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Adding apalutamide to abiraterone acetate significantly delays the time to radiographic progression in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogenous disease. Inhibition of multiple oncogenic pathways may offer better survival outcomes. Investigating apalutamide in combination with abiraterone and prednisone in chemotherapy-naïve mCRPC patients, the phase III ACIS trial reported a reduction in risk of progression of 31% at ASCO GU 2021.


Metastatic castration-resistant prostate cancer (mCRPC) is commonly driven by the activation of androgen receptors (AR) and elevated intratumoral androgens. Therefore, androgen annihilation may require inhibition of more than one pathway. Apalutamide (APA) and the combination of abiraterone acetate plus prednisone (AAP) are both approved for the treatment of patients and both work though inhibition of the AR signalisation. In the phase III ACIS TRIAL, investigators assessed whether the addition of APA to AAP would result in a superior clinical activity. To this end, 982 chemotherapy-naïve mCRPC patients with disease progression on androgen deprivation therapy (ADT) were randomized to receive APA (240 mg per day), plus AAP (AA: 1000 mg, four times a day. P: 5mg, twice a day), or placebo plus AAP. Participants remained on ADT throughout the study. The primary endpoint of this study was radiographic progression-free survival (rPFS), with key secondary endpoints including overall survival (OS), time to initiation of chemotherapy, time to pain progression and time to chronic opioid use.

APA plus AAP reduces the risk of radiographic progression by 31%

The median age of patients in the trial was 71 years, about 53% of patients had a Gleason score of more than 7 and the median baseline PSA level was 32 ng/mL. Approximately 15% of participants in both arms had visceral metastases, while about 85% had bone involvement. Slightly more paitents in the APA +AAP arm had M0 disease compared to the AAP arm (46.7% vs. 41.9%). After a median follow-up of 25.7 months, the combination of APA plus AAP was shown to significantly reduce the risk of radiographic progression or death by 31% (HR[95%CI]: 0.69[0.58-0.83], P< 0.0001). The median rPFS with APA + AAP was 22.6 months, which is 6 months longer than  the 16.6 months median rPFS seen with AAP alone. The benefit of this combination was observed across all prespecified subgroups, including patients with visceral metastases (HR[95%CI]: 0.69[0.45-1.05]) and patients aged ≥75 years (HR[95%CI]: 0.54[0.40-0.73]). At a median follow-up of 54.8 months, the benefit in rPFS was sustained at the final analysis of this trial (median rPFS: 24.0 vs. 16.6 months; HR[95%CI]: 0.70[0.60-0.83]). The benefit in rPFS did not translate into a significant OS benefit for APA plus AAP compared to AAP alone (median OS: 36.2 vs. 33.7 months, HR[95%CI]: 0.95[0.81-1.11], P= 0.498). Of note, a more pronounced OS benefit was seen in patients with visceral metastases (HR[95%CI]: 0.76[0.52-1.10]) and in patients ≥75 years of age (HR[95%CI]: 0.75[0.59-0.96]). Also the time to PSA progression, chronic opioid use, initiation of chemotherapy and pain progression did not differ significantly between the two arms. Adding APA to AAP did significantly improve the number of patients with a confirmed ≥50% decline in PSA level (79.5% vs. 72.9%, RR[95%CI]: 1.09[1.02-1.17], P= 0.015), as well as those with an undetectable PSA at any point during treatment (24.6% vs. 19.2%, RR[95%CI]: 1.28[1.01-1.62], P= 0.040). Patients with luminal disease and average of high AR activity also demonstrated an rPFS and OS benefit with APA plus AAP, although further studies are required to verify these results. Health-related quality of life (HRQoL) was comparable between both treatment arms and declined over time, in-line with progressive disease.  

Treatment-emergent adverse events (TEAEs) that lead to discontinuation occurred in 16.9% of patients receiving APA plus AAP, and 12.5% receiving AAP alone. TEAEs associated with death occurred in 3.5% and 7.6%, respectively. Grade ≥3 TEAEs of special interest included fatigue (4.7% vs. 3.9%), hypertension (20.6% vs. 12.5%), skin rash (4.5% vs. 0.4%), cardiac disorders (9.0% vs. 5.7%) and fracture and osteoporosis (4.1% vs. 1.4%).


In the final analysis of this trial, APA plus AAP extended rPFS by 7.4 months (P< 0.0001), compared to AAP alone in an mCRPC setting. The safety profile observed in this trial was also comparable to the profile of each individual agent. Despite the higher incidence of TEAEs with APA plus AAP, the quality of life was comparable between the two arms and TEAEs leading to death did not increase. To date no benefit in OS was observed with the APA + AAP combination Further investigation is required to determine which clinical and biomarker subgroups might derive the greatest clinical benefit from this regimen.


Rathkopf DE et al., Final results from ACIS, a randomized, placebo (PBO)-controlled double-blind phase 3 study of apalutamide (APA) and abiraterone acetate plus prednisone (AAP) versus AAP in patients (pts) with chemo-naïve metastatic castration-resistant prostate cancer (mCRPC). Presented at ASCO GU 2021; Abstract 9.

Speaker Dana Rathkopf

Dana Rathkopf

Dana Rathkopf, MD, Memorial Sloan Kettering Center


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