Clinical trialPhase 3Prostate cancer

Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer

NEJM Evidence · 2022796 patients (399 in the olaparib + abiraterone group and 397 in the placebo + abiraterone group)

Clarke NW, Armstrong AJ, Thiery-Vuillemin A, Oya M, Shore N, Loredo E, et al. NEJM Evidence. 2022. 1

A newer report of this study has been published: Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial (2023)

Study type: Clinical trial
Study name: PROpel
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled trial (1:1 randomisation)
Sample size: 796 patients (399 in the olaparib + abiraterone group and 397 in the placebo + abiraterone group)
Source: NEJM Evidence · 2022
Trial registration: NCT03732820

In plain words

In this study, men with advanced prostate cancer that no longer fully responded to hormone-lowering treatment were given either abiraterone with olaparib, or abiraterone with a placebo. Adding olaparib lengthened the time before the disease grew on scans (24.8 vs 16.6 months). This effect was studied in patients whether or not they had particular gene mutations. The most common side effects were anaemia (low red blood cells), tiredness and nausea. There was not yet enough information about the effect on how long people live.

Key results

24.8 months vs 16.6 months (abiraterone + olaparib vs abiraterone + placebo)

Median ibPFS (investigator assessment)

HR 0.66; 95% CI 0.54–0.81; P<0.001

HR 0.61

ibPFS by blinded independent central review

95% CI 0.49–0.74

HR 0.86

Overall survival (first analysis, immature data)

95% CI 0.66–1.12; P=0.29; data maturity 28.6%

Drugs in this study:Abiraterone (Zytiga)Olaparib (Lynparza)

Dose and schedule cards

Olaparib + abiraterone (PROpel)

First-line mCRPC with a BRCA mutation (FDA label indication; ESMO: abiraterone–olaparib for BRCA alterations without prior ARPI)Cycle length: ContinuousOn the page “Prostate cancer” · With DNA repair gene mutations (HRR/BRCA): PARP inhibitors in mCSPC and mCRPC

First-line mCRPC with a BRCA mutation (FDA label indication; ESMO: abiraterone–olaparib for BRCA alterations without prior ARPI)

Drug	Dose	Route	Schedule
Olaparib	300 mg twice daily	Oral	Daily
Abiraterone acetate	1000 mg once daily	Oral, on an empty stomach	Daily
Prednisone or prednisolone	5 mg twice daily	Oral	Daily
ADT (GnRH agonist or antagonist, or prior orchiectomy)	Per formulation	—	Continuous

Cycle length: Continuous
Duration: Until progression or unacceptable toxicity

Per the FDA label and the trial. Grade 3–4 anaemia occurred in 16%; olaparib dose modifications and monitoring as in the PROfound regimen.

On the page “Prostate cancer” · With DNA repair gene mutations (HRR/BRCA): PARP inhibitors in mCSPC and mCRPC

BRCA-mutated mCRPC, with abiraterone (PROpel)

With abiraterone and prednisone or prednisoloneCycle length: ContinuousOn the page “Olaparib (Lynparza)” · Standard dosing (FDA label)

With abiraterone and prednisone or prednisolone

Drug	Dose	Route	Schedule
Continuous
Olaparib	300 mg	Oral (with or without food)	Twice daily (about every 12 hours)
Abiraterone	1000 mg	Oral	Once daily
Prednisone or prednisolone	5 mg	Oral	Twice daily
GnRH analogue	As per that drug's label	Injection	Continue concurrently (unless bilateral orchiectomy has been done)

Cycle length: Continuous
Duration: Until progression or unacceptable toxicity

On the page “Olaparib (Lynparza)” · Standard dosing (FDA label)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Abiraterone + olaparib

Olaparib 300 mg (2 × 150 mg tablets) orally twice daily + abiraterone acetate 1000 mg orally once daily + prednisone or prednisolone 5 mg orally twice daily, with ADT, until radiographic progression or unacceptable toxicity (399 patients).

2Abiraterone + placebo

Olaparib placebo twice daily + abiraterone acetate 1000 mg once daily + prednisone or prednisolone 5 mg twice daily (397 patients).

Source of the regimen details: ClinicalTrials.gov NCT03732820 and the FDA label for LYNPARZA (DailyMed)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

796 patients aged 18 or older with first-line mCRPC (no prior systemic treatment for mCRPC; prior abiraterone not allowed; prior docetaxel at the localised or hormone-sensitive stage allowed), continuing ADT with testosterone below 50 ng/dL, ECOG performance status 0 to 1, life expectancy of at least 6 months, not selected by HRR status (HRR status determined after enrolment by tissue and ctDNA testing). Class II–IV heart failure or ejection fraction below 50% and uncontrolled hypertension were exclusion criteria.

Endpoints

Primary endpoint: imaging-based progression-free survival (ibPFS) by investigator assessment. Overall survival was a secondary endpoint.

Safety and side effects

The safety profile of the combination was consistent with the known profile of each drug; the most common adverse events in the combination group were anaemia, fatigue/asthenia and nausea. According to the FDA label: anaemia 48% (grade 3–4: 16%) versus 18% (3.3%); fatigue 38% versus 30%; nausea 30% versus 14%. Olaparib interruption 48%, dose reduction 21% and permanent discontinuation 16%.

Clinical significance and place in guidelines

This primary analysis showed that adding olaparib to abiraterone in first-line mCRPC significantly improves ibPFS, in patients enrolled regardless of HRRm status. Overall survival data were immature at this point and showed no significant difference, so interpreting the effect on survival requires longer follow-up. The status of drug approvals and guideline recommendations (including the indication by HRRm status) should be checked separately, as the abstract gives no information on them.

Limitations

At the primary analysis, overall survival data were immature (28.6% maturity) and showed no significant difference. The primary endpoint was investigator-assessed (although consistent with blinded independent central review). Other limitations and subgroup analyses by HRRm status are not described in the abstract and should be checked in the full text.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.