PROpel

LYNPARZA + abiraterone increased median rPFS by 8.2 additional months versus abiraterone alone¹

PROpel is a randomised, double-blind, placebo-controlled, multicentre Phase III clinical trial assessing the safety and efficacy of Lynparza (Olaparib) in combination with abiraterone against placebo-abiraterone as a first-line (1L) treatment alternative for patients with metastatic castration-resistant prostate cancer (mCRPC).²

Previous investigations in phase II clinical trial have highlighted the potency and the synergistic anti-tumor effect of combining Lynparza (olaparib) with next generation hormonal agent abiraterone in improved treatment response in mCRPC patients.³ Lynparza (olaparib) is the first PARP inhibitor approved in the European Union (EU) for treatment of patients with mCRPC with BRCA1/2 mutations, a subpopulation of homologous recombination repair (HRR) gene mutations in November 2020, based on a subgroup analysis of the PROfound Phase III trial.^1,4

The PROpel trial

This trial was designed to analyse the clinical response at 1L in mCRPC patients, comparing the combined Lynparza(olaparib)-abiraterone (+prednisone (n=399)) regimen against placebo-abiraterone (+prednisone (n=197)), irrespective of homologous recombination repair (HRR) genes mutational status. Dosage of this combination therapy is the same as to dosage of individual monotherapy. The primary endpoint was measured using radiographic progression-free survival (PFS), assessed by the investigator. Additionally, pre-specified sensitivity analysis of rPFS was performed by blinded independent central review (BICR). Overall survival (OS) was key secondary endpoint. Analysis was performed for entire clinical cohort as well as the divided equally in the two trial arms.²

1. Radiographic Progression Free Survival and Median Overall Survival results
2. BRCA mutated subgroup analysis results
3. HRR mutated subgroup analysis results
4. Safety Profile
5. Lynparza (olaparib) and abiraterone mechanism of action
6. PROpel study design 

Lynparza (olaparib) improves treatment response for mCRPC at 1L²

The PROpel phase III trial showed that the safety profile of combined treatment with abiraterone is similar to known effects of monotherapies.^2,4

With respect to intention-to-treat (ITT) population with combined Lynparza (olaparib) and abiraterone, the primary endpoint analyses indicated:

For disease progression (primary endpoint):

• A reduction of the risk of disease progression assessed by investigator - 34% (HR: 0.66, 95% CI: 0.54-0.81, P<0.001).²
• A reduction of the risk of disease progression confirmed by BICR - 39% (HR: 0.61, 95% CI: 0.49-0.74, P<0.001).²
• An overall improvement in median disease progression by 8.2 months (investigator) - 11.2 months (BICR) with addition of Lynparza.²

rPFS for all patients* (Primary endpoint)²

_{*r-PFS assessed by investigator
HR: Hazard Ratio, CI: Confidence Interval (Calculated using Cox regression analysis)}

For patient survival based on OS (secondary endpoint):

• An increased patient survival (maturity 47.9%, HR: 0.81, 95% CI: 0.67-1.00, P= 0.0544).⁵
• An overall improvement in median survival of 7.4 months with addition of Lynparza (median OS was 42.1 months in Olaparib + abiraterone arm and 34.7 months in placebo + abiraterone arm).⁵

Safety profile

The most common side effects in the combination arm were anemia (50%), fatigue/asthenia (39%), and nausea (31%). Grade 3 or higher adverse events was most commonly anemia (16%) with pulmonary embolism in 7% of patients in combination arm. 17% of patients discontinued Lynparza (olaparib) or the placebo due to an adverse event.Discontinuations of abiraterone as a result of adverse events occurred in 11% patients in the combination arm.⁶ All safety information is available at www.fass.se

The primary results from the PROpel Phase III trial were published in The New England Journal of Medicine (NEJM) Evidence in June 2022.²

PROpel study design and patient characteristic²

In this study:

• 796 patients were randomized 1:1 into the combination treatment arm (n=399) receiving Lynparza (300 mg (2 x 150 mg tablets) twice daily) + abiraterone (1000mg (2 x 500 mg tablets)) and placebo-control arm (n=397) receiving abiraterone (1000mg (2 x 500 mg tablets)).
• Patients in both arms also received either prednisone or prednisolone 5 mg twice daily.
• Patients were stratified based on prior docetaxel treatment at the mHSPC stage and by distant metastasis type at baseline.
• Treatment was given until objective disease progression was assessed by investigator or at unacceptable toxicity.
• Continued treatment was given, if necessary, as determined by the investigator.
• Separate analysis was conducted by BICR for re-evaluation to confirm assessment previously made by investigator.
• HRRm testing was performed and aggregated using tumor tissue and ctDNA analysis. Approximately 28% and 69% of patients were included in the HRRm and non-HRRm subgroups, respectively; 2% of patients had unknown HRRm status.
• Median time to treatment exposure was 17.5 months for Lynparza (olaparib).^1,2

Demographic and baseline characteristics were balanced between the two treatment arms. The median age of patients was 69 years overall, and the majority (71%) of patients were in the age group ≥ 65 years. 189 patients (24%) had previously been treated with docetaxel at the mHSPC stage. A total of 434 (55%) patients had bone metastases (metastases in bone and no other distant site), 105 (13%) patients had visceral metastases (distant soft tissue metastases in an organ, eg liver, lungs) and 257 (32%) ) patients had other metastases (which could include, for example, patients with bone metastases and distant lymph nodes or patients with disease in distant lymph nodes only). Most patients in both arms (70%) had an ECOG performance status of 0. There were 103 (25.8%) symptomatic patients in the olaparib group and 80 (20.2%) in the placebo group. According to the brief pain scale (Brief Pain Inventory-Short Form, BPI-SF item #3), patients with a score ≥ 4 and/or use of opiates at baseline were characterized as symptomatic patients.¹

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Lynparza (olaparib) Antineoplastiska läkemedel, övriga antineoplastiska läkemedel, PARP-hämmare. ATC-kod: L01XK01 Filmdragerade tabletter 100 och 150 mg. Rx.

Filmdragerade tabletter 100 och 150 mg.

Indikationer:

Prostatacancer:

1) Lynparza tabletter är indicerade som monoterapi för behandling av vuxna patienter med metastaserande kastrationsresistent prostatacancer och BRCA1/2-mutationer (nedärvd och eller somatisk) som har progredierat efter tidigare behandling som inkluderade typen nya hormonella läkemedel.

(F) = Ingår i förmånen med begränsning. Subventioneras vid ovanstående indikation och där behandling med docetaxel, kabazitaxel och radium-223 gett otillräcklig effekt eller inte är lämplig.

2) Lynparza tabletter i kombination med abirateron och prednison eller prednisolon för behandling av vuxna patienter med mCRPC hos vilka kemoterapi inte är kliniskt indicerad

(F) = Ingår i förmånen med begränsad subvention. Subvetionen gäller i kombination med abirateron och prednison eller prednisolon för behandling av vuxna patienter med metastaserande kastrationsresistent prostatacancer (mCRPC) och BRCA1/2-mutation hos vilka kemoterapi inte är kliniskt indicerad

Dosering: Behandling med Lynparza ska initieras och övervakas av läkare med erfarenhet av cancerläkemedel.

Kontraindikationer: Överkänslighet mot den aktiva substansen eller mot något hjälpämne. Amning under behandlingen och 1 månad efter den sista dosen.

Varningar och försiktighet:

Lynparza får inte användas under graviditet.

Hematologisk toxicitet: Provtagning vid initiering av behandlingen och därefter månatliga kontroller av fullständig blodstatus rekommenderas under de första 12 behandlingsmånaderna och därefter med jämna mellanrum. Om en patient får allvarlig hematologisk toxicitet eller är beroende av blodtransfusioner, ska behandlingen med Lynparza avbrytas och lämpliga blodtester göras.

Myelodysplastiskt syndrom/akut myeloisk leukemi: Om MDS/AML misstänks ska patienten remitteras till en hematolog för vidare utredning, inklusive benmärgsanalys och blodprovtagning för cytogenetik. Om MDS/AML bekräftas efter utredning avseende långvarig hematologisk toxicitet ska Lynparza sättas ut och patienten ska erhålla lämplig behandling.

Senaste översyn av Produktresumén: 20231005

För ytterligare information och priser se www.fass.se.

AstraZeneca AB, 151 85 Södertälje tel: 08 – 553 260 00. www.astrazeneca.se