Clinical trialPhase 3Prostate cancer

Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer

N Engl J Med · 2020387 patients (256 in the olaparib group and 131 in the control group)

Hussain M, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, et al. N Engl J Med. 2020. 383:2345-2357

Study type: Clinical trial
Study name: PROfound
Phase: Phase 3
Design: Randomised, open-label, phase 3 trial with 2:1 randomisation
Sample size: 387 patients (256 in the olaparib group and 131 in the control group)
Source: N Engl J Med · 2020
Trial registration: NCT02987543

In plain words

This study was done in men whose prostate cancer had spread to other parts of the body and no longer responded to the newer hormone treatments. In patients whose tumour had changes in the BRCA1, BRCA2 or ATM genes, the drug olaparib raised the median survival to 19.1 months, compared with 14.7 months with enzalutamide or abiraterone. This advantage was seen even though most patients in the comparison group later switched to olaparib. Treatment decisions should be made with your treating doctor, based on the result of the genetic test of the tumour.

Key results

19.1 months with olaparib vs 14.7 months with control treatment

Median overall survival in cohort A (BRCA1, BRCA2 or ATM)

HR for death 0.69; 95% CI 0.50–0.97; P=0.02

14.1 months with olaparib vs 11.5 months with control treatment

Median overall survival in cohort B

17.3 months vs 14.0 months

Median overall survival in the overall population (cohorts A and B)

86 of 131 patients (66%)

Crossover to olaparib in the control group

In cohort A: 56 of 83 patients (67%)

0.42

Crossover-adjusted sensitivity analysis: HR for death in cohort A

95% CI 0.19–0.91

0.83

Crossover-adjusted sensitivity analysis: HR for death in cohort B

95% CI 0.11–5.98

0.55

Crossover-adjusted sensitivity analysis: HR for death in the overall population

95% CI 0.29–1.06

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 group

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 group

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

The primary endpoint (imaging-based progression-free survival) and other key secondary endpoints had been reported previously. In this report, overall survival in cohort A, a key secondary endpoint, was analysed with a stratified, alpha-controlled log-rank test at about 60% data maturity.

Safety and side effects

The abstract of this report gives no safety data. 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

This final analysis showed that olaparib significantly improves overall survival in patients with mCRPC with BRCA1, BRCA2 or ATM alterations who have progressed after a new hormonal agent, despite extensive crossover in the control group. This finding supports genetic testing of the tumour to identify HRR gene alterations in these patients. The status of drug approvals and guideline recommendations should be checked separately.

Limitations

Overall survival in cohort A was a key secondary endpoint, and the analysis was performed at about 60% data maturity. Extensive crossover (66%) from the control group to olaparib makes interpretation of the survival effect difficult. In cohort B and the overall population, the confidence intervals of the crossover-adjusted analyses were wide (cohort B: 0.11–5.98; overall population: 0.29–1.06). The trial was open-label.

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.