ASCO GU 2022: Discussion - PROpel and MAGNITUDE

(UroToday.com) The 2022 GU ASCO Annual meeting included a prostate cancer oral abstract session and a discussant presentation by Dr. Celestia Higano discussing “Phase 3 MAGNITUDE study: First results of niraparib with abiraterone acetate and prednisone as first-line therapy in patients with mCRPC with and without HRR gene alterations” presented by Dr. Kim Chi, and “PROpel: Phase III trial of olaparib and abiraterone versus placebo and abiraterone as first-line therapy for patients with mCRPC” presented by Dr. Fred Saad.


Dr. Higano notes that the story of abiraterone + prednisone in the first line treatment of mCRPC dates back to the COU-302 trial,1-2 which tested abiraterone acetate + prednisone versus placebo. In this trial abiraterone acetate + prednisone was associated with a median rPFS of 16.5 months versus 8.2 months for placebo (HR 0.52, 95% CI 0.45-0.61): 

Median overall survival for abiraterone + prednisone was 34.7 months compared to 30.3 months for the placebo arm (HR 0.81, 95% CI 0.70-0.93). Dr. Higano notes that overall survival was reported 5 years after the trial started and that rPFS was consistent and highly associated with overall survival.

With regards to the current landscape of first line therapy for mCRPC, since abiraterone + prednisone and enzalutamide single agent trails were reported, the median overall survival of first line therapy for these patients has not improved. Subsequent developments have included (i) PARP inhibitors, (ii) finding that 25-30% of mCRPC patients harbor HRR mutations, and (iii) preclinical data demonstrated that androgen receptor signaling regulates DNA repair in prostate cancer.

From a global perspective, Dr. Higano highlighted that there appear to be several similarities between PROpel and MAGNITUDE. Both trials:

  • Are phase 3 trials
  • Are in first line mCRPC
  • Are testing a PARP inhibitor + abiraterone + prednisone versus placebo + abiraterone + prednisone
  • Have a primary endpoint of rPFS
  • Have OS as a secondary endpoint 

However, Dr. Higano notes that these are quite different clinical trials.

MAGNITUDE (NCT03748641) is a randomized, double-blind phase 3 study. In eligible mCRPC patients, ≤4 months of prior abiraterone acetate/prednisone for mCRPC was allowed. Patients with (HRR biomarker positive: ATMBRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2) and without specified gene alterations (HRR biomarker negative) were randomized 1:1 to receive niraparib 200 mg once daily + abiraterone acetate/prednisone or placebo + abiraterone acetate/prednisone. The primary endpoint was radiographic progression-free survival (rPFS) assessed by blinded independent central review in the BRCA1/2 group followed by all HRR biomarker positive patients. Secondary endpoints were time to initiation of cytotoxic chemotherapy, time to symptomatic progression, and overall survival. Other endpoints included time to PSA progression and objective response rate. The trial design for MAGNITUDE is as follows:

Celestia Higano-1.jpg 

A stratified clinical trial design can look at treatment effects within each biomarker and across groups. However, a formal statistical test must be done to look at the interaction between the biomarker and treatment. Disadvantages of this clinical trial design include the large sample sizes required and the potential for overtreatment of metastasis negative patients.

Dr. Higano also notes that the statistical analysis plan for MAGNITUDE is really assessing two different cohorts: the HRR biomarker negative cohort and the HRR biomarker positive cohort. In the HRR biomarker negative cohort, a prespecified futility analysis was planned after enrolling ~200 of a planned 600 patients and ~125 composite progression events (first of either radiographic or PSA progression or death). IDMC was to recommend whether the HRR biomarker negative cohort should continue or discontinue enrollment to support patient safety and prevent overtreatment. In the HRR biomarker positive cohort, the primary and secondary endpoints were tested using a prespecified statistical hypothesis testing strategy to control the family-wise Type I error rate at a 2-sided level of 0.05. For the primary endpoint, the BRCA1/2 subgroup was specifically powered and tested first, and if statistical significance was reached all HRR biomarker positive patients were to be tested. A total of 400 patients were planned to be enrolled into the HRR biomarker positive cohort; ~50% were to be BRCA1/2 positive.

In the HRR biomarker negative cohort, the preplanned futility analysis showed no benefit of adding niraparib to abiraterone acetate/prednisone in the prespecified composite endpoint (first of PSA progression or rPFS: HR 1.09, 95% CI 0.75-1.59): 

Celestia Higano-2.jpg 

Dr. Higano highlighted that there was additional grade 3/4 toxicity observed using abiraterone acetate/prednisone or placebo + abiraterone acetate/prednisone and that based on futility in the HRR biomarker negative cohort, the IMDC recommended stopping enrollment. When breaking down the composite endpoints in this cohort, there was no signal for benefit at all based on 83 PSA events (HR 1.03, 95% CI 0.67-1.59) and 65 rPFS events (HR 1.03, 0.63-1.67).

PROpel is a randomized, double-blind, placebo-controlled Phase III trial in patients with mCRPC undergoing first-line treatment after failure of primary androgen deprivation therapy, enrolled independently of HRR status. Patients were randomized 1:1 to receive olaparib (300 mg twice daily) or placebo, and abiraterone (1000 mg once daily) + prednisone or prednisolone (5 mg twice daily). The primary endpoint was investigator-assessed rPFS with multiple secondary endpoints, including overall survival. The trial design for PROpel is as follows:

Celestia Higano-3.jpg 

Dr. Higano notes that when looking at the population of patients in each trial, there are several differences, particularly with regards to not specifying BRCA 1/2 patients in the PROpel trial: 

Celestia Higano-4.jpg

Median rPFS by blinded independent review in the PROpel trial showed an improvement of 11.2 months in the combination arm (8.2 months by investigator review) compared to a median rPFS improvement of 2.8 months in the combination arm of the MAGNITUDE HRR biomarker positive cohort (5.1 months by investigator review):

Celestia Higano-5.jpg 

Within MAGNITUDE, the median rPFS among BRCA 1/2 patients showed an improvement of 5.7 months in the combination arm (6.9 months by investigator review) compared to a median rPFS among all HRR biomarker positive patients showing an improvement of 2.8 months in the combination arm (5.1 months by investigator review):

Celestia Higano-6.jpg 

So, is rPFS a surrogate for clinical benefit in mCRPC? Clinical benefit can be defined as prolonged overall survival and/or improved quality of life, however overall survival in these trials is not mature. Quality of life appears stable in both trials compared to baseline. In MAGNITUDE, patients had a BPI <=3, so there was not much room for improvement but there was no deterioration. In PROpel, 20-25% of patients were symptomatic (BPI >4), but quality of life was stable. 

Dr. Higano concluded her discussion of the PROpel and MAGNITUDE trials with the following take-home messages:

  1. PROpel: should we use the combination of abiraterone acetate + prednisone and olaparib as first line therapy for all patients with mCRPC? No, we must await overall survival data before using the combination as there is drug and financial toxicity with the combination, however, rPFS is outstanding. We need a better understanding of which patients benefit the most, then the combination should be considered one option for first-line treatment
  2. MAGNITUDE: should we use niraparib and abiraterone acetate + prednisone as first line mCRPC therapy for all patients with HRR mutations? No, we must await overall survival data and the biomarker analysis (assume BRCA vs non-BRCA) planned for ASCO 2022
  3. MAGNITUDE: should we use niraparib and abiraterone acetate + prednisone as first-line treatment of mCRPC for BRCA 1/2 patients before overall survival data is available? Maybe, this a poor prognosis subset of patients and it appears to have significant benefit in terms of rPFS. It may be reasonable to treat such patients even before overall survival is available, given the poor outcomes with abiraterone acetate + prednisone alone

Presented by: Celestia S. Higano, MD, University of British Columbia, Vancouver, British Columbia, Canada

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday Feb 17 – Saturday Feb 19, 2022 

References:

  1. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-148.
  2. Rathkopf DE, Smith MR, de Bono JS, et al. Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302). Eur Urol. 2014;66(5):815-825.
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