CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: April 18, 2022
Expiration: April 17, 2023
Daniel P. Petrylak, MD:
The ongoing double-blind phase III ARASENS trial randomized 1306 patients with newly diagnosed metastatic CSPC to receive darolutamide vs placebo in combination with ADT and docetaxel.1,2 All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1 and were enrolled from 286 sites across 23 countries. Stratification was based on metastasis stage (M1a vs M1b vs M1c) and alkaline phosphatase level.
Patients randomized to the experimental group received 75 mg/m2 docetaxel on Day 1 of six 28-day cycles plus ADT and 600 mg darolutamide orally twice each day. Patients in the control group received the same schedule of docetaxel and ADT with placebo. Treatment continued until symptomatic progression, change in neoplastic treatment, or unacceptable toxicity.
The primary endpoint of ARASENS is OS; secondary endpoints include time CRPC, time to pain progression, time to initiation of subsequent anticancer therapy, and safety. Results from ARASENS were presented by Smith and colleagues at ASCO GU 2022.2
Daniel P. Petrylak, MD:
The median age of patients was 67 years in both arms, and the most common metastatic stage at initial diagnosis was M1 with distant metastases (~86% in each arm).1 At screening, approximately 17% of patients in each arm had visceral metastases. The volume of bone disease, median prostate-specific antigen (PSA) levels, and alkaline phosphatase values were also very similar between arms.
Daniel P. Petrylak, MD:
The primary endpoint of OS was met, with a median survival not yet reached in the darolutamide plus docetaxel arm vs 48.9 months in the placebo plus docetaxel arm (HR: 0.68; 95% CI: 0.57-0.80; P <.001).1 The OS benefit was observed across most subgroups, including those stratified by metastatic stage at initial diagnosis. There was an HR: 0.707 for patients with M1 disease and an HR: 0.605 for patients with M0 disease. Of importance, 75.6% of the patients in the placebo arm received subsequent life-prolonging systemic therapy.
Daniel P. Petrylak, MD:
A benefit for darolutamide plus docetaxel was also observed for time to CRPC (HR: 0.36; 95% CI: 0.30-0.42; P <.001) and time to pain progression (HR: 0.79; 95% CI: 0.66-0.95; P = .01).1
Daniel P. Petrylak, MD:
Other secondary endpoints were met, including symptomatic skeletal event (SSE)-free survival (HR: 0.61; 95% CI: 0.52-0.72; P <.001).1 The median time to first SSE was not reached in either arm (HR: 0.71; 95% CI: 0.54-0.94; P = .02). Median time to the initiation of subsequent antineoplastic treatment has not yet been reached in the darolutamide plus docetaxel arm but was 25.3 months with placebo plus docetaxel (HR: 0.39; 95% CI: 0.33-0.46; P <.001). Time to worsening of disease‑related symptoms was similar at 19.3 months with darolutamide and 19.4 months with placebo (HR: 1.04; 95% CI: 0.89-1.22; P = .59).
Daniel P. Petrylak, MD:
There were no differences in the rates of neutropenia, febrile neutropenia, anemia, pneumonia, and hyperglycemia.1 There is a higher rate of hypertension with darolutamide (6.4% vs 3.2%), but this was not unexpected. There were comparable rates of any‑grade adverse events (AEs), grade 3‑5 AEs, serious AEs, and treatment‑related AEs (TRAEs) resulting in death (~4% in both arms).
Daniel P. Petrylak, MD:
AEs of special interest, including rash and fractures, were slightly more common in the darolutamide arm than with placebo.1 The incidence of diabetes was similar, and as I just mentioned, the incidence of hypertension was higher with darolutamide.
Daniel P. Petrylak, MD:
The addition of darolutamide to ADT plus docetaxel significantly prolonged OS vs placebo plus ADT and docetaxel in patients with newly diagnosed metastatic CSPC.1,2 The median OS was not reached in the darolutamide arm but was 48.9 months in the placebo arm. The OS benefit was consistent across prespecified subgroups, including patients with de novo vs recurrent metastatic disease at diagnosis.
The addition of darolutamide significantly improved multiple secondary endpoints: SSE-free survival, time to CRPC, time to pain progression, time to first SSE, and time to first subsequent antineoplastic therapy. AE rates were comparable between arms, with no new safety signals observed. I was definitely pleased to see that there was no difference in the rates of neutropenia between arms. The investigators concluded that darolutamide plus ADT and docetaxel should become a new standard of care for patients with metastatic CSPC.
Dr. Choueiri, what are your thoughts on these results? Will you adopt this approach in your practice?
Toni K. Choueiri, MD:
I will once this regimen is approved by the FDA as I think the data are very compelling with the OS benefit. I am very happy that multiple secondary endpoints were met, and I anticipate that this approach will become standard of care.
We are already familiar with the safety profile of darolutamide, which is quite favorable in the castration‑resistant setting. There have been questions about whether we need docetaxel, but the study was not designed to answer this.
Daniel P. Petrylak, MD:
These data dovetail well with the PEACE‑1 trial, which showed a survival benefit with the addition of abiraterone/prednisone to ADT plus docetaxel vs ADT plus docetaxel alone.3 An advantage with the ARASENS regimen is the different toxicity pattern. One does not have to give prednisone with this regimen, which on a long‑term basis can cause skin problems, hypertension, hypokalemia, and liver function abnormalities. The only real difference we see in toxicity with darolutamide plus docetaxel is hypertension, which is a known AE associated with antiandrogen therapy. I think this is an acceptable alternative and should be adopted in practice when FDA approved. This regimen is also comparatively easy to give. I am very positive on this regimen even though it remains unclear whether antiandrogen monotherapy provides the same results.
Toni K. Choueiri, MD:
Abiraterone costs less than darolutamide, so I would argue that could be a factor when cost is an issue.4
Daniel P. Petrylak, MD:
I have become more conscious of the cardiovascular issues with abiraterone, particularly since a study found a significant increase in hospitalizations and mortality among patients with preexisting cardiovascular disease who are receiving abiraterone.5 If you plan to treat patients long‑term with abiraterone, it is important to be very aware of their cardiac status.
Daniel P. Petrylak, MD:
PROpel is an international, randomized, double-blind phase III trial comparing olaparib plus abiraterone vs placebo plus abiraterone in 796 patients with previously untreated metastatic CRPC.6,7 Patients had ongoing ADT and were allowed prior docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC) but could not have previously received abiraterone. Screening for HRR mutations was not required—which we will discuss in more detail shortly—but optional biopsies and blood were collected for next-generation sequencing (NGS). Stratification was based on the site of metastatic disease (bone only vs visceral vs other) and whether patients had received a taxane for mHSPC (yes vs no). Treatment continued until radiographic progression or unacceptable toxicity, and crossover from the placebo to olaparib arm was not permitted.
The primary endpoint is investigator-assessed rPFS and key secondary endpoints include OS, time to subsequent therapy or death, time to second progression, or death (PFS2), overall response rate (ORR), and safety. The current interim analysis was presented by Saad and colleagues at ASCO GU 2022.6
Daniel P. Petrylak, MD:
Median age, rate of symptomatic pain, and ECOG performance status were well matched between the arms.6 The most common sites of metastases were bone (85% to 87%) and distant lymph nodes (30% to 33%), but lung was the site of metastases in 10% and liver in ~4%. Docetaxel had been received for mHSPC in 22% of patients.
It is important to note that trial enrollment was not based on biomarkers. HRR status was established for 97.7% of the patients. Biopsy and/or blood samples taken at baseline were assessed by NGS using the FoundationOne CDx assay for tissue and FoundationOne Liquid CDx assay for plasma circulating tumor DNA. HRRm classification was based on the presence of ≥1 HRR mutation detected by either assay among the following genes: ATM, BRCA1, BRCA2, BARD1, BRIP1,CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD51L. Non-HRRm patients had no mutations detected, and unknown status was assigned when there were no valid results. Approximately 28% of patients in both arms were HRRm, consistent with previous data.8 Of the remaining patients, 70% were non‑HRRm, and 2.3% had unknown status.6
Daniel P. Petrylak, MD:
The primary endpoint of investigator-assessed rPFS was met.6 There was a median investigator-assessed rPFS of 24.8 months in the olaparib arm vs 16.6 months with placebo for an HR: 0.66 (95% CI: 0.54-0.81; P <.0001). The rPFS benefit was maintained through 24 months, and the 24-month rPFS rate was 51.4% vs 33.6% in favor of olaparib.
The rPFS by central review was very similar, with a median of 27.6 months vs 16.4 months, respectively, again in favor of olaparib. The addition of olaparib reduced the risk of progression or death by 34% as determined by investigators and by 39% as determined by central review.
The rPFS benefit with olaparib was observed across all prespecified subgroups, including HRRm and non-HRRm. That being said, there was a signal that the HRRm subgroup benefited more from this regimen than the non-HRRm subgroup. In the HRRm subgroup, the median rPFS was not reached in the olaparib arm vs 13.9 months in the placebo arm, translating to an HR: 0.50 (95% CI: 0.34-0.73). In the non-HRRm subgroup, the median rPFS was 24.1 vs 19.0 months, respectively, translating to an HR: 0.76 (95% CI: 0.60-0.97).
Daniel P. Petrylak, MD:
OS data are at 28.6% maturity, with a current HR: 0.86.6 The median time to first subsequent therapy was 25.0 months with olaparib vs 19.9 months with placebo (HR: 0.74; 95% CI: 0.61-0.90). PFS2 has not been reached in either arm but favors olaparib with an HR: 0.69 (95% CI: 0.51-0.94). The ORR was 58.4% with olaparib vs 48.1% with placebo for an odds ratio of 1.60 (95% CI: 1.02-2.53; nominal P = .0409).
Daniel P. Petrylak, MD:
We do see some notable differences in safety profile between the treatment arms. The overall incidence of any AE was similar between the arms, but grade ≥3 AEs were slightly more common in the olaparib arm (47.2% vs 38.4%).6 The rate of AEs leading to dose interruption, reduction, or discontinuation were all much higher in the olaparib-containing arm.
The incidence of arterial embolic and thromboembolic events was similar between arms, as was the rate of cardiac failure. However, venous embolic and thromboembolic events were more than twice as common in the combination arm, affecting 7.3% vs 3.3% of patients, respectively, with a pulmonary embolism rate of 6.5% vs 1.8%.
The incidence of new primary malignancies and pneumonitis were balanced between the arms, and no cases of myelodysplastic syndromes/acute myeloid leukemia were reported. The health-related quality of life was also comparable between the arms.
Daniel P. Petrylak, MD:
Anemia, fatigue, and gastrointestinal AEs were all more common among patients receiving olaparib.6 The incidence of hypertension and back pain were similar between the arms, whereas arthralgias were actually more common with placebo vs olaparib.
Daniel P. Petrylak, MD:
The addition of olaparib to first‑line abiraterone significantly prolonged investigator-assessed rPFS vs placebo plus abiraterone in patients with metastatic CRPC, with an 8-month increase from 16.6 to 24.8 months.6 The rPFS benefit was observed across all prespecified groups, including HRRm and non-HRRm, although there was a signal that the HRRm subgroup had greater benefit.
The safety profiles were consistent with the established profiles for each drug. This trial excluded patients with cardiovascular disease, and based on the rate of pulmonary emboli, patients at risk for thromboembolic or cardiovascular events definitely should not receive this combination.
Based on this trial, olaparib plus abiraterone is the first combination regimen to demonstrate clinical benefit in first‑line metastatic CRPC regardless of HRRm status. I think that this is a very intriguing trial that asked important questions relevant to the biology of metastatic CRPC.
Dr. Choueiri, what are your thoughts on PROpel?
Toni K. Choueiri, MD:
These are compelling data, and I think the 8-month improvement in rPFS is clinically relevant. These results were encouraging, and this is potentially a new standard of care.
It is important to note that although all patients had a rPFS benefit, the signal in the HRRm population was much stronger. I would not be surprised if an OS signal is observed in the HRRm population before the non-HRRm. But I think clinicians can still talk to their non-HRRm patients about using olaparib.
Daniel P. Petrylak, MD:
It was striking that there was no prespecified analysis comparing HRRm vs non-HRRm. Furthermore, the entry criteria stipulated that patients could not have had testing. In reality, we know they certainly could have undergone testing and that could have influenced the proportion of patients who had the mutations.
Unfortunately, since patients were excluded from study entry if they had received abiraterone/prednisone, enzalutamide, and apalutamide—agents regularly used for patients for HSPC—this will limit the number of patients eligible for PROpel. Despite positive data for earlier use of next-generation antiandrogens, only half of patients receive these agents in the hormone-sensitive setting. We would expect the number of patients treated in the hormone-sensitive setting to increase. How should we treat these patients? Do we continue abiraterone and add a PARP inhibitor, or do we stop abiraterone and give a PARP inhibitor alone? We need a randomized trial of patients treated with abiraterone for HSPC where patients are randomized to continuing or discontinuing abiraterone and adding olaparib.
Toni K. Choueiri, MD:
I agree. Based on these data, I think people will change their attitudes if this regimen receives FDA approval, and they may add olaparib to abiraterone even if the patient has responded or in case of any PSA jump.
Daniel P. Petrylak, MD:
Yes. It has been a battle getting oncologists and urologists to do NGS, but it is a huge therapeutic advantage when patients with these mutations can benefit from targeted therapies.
Toni K. Choueiri, MD:
One final issue before moving on: How do we define HRRm? The definition of HRRm varies among studies, as we will see shortly in our discussion on the MAGNITUDE trial.
Daniel P. Petrylak, MD:
MAGNITUDE is a double-blind phase III trial evaluating first‑line niraparib plus abiraterone and prednisone in 670 patients with metastatic CRPC.9,10 Patients could not have received systemic therapy for metastatic CRPC or prior PARP inhibitors. They could have received prior abiraterone acetate for metastatic CRPC if it were ≤4 months. All patients had a Brief Pain Inventory–Short Form worst pain score ≤3 and no uncontrolled hypertension, myocardial infarction, or ischemia.
In contrast to PROpel, patients enrolled on MAGNITUDE were prescreened for their HRR biomarker status and assigned to biomarker-positive and biomarker-negative cohorts. In each cohort, patients were randomized to receive niraparib plus abiraterone acetate and prednisone vs placebo. Treatment continues until disease progression, unacceptable toxicity, or study end (~66 months). The primary endpoint is rPFS by central review. Secondary endpoints are OS, time to symptomatic progression, and time to cytotoxic chemotherapy. Initial OS data and final rPFS data were presented at ASCO GU 2022 by Chi and colleagues.9
Daniel P. Petrylak, MD:
As I mentioned, all patients were prescreened for HRR status and assigned to the HRR biomarker–positive or HRR biomarker–negative cohort before randomization.9 The HRR panel consisted of ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, and PALB2, which slightly differs from the PROpel trial. Biomarkers were assessed using the FoundationOne CDx assay for tissue, Resolution Bioscience’s liquid test for circulating tumor DNA, AmoyDx blood and tissue assays, Invitae germline testing of blood and saliva, and/or local laboratory testing.
Patients were deemed HRR biomarker positive if they were positive by ≥1 assay. To be considered HRR biomarker negative, patients had to be negative by both tissue and plasma assays.
A prespecified futility analysis was performed in the HRR biomarker–negative cohort after enrolling approximately 200 of 600 planned patients with approximately 125 composite progression events (first event of rPFS or PFS progression). The composite progression endpoint was met, where futility was defined as ≥1. The HR for composite progression was 1.09 (95% CI: 0.75-1.59). As one would expect, higher rates of grade 3/4 AEs were observed in the niraparib vs placebo arm. Due to the added toxicity and lack of efficacy with niraparib, the independent data monitoring committee recommended stopping enrollment in the HRR biomarker–negative cohort.
Daniel P. Petrylak, MD:
Moving forward, we will be reviewing results from the HRR biomarker–positive cohort only. In this cohort, the median age in both arms was 69 years, and the most common biomarker alteration was BRCA2 in approximately 41% of patients in each arm.9 BRCA1 mutations were present in 5.7% of the patients in the niraparib arm vs 1.9% of patients in the placebo arm. ATM alterations were present in 20% and between 8.5% and 9.5% of patients had mutations in CHEK2. Co-occurring alterations were observed in 14% to 15% of patients.
Daniel P. Petrylak, MD:
The primary endpoint of rPFS by central review was met in all HRR biomarker–positive patients and in the subgroup with mutated BRCA1/2.9 In the BRCA1/2-mutated population, there was a 6‑month difference in median rPFS in favor of niraparib at 16.6 months vs 10.9 months with the placebo arm (HR: 0.53; 95% CI: 0.36-0.79). Among all HRR biomarker–positive patients, there was a smaller rPFS benefit (16.5 vs 13.7 months), but this result still favored niraparib (HR: 0.73; 95% CI: 0.56-0.96).
To summarize, the primary endpoint was met with the risk of progression or death reduced by 47% in BRCA1/2-mutated patients and by 27% in all HRR biomarker–positive patients. The benefit was consistent across prespecified subgroups.
Daniel P. Petrylak, MD:
The median time to cytotoxic chemotherapy and symptomatic progression improved with the addition of niraparib, with an HR: 0.58 for patients with mutated BRCA1/2 and an HR: 0.59 for all HRR biomarker–positive patients.9 After a median follow-up of 18.6 months, OS data remain immature in the HRR biomarker–positive cohort (46.3% of the events have occurred; HR: 0.94).
Daniel P. Petrylak, MD:
The median time to PSA progression was not reached in the BRCA1/2-mutated population receiving niraparib but was 9.2 months in the placebo arm.9 Among all HRR biomarker–positive patients, there was approximately a 9‑month benefit in time to PSA progression favoring niraparib (median: 18.5 vs 9.3 months; HR: 0.57).
ORR was nearly doubled with the addition of niraparib among both BRCA1/2-mutated patients and all HRR biomarker–positive patients. The addition of niraparib approximately doubled the median time to PSA progression. There was no difference in quality of life.
Daniel P. Petrylak, MD:
Dose reduction due to AE affected 19.8% of patients in the niraparib arm vs 3.3% of the patients in the control arm.9 The AEs most frequently leading to dose reduction in the niraparib arm were anemia (13.2%) and thrombocytopenia (2.8%). Discontinuation of niraparib due to an AE occurred in 10.8% of patients whereas 4.7% of patients receiving placebo discontinued placebo due to AE. The median relative dose intensity in the niraparib arm was 99%.
Daniel P. Petrylak, MD:
Anemia was the predominant TEAE in the arm with niraparib, with 46.2% of patients experiencing any-grade anemia.9 In the placebo arm, only 20.4% of patients developed any-grade anemia. The rates of thrombocytopenia and neutropenia were also higher with niraparib, as were hypertension and arrhythmia.
Daniel P. Petrylak, MD:
In this multicohort phase III trial, the addition of niraparib to front-line abiraterone acetate and prednisone significantly improved rPFS by central review vs placebo plus abiraterone and prednisone in patients with metastatic CRPC and HRR gene alterations.9 The risk of progression or death was significantly reduced by 47% in the BRCA1/2-mutated subgroup and by 27% in all HRR biomarker–positive patients. The prespecified futility analysis found no benefit with the addition of niraparib in patients who were HRR biomarker negative, and the independent data monitoring committee stopped enrollment of this cohort.
Other clinical outcomes including the time to cytotoxic chemotherapy, time to symptomatic progression, time to PSA progression, and ORR were also improved with the addition of niraparib to abiraterone and prednisone, and health‑related quality of life was maintained. No new safety signals were identified. The investigators concluded that the combination is effective in first‑line disease, and it underscores the need for HRR testing.
An important difference between PROpel and MAGNITUDE is that the latter prescreened based upon HRR status and assigned patients to cohorts before randomization. MAGNITUDE did not observe a benefit in the HRR biomarker–negative population. The benefit among HRR biomarker–positive patients seemed greatest in patients with BRCA1/2 mutations.
What are your thoughts, Dr. Choueiri?
Toni K. Choueiri, MD:
MAGNITUDE and PROpel defined HRR biomarker positivity differently. Although I personally do not believe there is a major difference between niraparib and olaparib, it is difficult to compare between different trials. Although the benefits with niraparib were statistically significant, the absolute benefit was not huge. We should bear in mind that patients with BRCA1/2 mutations do not respond well to abiraterone.
Ultimately, I would use niraparib in patients with HRR biomarker positivity as defined by MAGNITUDE.
Daniel P. Petrylak, MD:
Agreed.
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