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Abiraterone and Olaparib for metastatic castration-resistant prostate cancer

  • Noel W. Clarke,
  • Andrew J. Armstrong,
  • Antoine Thiery-Vuillemin,
  • Mototsugu Oya,
  • Neal Shore,
  • Eugenia Loredo,
  • Giuseppe Procopio,
  • Juliana de Menezes,
  • Gustavo Girotto,
  • Cagatay Arslan,
  • Niven Mehra,
  • Francis Parnis,
  • Emma Brown,
  • Friederike Schlürmann,
  • Jae Y. Joung,
  • Mikio Sugimoto,
  • Juan A. Virizuela,
  • Urban Emmenegger,
  • Jiri Navratil,
  • Gary L. Buchschacher,
  • Christian Poehlein,
  • Elizabeth A. Harrington,
  • Chintu Desai,
  • Jinyu Kang,
  • Fred Saad,
  • for the PROpel Investigators

Publication: NEJM Evidence, June 2022

DOI: https://doi.org/10.1056/EVIDoa2200043

Background

Preclinical studies and results of a phase 2 trial of abiraterone and olaparib suggest a combined antitumor effect when the poly(adenosine diphosphate[ADP]-ribose) polymerase inhibitor olaparib is combined with next-generation hormonal agent abiraterone to treat metastatic castration-resistant prostate cancer (mCRPC).

Methods

We conducted a double-blind, phase 3 trial of abiraterone and olaparib versus abiraterone and placebo in patients with mCRPC in the first-line setting. Patients were enrolled regardless of homologous recombination repair gene mutation (HRRm) status. HRRm status was determined following enrollment by tumor tissue and circulating tumor DNA tests. Patients were randomly assigned (1:1) to receive abiraterone (1000 mg once daily) plus prednisone or prednisolone with either olaparib (300 mg twice daily) or placebo. The primary end point was imaging-based progression-free survival (ibPFS) by investigator assessment. Overall survival was among the secondary end points.

Results

At this planned primary analysis at the first data cutoff, median ibPFS was significantly longer in the abiraterone and olaparib arm than in the abiraterone and placebo arm (24.8 vs. 16.6 months; hazard ratio, 0.66; 95% confidence interval [CI], 0.54 to 0.81; P<0.001) and was consistent with blinded independent central review (hazard ratio, 0.61; 95% CI, 0.49 to 0.74). At this data cutoff, overall survival data were immature (28.6% maturity; hazard ratio, 0.86; 95% CI, 0.66 to 1.12; P=0.29). The safety profile of olaparib and abiraterone was consistent with the known safety profiles of the individual drugs. The most common adverse events in the abiraterone and olaparib arm were anemia, fatigue/asthenia, and nausea.

Conclusions

At primary analysis at this first data cutoff, abiraterone combined with olaparib significantly prolonged ibPFS compared with abiraterone and placebo as first-line treatment for patients with mCRPC enrolled irrespective of HRRm status. (Funded by AstraZeneca and Merck Sharp & Dohme, LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; ClinicalTrials.gov number, NCT03732820.)

Expert's summary

By Dr. Constance Thibault 

A quarter of patients with a metastatic castration resistant prostate cancer (mCRPC) harbour somatic or germline alterations in homologous recombination repair genes (HRR+). PARP inhibitors (PARPi) have therefore been evaluated in this setting. The first drug approved in the mCRPC study is Olaparib, based on a progression-free survival (PFS), and overall survival (OS) benefit compared to a new hormonal therapy (NHT) in mCRPC HRR+ previously treated with at least one NHT.

However, the benefit in patients with HRR+ other than BRCA1/2 was limited. Olaparib has therefore been approved by the European Medical Agency in 2020 but only in patients with a somatic or germline BRCA1/2 mutation. Preclinical studies suggest a synergic effect combining PARPi with NHT. One hypothesis is that NHT inhibits transcription of some HRR genes, thereby inducing HRR deficiency. Therefore, combining NHT + PARPi might be an interesting option even in patients without alterations in homologous repair genes (HRR-).  PROpel trial is a phase III multicentre double-blind trial that compared acetate abiraterone + olaparib/placebo as first line treatment in patients with mCRPC.

To be enrolled, patients had to have a mCRPC and be naïve of treatment. However, docetaxel at mHSPC stage was allowed. All patients received acetate abiraterone (1g/d) + prednisone (5 mg BID) and placebo/olaparib (300 mg BID). HRR status was assessed retrospectively on ctDNA (FondationOne Liquid CDx test) or tumor tissue (FondationOne CDx). The primary end point was radiological PFS (rPFS) assessed by investigator. Secondary endpoints were: time to first subsequent therapy or death (TFST), time to second progression or death (PFS2), and quality of life.  

A total of 796 patients were randomly assigned to abiraterone + placebo (n=397) or abiraterone + olaparib (n=399) between October 2018 and January 2020. The median PSA at baseline was 17 ng/ml. Only 22% of the patients had previously received docetaxel at mHSPC stage. Patients HRR+ and BRCA2 mutated represented respectively 27% and 9% of the population. The rPFS was significantly longer for the abiraterone + olaparib arm than for the abiraterone + placebo arm (24.8 vs. 16.6 months; hazard ratio, 0.66; 95% CI, 0.54 to 0.81; P<0.001). The difference was still significant when rPFS was assessed by blinded independent central review (median, 27.6 vs. 16.4 months; hazard ratio, 0.61; 95% CI, 0.49 to 0.74).

The benefit was observed across all pre-specified subgroups, including patients HRR- (hazard ratio, 0.76; 95% CI, 0.60 to 0.97), regardless of the test used to determine HRR status. Among patients with measurable disease at baseline (40%), the objective response rate was statistically higher in abiraterone + olaparib arm (58%) compared to abiraterone + placebo armo (48%) (odds ratio, 1.60; 95% CI, 1.02 to 2.53). The overall survival data was immature but a trend in favour of abiraterone + olaparib was observed (Hazard ratio for death, 0.86) (95% CI, 0.66 to 1.12).

The most common adverse events in the abiraterone and olaparib arm were anaemia (15% of grade ≥3), fatigue/asthenia, and nausea. The discontinuation of olaparib/placebo rate was more frequent in olaparib arm (14% vs 7%), but not the discontinuation of abiraterone (8% vs 8%). The incidence of cardiovascular events was similar but a higher proportion of pulmonary embolism occurred in olaparib arm compared to placebo arm (6.5% vs 1.8%).

Expert's comment

By Dr. Constance Thibault 

PROpel trial is the first phase III to report an rPFS benefit of the combination abiraterone + olaparib in first line treatment in mCRPC, regardless of HRR status. Conversely, MAGNITUDE has not been yet published but has been presented at ASCO GU 2022 congress. This trial was also a phase III trial evaluating the efficacy of NHT (abiraterone) + PARPi (niraparib) in first line treatment in mCRPC in two different cohorts: patients with mCRPC HRR+, and HRR-. But the mCRPC HRR- was closed earlier for futility after the first interim analysis.

Therefore, these conflicting results raise a lot of questions: Is olaparib a better PARPi than niraparib? Is ctDNA an effective test to determine HRR status? Several other trials with a design similar to MAGNITUDE trial are ongoing and might help to answer questions. Yet, the proportion of patients with a metastatic prostate cancer naïve of NHT when becoming castration resistant will decrease in the coming years as the new standard of care in mHSPC stage include NHT. Moreover, the European Medicine Agency might wait for the overall survival data before they approve the combination abiraterone + olaparib in all patients in first line treatment.