Clinical trialPhase 3Prostate cancer

Olaparib for Metastatic Castration-Resistant Prostate Cancer

N Engl J Med · 2020387 patients (cohort A: 245; cohort B: 142)

de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, et al. N Engl J Med. 2020. 382:2091-2102

Study type: Clinical trial
Study name: PROfound
Phase: Phase 3
Design: Randomised, open-label trial (2:1 ratio)
Sample size: 387 patients (cohort A: 245; cohort B: 142)
Source: N Engl J Med · 2020
Trial registration: NCT02987543

In plain words

Some prostate cancers have changes (mutations) in genes such as BRCA1, BRCA2 or ATM. In this study, olaparib tablets roughly doubled the time the disease was kept under control in men with such mutations whose cancer had grown on the newer hormone drugs, and in the final analysis they also helped these men live longer. That is why genetic testing of the tumour matters in advanced disease.

Key results

7.4 vs 3.6 months

Imaging-based progression-free survival — cohort A

HR 0.34; 95% CI 0.25–0.47; P<0.001

19.1 vs 14.7 months

Overall survival — cohort A (final analysis)

HR 0.69; 95% CI 0.50–0.97; P=0.02; despite 67% crossover (Hussain et al, NEJM 2020; doi:10.1056/NEJMoa2022485)

17.3 vs 14.0 months

Overall survival — overall population (final analysis)

Cohorts A and B

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

Dose and schedule cards

Single-agent olaparib (PROfound)

mCRPC with HRR gene mutations (greatest benefit with BRCA1, BRCA2 and ATM) after progression on enzalutamide or abirateroneCycle length: ContinuousOn the page “Prostate cancer” · With DNA repair gene mutations (HRR/BRCA): PARP inhibitors in mCSPC and mCRPC

mCRPC with HRR gene mutations (greatest benefit with BRCA1, BRCA2 and ATM) after progression on enzalutamide or abiraterone

Drug	Dose	Route	Schedule
Olaparib	300 mg twice daily	Oral, with or without food; swallow the tablets whole	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. Moderate renal impairment (CrCl 31 to 50): 200 mg twice daily. Dose reduction: 250 mg, then 200 mg twice daily; with a strong CYP3A inhibitor, 100 mg twice daily, and with a moderate inhibitor, 150 mg twice daily. Complete blood count at baseline and monthly thereafter; warnings: MDS/AML, pneumonitis and venous thromboembolism.

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

mCRPC with HRR gene mutations (PROfound)

Progression after enzalutamide or abirateroneCycle length: ContinuousOn the page “Olaparib (Lynparza)” · Standard dosing (FDA label)

Progression after enzalutamide or abiraterone

Drug	Dose	Route	Schedule
Continuous
Olaparib	300 mg	Oral (with or without food)	Twice daily (about every 12 hours)
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

1Olaparib

Olaparib 300 mg (2 × 150 mg tablets) orally twice daily, until radiographic progression or unacceptable toxicity; 100 mg tablets for dose reduction; with continued LHRH analogue or prior orchiectomy (256 patients).

2Control (physician's choice)

Physician's choice: enzalutamide 160 mg orally once daily, or abiraterone acetate 1000 mg orally once daily with prednisone 5 mg twice daily (prednisolone allowed) (131 patients). Crossover to olaparib after radiographic progression was allowed.

Source of the regimen details: ClinicalTrials.gov NCT02987543 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

Men with mCRPC with radiographic progression on ADT who had previously progressed on a new hormonal agent (abiraterone and/or enzalutamide) and had a qualifying alteration in one of 15 HRR genes in tumour tissue (prospective central testing); cohort A: BRCA1, BRCA2 or ATM (245 patients); cohort B: one of the other 12 genes (142 patients). Prior treatment with a PARP inhibitor or DNA-damaging chemotherapy was an exclusion criterion.

Endpoints

Primary outcome: imaging-based progression-free survival in cohort A (blinded independent central review). Key secondary outcomes: confirmed objective response, time to pain progression and overall survival in cohort A.

Safety and side effects

According to the FDA label: anaemia 46% (grade 3–4: 21%) versus 15% (5%); nausea 41% versus 19%; fatigue 41% versus 32%; thrombocytopenia 12% (grade 3–4: 4%); venous thromboembolism 7%. Dose interruption 45% and dose reduction 22% (mainly because of anaemia); the most common reason for permanent discontinuation was anaemia (7%). Fatal adverse events 4%.

Clinical significance and place in guidelines

PROfound led to FDA approval (2020) of olaparib for mCRPC with HRR gene mutations after progression on enzalutamide or abiraterone (the EMA restricted approval to BRCA1/2 mutations). This trial made genomic tumour testing part of standard care in mCRPC.

Limitations

Open-label design; the control arm was another ARPI, which has limited activity after progression on a prior ARPI; the benefit in cohort B and for some genes (such as ATM and CDK12) is less certain; extensive crossover makes interpretation of overall survival difficult.

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.