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Addition of ipatasertib, an AKT inhibitor to abiraterone acetate (Zytiga) and prednisone, delayed disease progression and induced superior anti-tumor activity in cancer patients metastatic castration-resistant prostate (mCRPC) whose tumors exhibited loss of PTEN, according to results published in the Lancet.1
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 (RR: 0.77; P = 0.0335) in a subgroup of patients with mCRPC and loss of PTEN. The estimated 1-year event-free survival rates were 64.4% versus 63.3%, respectively.
Although there was a numerical benefit of median rPFS with ipatasertib in the intention-to-treat (ITT) population of the study (RR: 0.84; 19.2 vs. 16.6 months), the difference did not meet the statistical superiority threshold 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.
It should also be noted that ipatasertib has been associated with improved prostate specific antigen (PSA) progression and PSA response rates.
“We have shown that combining an existing drug and a new drug to attack cancer on two different fronts can keep men with prostate cancer healthier for longer. The results offer a promising new treatment option for patients with a common and aggressive type of prostate cancer and could potentially change clinical practice for these men, ”study lead author Johann de Bono, MB CHB, PhD, MSC, professor of experimental cancer medicine at the Institute of Cancer Research in London and the consultant medical oncologist at the Royal Marsden NHS Foundation Trust, said in a press release.2 “PTEN is one of the most frequently deleted genes in prostate cancer, so this study offers hope for many patients. “
Between 40% and 50% of mCRPC patients experience loss of PTEN, which is associated with a poorer prognosis and reduced benefit from RA blockade. Reciprocal crosstalk has been demonstrated between AR signaling and PI3K / AKT because AR blockade can activate PI3K / AKT signaling and allow survival of prostate cancer cells.
The phase 3 IPATential150 study randomized 1101 patients with previously untreated asymptomatic or mildly symptomatic mCRPC (ITT population) in a 1: 1 ratio to ipatasertib or placebo plus abiraterone and prednisone. The characteristics of the patients at baseline were well balanced between the 2 arms of the study, as well as between the ITT population and the population PTEN-Loss subgroup (n = 521). Overall, the median age was 69.5 years and 69.2% of patients were Caucasian. A total of 17.9% of patients had previously received a taxane and about half of the patients had a progression factor related solely to PSA. Most patients had a site of metastatic disease in bone (84.2%), followed by lymph nodes (39.1%), lung or liver (11.9%) and others (6, 5%).
At the time of data analysis, 377 patients in the placebo / abiraterone arm were still in the study versus 367 in the ipatasertib arm, with 33% and 36% on treatment, respectively. In the placebo arm, 177 patients discontinued the study compared to 180 in the ipatasertib arm, with 25% of patients treated with placebo and 22% of patients treated with ipatasertib discontinuing due to death.
The ipatasertib dosing regimen was associated with a benefit of rPFS in several patient subgroups: ECOG performance index of 0 (HR: 0.76); at least 75 years old (HR, 0.67); levels of lactate dehydrogenase which are the upper limit of normal and higher (HR, 0.77); no prior taxane treatment (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 versus 14.2 months with placebo (RR: 0.65; P = .0206).
ORR confirmed in PTEN– loss subgroup, was 61% with ipatasertib / abiraterone, with a complete response rate (CR) of 19% and a partial response rate (PR) of 41%; 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 the placebo.
The ORR was 61% with ipatasertib in the ITT population, with a CR rate of 18% and a RP rate of 43%; the placebo / abiraterone arm had an ORR of 44%, CR rate of 9%, and PR rate of 34%. The median DOR was 15.9 months with ipatasertib versus 16.2 months with placebo.
PSA response rates were 84% and 72% with ipatasertib and placebo, respectively, in the PTEN-loss subgroup (P = 0.0012). In the ITT population, PSA response rates were 81% and 76%, respectively (P = .0183). In addition, the time to progression of PSA favored the ipatasertib arms in both PTEN-loss subgroup (HR, 0.69; P = 0.0013) and the ITT population (RR: 0.73; 95% CI: 0.62-0.85; P <.0001).
At the time of analysis, the SG data were immature; however, the investigators noted an early trend showing survival in favor of 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 reactions (AEs) were higher with ipatasertib (70.1% and 4.4%, respectively) compared to placebo (39.0% and 3.7 %). The serious AEs in the experimental and placebo arms were 39.6% and 22.7%, respectively. In addition, more patients on ipatasertib compared to placebo discontinued treatment (21.1% vs. 5.1%) and had dose reductions (39.9% vs. 6.2%). Grade 3/4 AEs with ipatasertib reported greater than 2% versus placebo included rash, diarrhea, hyperglycemia, increased alanine aminotransferase, increased aspartate aminotransferase, and dehydration. In an effort to ease drug stoppages, de Bono said instituting prophylactic loperamide and antihistamines can manage diarrhea and skin 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 drugs so that we can attack patients’ cancers in multiple ways at once. This new study brings together abiraterone, a benchmark prostate cancer drug discovered at the ICR, and a new investigational drug, to slow the growth and progression of cancer. The combination could extend the time before prostate cancer in men gets worse, helping them stay healthy longer so they can spend as much time as possible with their loved ones, ”Paul Workman, FRS , FRSC, FMedSci, CEO of the Cancer Research Institute. , London, said in the press release.
The references
1. Sweeney C, Bracarda S, Sternberg CN, et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicenter, randomized, double-blind phase 3 trial. 2021: 398 (10295); 131-142. doi: 10.1016 / S0140-6736 (21) 00580-8
2. A new drug combination attacks prostate cancer on two fronts to keep men healthy longer. Published online July 8, 2021. Accessed July 9, 2021. https://bit.ly/3e39o2J.
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