The phase 3 PROfound trial reported favorable progression-free survival (PFS) outcomes for olaparib vs enzalutamide or abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC) who had disease progression while receiving a new hormonal agent.
Data presented at ESMO 2020 demonstrated that olaparib resulted in a statistically significant and clinically meaningful prolongation of overall survival (OS) vs sequential therapy with enzalutamide or abiraterone in this population of men, with a 31% reduction in the risk for death.
Men with mCRPC and disease progression on a prior new hormonal agent were randomized 2:1 to olaparib or control treatment. Patients could crossover to olaparib upon radiographic disease progression.
At data cut-off (March 20, 2020), median final OS in Cohort A was significantly longer with olaparib than with physician’s choice of enzalutamide or abiraterone (HR, 0.69; 95% CI, 0.50–0.97; P=0.0175), with a trend towards improvement in the overall population (HR, 0.79; 95% CI, 0.61–1.03; nominal P=0.0515). In the control arm, 56 (67%) of patients in Cohort A and 86 (66%) in the overall population crossed over to olaparib.
Commenting on the study, Maha Hussain, MD, Professor of Medicine, Northwestern Medicine, Chicago, said, “This survival endpoint is not just statistically significant but considering how heavily pretreated this patient population was it is very much clinically significant. I want to say how much of a landmark trial this is because up until now prostate cancer was managed with a one-size-fits-all approach.”
First-line treatment with ipatasertib plus abiraterone for metastatic castration-resistant prostate cancer (mCRPC) resulted in significantly improved radiographic progression-free survival (rPFS) and antitumor activity in patients with PTEN-loss mCRPC. Results of the phase 3 IPATential150 trial were reported at the European Society of Medical Oncology (ESMO) 2020 Virtual Meeting.
The trial randomized 1,101 patients with mCRPC to ipatasertib (400 mg/daily)—an oral AKT inhibitor—and abiraterone (1000 mg/daily)—an androgen biosynthesis inhibitor versus abiraterone and placebo. Prednisone was added to each arm.
After a median follow-up of 19 months, the median rPFS among patients with PTEN loss was 18.5 months (95% CI, 16.3–22.1) in the ipatasertib plus abiraterone/prednisone arm, and 16.5 months (95% CI, 13.9–17.0) for patients in the abiraterone/prednisone and placebo arm (HR, 0.77; 95% CI, 0.61–0.98; P=0.0335. In the intention-to-treat (ITT) group, rPFS was 19.2 months (95% CI, 16.5–22.3) in the ipatasertib plus abiraterone/prednisone arm and 16.6 months (95% CI, 15.6–19.1) in the abiraterone/prednisone and placebo arm (HR, 0.84; 95% CI, 0.71–0.99; P=0.0431).
Secondary endpoints favored the ipatasertib plus abiraterone/prednisone arm. Serious adverse events occurred in 40% in the ipatasertib plus abiraterone/prednisone arm and 23% in the abiraterone/prednisone and placebo arm. AEs leading to discontinuation of ipatasertib plus abiraterone/prednisone and abiraterone/prednisone and placebo occurred in 21% and 5%, respectively.
Commenting on the adverse events data, Johann de Bono, UK, said, “we had evidence that the combination had more adverse events than a single agent, necessitating more discontinuations and dose reductions, although we believe that this may be managed and prevented by the use of prophylactic antidiarrheals and antihistamine treatments as this was largely due to diarrhea and skin rash.”
“In conclusion, this combination appears superior to abiraterone alone, particularly for tumors with PI3K/AKT activation through primary PTEN loss,” he said.
The ARCHES trial, originally presented at the American Society of Clinical Oncology Cancers Symposium in 2019, showed improved radiographic progression-free survival (rPFS) (HR, 0.39; 95% CI, 0.30–0.50) for patients with metastatic hormone-sensitive prostate cancer (mHSPC) who received enzalutamide and androgen deprivation therapy (ADT) compared with ADT alone. At ESMO 2020, a post hoc analysis of the primary endpoint (rPFS) and secondary endpoints were presented in the poster session.
Among 1,150 enrolled patients, the vast majority (>90%) had received pre-treatment with ADT and 18% had previously received docetaxel. However, median ADT duration prior to randomization was quite short with a median of 1.6 months (range 0.03 to 55.3) among those randomized to enzalutamide and 1.6 months (range 0.03 to 198.8) and those randomized to placebo.
Baseline PSA data were available for 1,146 patients. Of these, 135 patients had PSA ≤0.2 ng/mL, 388 had PSA 0.2-4 ng/mL, and 623 had PSA >4 ng/mL at baseline. The authors found that the relative benefit of enzalutamide to placebo in terms of rPFS was relatively consistent across these three strata of baseline PSA values. A similar effect was observed examining other endpoints including time to PSA progression and time to castration resistance.
The investigators concluded that these post hoc analyses demonstrate the clinical benefit of enzalutamide plus ADT versus placebo plus ADT based on rPFS and secondary clinical endpoints in patients with mHSPC, irrespective of patients’ baseline PSA values.
In the STAMPEDE trial, reported at the ESMO 2020 Virtual Meeting, a sustained and substantial improvement in overall survival (OS) of patients with M1 prostate cancer was achieved with ADT plus abiraterone acetate plus prednisolone, irrespective of burden of disease.
Abiraterone acetate plus prednisolone previously showed a clear survival advantage in men starting long-term hormone therapy for prostate cancer in STAMPEDE, a randomized controlled trial using a multi-arm, multi-stage platform design. STAMPEDE included a wide range of men with M1 or M0 disease. The LATITUDE trial, which compared ADT plus abiraterone plus prednisone with ADT plus dual placebos in patients with high-burden M1 disease only, reported a similar magnitude of effect to the comparable subset of STAMPEDE patients.
In STAMPEDE, all patients received ADT. Stratified randomization allocated patients 1:1 to ADT alone or adding daily abiraterone acetate 1000 mg plus prednisolone 5 mg (ADT + AAP) continued until PSA, radiological and clinical progression. The primary outcome measure was death from any cause. The data freeze for this long-term analysis was planned for 3 years after the primary survival results when a meaningful increase in data was anticipated.
Of 1,917 patients contemporaneously randomized to these groups 1,003 (52%) had M1 disease. The M1 groups were balanced: median age 67 years; 48% high-burden, 44% low-burden, 8% burden not assessable; 94% newly-diagnosed; median PSA 97ng/ml. The median follow-up had increased from 3.5 years to 6.1 years and the number of ADT-only deaths increased by 50%, from 218 previously to 329. With 244 ADT + AAP deaths, the adjusted HR=0.60 (95%CI, 0.50–0.71; P=0.31x109) favoring ADT + AAP, with 5-year survival improved from 41% ADT-only to 60% ADT + AAP. The relative effect of abiraterone was similar in low-burden (HR=0.55; 95% CI, 0.41– 0.76) and high-burden (HR=0.54; 95% CI, 0.43-0.69) patients. Median time on ADT + AAP was 2.4 years, with a current maximum of 8.1 years. Toxicity at 4-year post-randomization was similar, with 16% of patients in each group reporting grade 3 or higher toxicity.
In conclusion, at a median of 6.1 years of follow-up, the addition of abiraterone acetate to standard of care therapy for men with metastatic hormone-sensitive prostate cancer (mostly de novo metastatic disease) confers a survival benefit irrespective of risk status, including the LATITUDE trial’s high and low-risk patients and the CHAARTED trials high-and low-volume metastatic disease burden.
The benefit of abiraterone extends to failure-free survival and skeletal related events, with no evident new toxicity with long term follow-up reported. Information regarding bone health (such as development of osteoporosis) with long term therapy will be forthcoming.