partial response (PR) rate; these rates in the placebo arm were 39%, 6%, and 32%, respectively. The median duration of response (DOR) was 17.7 months (95% CI, 14.0–not estimable) with ipatasertib and 13.9 months (95% CI, 12.1-18.0) with placebo.

The ORR was 61% with ipatasertib in the ITT population, with an 18% CR rate and a 43% PR rate; the placebo/abiraterone arm experienced a 44% ORR, a 9% CR rate, and a 34% PR rate. The median DOR was 15.9 months with ipatasertib compared with 16.2 months with placebo.

The PSA response rates were 84% and 72% with ipatasertib and placebo, respectively, in the PTEN-loss subgroup (P = .0012). In the ITT population, the PSA response rates were 81% and 76%, respectively (P = .0183). Additionally, time to PSA progression favored the ipatasertib arms in both the PTEN-loss subgroup (HR, 0.69; P = .0013) and the ITT population (HR, 0.73; 95% CI, 0.62-0.85; P <.0001).

At the time of the analysis, the OS data were immature; however, the investigators noted an early trend showing survival favoring the ipatasertib arm in the PTEN-loss group (HR, 0.91) and ITT population (HR, 0.93).

Regarding safety, grade 3/4 and 5 adverse effects (AEs) were higher with ipatasertib (70.1% and 4.4%, respectively) versus placebo (39.0% and 3.7%). Serious AEs in the experimental and placebo arms were 39.6% and 22.7%, respectively. Additionally, more patients on ipatasertib versus placebo discontinued treatment (21.1% vs 5.1%) and had dose reductions (39.9% vs 6.2%). Grade 3/4 AEs with ipatasertib reported more than 2% than with placebo included rash, diarrhea, hyperglycemia, increased alanine aminotransferase, increased aspartate aminotransferase, and dehydration. In an effort to mitigate drug discontinuations, de Bono said the institution of prophylactic loperamide and antihistamines can manage diarrhea and cutaneous AEs, respectively.

“The major challenge we face with cancer is its ability to evolve and become resistant to treatment. To overcome or prevent drug resistance, we are increasingly combining precision medicines so that we can attack patients’ cancers in several ways at once. This new study brings together abiraterone, a gold standard prostate cancer medicine which was discovered at the ICR, and a new experimental drug, in order to slow down cancer’s growth and progression. The combination could extend the time before men’s prostate cancer worsens, helping keep them healthy for longer so that they can spend as much time as possible with their loved ones,” Paul Workman, FRS, FRSC, FMedSci, CEO of The Institute of Cancer Research, London, stated in the press release.

References

1. Sweeney C, Bracarda S, Sternberg CN, et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. 2021:398(10295);131-142. doi: 10.1016/S0140-6736(21)00580-8

2. New drug combination attacks prostate cancer on two fronts to keep men healthy for longer. Published online July 8, 2021. Accessed July 9, 2021. https://bit.ly/3e39o2J.