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Time to challenge expectations in mCRPC treatment for patients with BRCA1/2 mutations
LYNPARZA monotherapy is recommended by NICE and accepted by SMC for treating hormone-relapsed mCRPC with BRCA1/2-mutations that has progressed after NHA (such as abiraterone or enzalutamide) in adults.1,2
LYNPARZA tablets are indicated as monotherapy for the treatment of adult patients with mCRPC and BRCA1/2-mutations (germline and/ or somatic) who have progressed following prior therapy that included an NHA.3
PROfound was the first study evaluating the efficacy and safety of LYNPARZA monotherapy vs NHAs in patients with HRRm mCRPC3–6
LYNPARZA (tablets) is indicated as monotherapy for the treatment of adult patients with mCRPC and BRCA1/2 gene mutations (germline and/or somatic) who have progressed following a prior NHA.3
*Cohort A included patients with BRCA1, BRCA2 or ATM mutations, Cohort B included patients with BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L mutations.
†Physician’s choice of either enzalutamide or abiraterone.
Adapted from LYNPARZA SmPC and de Bono et al. 20203,4
LYNPARZA (tablets) is indicated as monotherapy for the treatment of adult patients with mCRPC and BRCA1/2 gene mutations (germline and/or somatic) who have progressed following a prior NHA3
*Cohort A included patients with BRCA1, BRCA2 or ATM mutations, Cohort B included patients with BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L mutations.
†The study was not powered for gene-by-gene analysis. ‡Physician’s choice of either enzalutamide or abiraterone.
Discover the efficacy outcomes for LYNPARZA monotherapy
The primary analysis of the PROfound trial found that LYNPARZA alone improves rPFS by 3.8 months and reduces the risk of progression or death by 66% compared to NHAs alone, in patients with BRCA1/2 or ATM mutations*4
Primary endpoint: rPFS by BICR in patients with alterations in BRCA1/2 or ATM
(Cohort A)
Adapted from de Bono J et al. 2020.4
*A small number of patients were censored in the rPFS analysis because they were lost to follow-up/withdrew consent. This included patients that missed two consecutive soft tissue or bone assessment appointments and experienced disease progression or death. As the numbers of patients who were lost to follow-up were small, comparisons are challenging to make, and there are no clear differences between these sub-populations. An exploratory sensitivity analysis was conducted to consider the impact of censoring these patients on rPFS.
†Physician’s choice of either enzalutamide or abiraterone.
In an exploratory analysis, mOS for patients with a BRCAm was approximately 20 months
with LYNPARZA*3
P not tested
mOS by BICR in patients with alterations in BRCA1/2
Adapted from LYNPARZA SmPC.3
Data cut-off: 20 March 2020.
*The PROfound study was not powered for gene-by-gene analysis.
†Physician’s choice of either enzalutamide or abiraterone.
In the secondary analysis, numerically, more patients reported HRQoL improvements with
LYNPARZA vs. physician’s choice*6
P not significant
Patient-reported improvements in HRQoL after treatment in Cohort A† vs. control*
Adapted from Thiery-Vuillemin et al. 2022.5
*Physician’s choice of either enzalutamide or abiraterone.
†Cohort A included patients with BRCA1, BRCA2 or ATM mutations.
LYNPARZA monotherapy is indicated for mCRPC in patients with BRCA1/2
mutations who have progressed following prior therapy with a NHA3,4
An exploratory analysis of the PROfound trial assessed the efficacy of LYNPARZA monotherapy in
mCRPC patients with BRCA1/2 mutations.3,4
In patients with BRCA mutations, median imaging-based PFS was 9.8 months in the experimental
arm vs 3.0 months in the control arm.*4
P not tested
rPFS by BICR in patients with alterations in BRCA1/2 (as licensed)
Adapted from de Bono J et al. 2020.4
*A small number of patients were censored in the rPFS analysis because they were lost to follow-up/withdrew consent. This included patients that missed two consecutive soft tissue or bone assessment appointments and experienced disease progression or death. As the numbers of patients who were lost to follow-up were small, comparisons are challenging to make, and there are no clear differences between these sub-populations. An exploratory sensitivity analysis was conducted to consider the impact of censoring these patients on rPFS.
†Physician’s choice of either enzalutamide or abiraterone.
The most common AEs (≥15% of patients) in PROfound were consistent with
prior studies of other tumour types*7
At the final OS DCO, median duration of treatment was 7.6 months in the LYNPARZA arm and 3.9 months in the control arm.
At the primary DCO no cases of MDS / AML were reported
- One case of fatal AML was reported in a patient who was diagnosed 54 days after discontinuation of LYNPARZA (duration of LYNPARZA exposure 15.7 months)
Pulmonary embolism was reported in 5% of patients in the LYNPARZA group compared with 1% in the control group, but none were fatal‖
Adapted from Hussain et al. 2020.7
Data cut-off: 20 March 2020.
*Patients had alterations in BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and/ or RAD54L.
†Physician’s choice of either abiraterone or enzalutamide.
‡Patients in the physician’s choice group were allowed to cross over to receive LYNPARZA after disease progression in accordance with the protocol.
§Grouped term includes anaemia, decreased haemoglobin level, decreased red-cell count, decreased haematocrit level, erythropenia, macrocytic anaemia, normochromic anaemia, normochromic normocytic anaemia, and normocytic anaemia.
‖MDS/AML and VTE are listed as special warnings in the SmPC. Please refer to the SmPC for further details on these and other listed special warnings.
¶The safety analyses conducted at the time of the primary analysis revealed an imbalance between the two treatment arms in the incidence of pulmonary embolism (4% with LYNPARZA vs. 1% with control therapy). There has since been one additional case of pulmonary embolism in the LYNPARZA treatment arm; the rate of pulmonary embolism with LYNPARZA after this longer follow-up was thus similar to that reported in the primary analysis (5% vs. 1%). Patients receiving LYNPARZA should be monitored for clinical signs and symptoms of VTE and PE and treated as medically appropriate. Patients with a prior history of VTE may be more at risk of a further occurrence and should be monitored appropriately.
The majority of patients remained on the full dose of LYNPARZA without a dose
reduction due to AEs3,7
Data cut-off: 20 March 2020.
4 out of 5 patients remain on LYNPARZA monotherapy without discontinuation due to AEs, however 46% of patients did require a dose interruption.7
For full details on the LYNPARZA special warnings and precautions, and drug interactions please refer to the Summary of Product Characteristics.3
Molecular testing
Germline and somatic BRCA mutations have been found in prostate cancer tumour cells8 with approximately 10% of patients with mCRPC screened for inclusion in the PROfound trial having a BRCA mutation.9 Approximately half of those with a germline mutation were identified as having a BRCA mutation.8
*For patients who have unknown BRCA germline mutation status.
A failed BRCA tumour test is not the same as a negative test result.9
Choose LYNPARZA monotherapy for patients with BRCA-mutated mCRPC
following progression on NHA
- Olaparib for previously treated BRCA mutation-positive hormone-relapsed metastatic prostate cancer. May 2023. https://www.nice.org.uk/guidance/ta887/resources/olaparib-for-previously-treated-brca-mutationpositive-hormonerelapsed-metastatic-prostate-cancer-pdf-82613738657221. Accessed January 2024.
- Scottish Medicines Consortium. Olaparib (Lynparza). October 2021. Available at: https://www.scottishmedicines.org.uk/medicines-advice/olaparib-lynparza-full-smc2366/ Accessed January 2024.
- LYNPARZA (olaparib). Summary of Product Characteristics. https://www.medicines.org.uk/emc/product/9488. Accessed January 2024.
- de Bono J, et al. N Engl J Med. 2020;382:2091–2102; Supplemental data.
- Clinicaltrials.gov. Study of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer (PROfound Study). Available at: https://www.clinicaltrials.gov/study/NCT02987543 Accessed January 2024.
- Thiery-Vuillemin A, et al. Lancet Oncol. 2022;23:393–405; Supplemental data.
- Hussain M, et al. N Engl J Med. 2020;383:2345–2357; Supplemental data.
- Abida W, et al. JCO Precis Oncol. 2017;2017:PO.17.00029.
- de Bono J, et al. Poster presented at ESMO Annual Congress 2019. 27 September–1 October. Barcelona, Spain. Poster 847PD
- Boerrigter E, et al. Exp Rev Mol Diagn. 2020;20:219–230.
- Gillessen S, et al. Eur Urol. 2020;77:508–547.
- Parker C, et al. Ann Oncol. 2020;31:1119–1134.
- Yadav S, et al. Fam Cancer. 2017;16:319–328.
- National Cancer Control Programme. BRCA test FAQ. Available at: https://www.hse.ie/eng/services/list/5/cancer/profinfo/medonc/sactguidance/brca%20test%20faq.pdf. Accessed January 2024.
Abbreviations
ADT=androgen deprivation therapy; AE=adverse event; AML=acute myeloid leukaemia; BICR=blinded independent central review; BID=twice a day; BRCA1/2m=BRCA1/2 mutation; CBC=complete blood count; CTCAE=Common Terminology Criteria for Adverse Events; ctDNA=circulating tumour DNA; ECOG PS=Eastern Cooperative Oncology Group Performance Status; FACT-G TS=Functional Assessment of Cancer Therapy–General total score; FACT-P TS=Functional Assessment of Cancer Therapy–Prostate total score; FAPSI-6=Functional Assessment of Cancer Therapy Advanced Prostate Symptom Index 6; FWB=functional wellbeing; HR=hazard ratio; HRQoL=health-related quality of life; HRR=homologous recombination repair; HRRm=homologous recombination repair mutation; LFT=liver function test; mCRPC=metastatic castration-resistant prostate cancer; MDS=myelodysplastic syndrome; mOS=median overall survival; mPC=metastatic prostate cancer; NHA=new hormonal agent; NICE=National Institute for Health and Care Excellence; OS=overall survival; PCS=prostate cancer subscale; PCWG3=Prostate Cancer Working Group 3; PE=pulmonary embolism; PO=orally; PWB=physical wellbeing; RECIST=Response Evaluation Criteria in Solid Tumors; rPFS=radiographic progression‑free survival; SMC=Scottish Medicines Consortium; TOI=Trial Outcome Index; VTE=venous thromboembolism.
February 2025 | Job code: GB-64097