LYNPARZA in
combination

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Challenge mCRPC with LYNPARZA + abiraterone + prednisone or prednisolone

LYNPARZA in combination with abiraterone and prednisone or prednisolone is recommended by NICE and accepted by the SMC for the treatment of adult patients with mCRPC in whom chemotherapy is not clinically indicated.​1,2

LYNPARZA + abiraterone + prednisone/prednisolone is the first PARPi-based combination therapy for 1L mCRPC patients not previously treated with an NHA, irrespective of HRRm status.3

LYNPARZA tablets are indicated in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with mCRPC in whom chemotherapy is not clinically indicated.3

  

PROpel was a Phase III, randomised, double-blind trial that evaluated LYNPARZA combination therapy in 1L mCRPC with any HRRm status4,5
 

Basic outline of the PROpel study design
Basic outline of the PROpel study design

 

Adapted from Clarke NW et al. 2022.5

*Except abiraterone; †Both therapies were used at full dose, equivalent to monotherapy regimens. Patients in both treatment arms also received
prednisone/prednisolone 5 mg BID; ‡rPFS assessed by investigator per RECIST 1.1 (soft tissue) and PCWG-3 (bone) criteria.
 

Key secondary endpoint:

  • OS

Additional endpoints:

  • TFST
  • PFS2
  • ORR
  • Time to an SSRE
  • CTC conversion
  • Time to opiate use
  • HRRm status (pre-defined, post- randomisation testing)
  • HRQoL (FACT-P)
  • Safety and tolerability

Table containing PROpel baseline characteristics
Table containing PROpel baseline characteristics

Adapted from Clarke NW et al. 2022.3

*Baseline pain score is based on a patient completing the BPI-SF questionnaire item 3 (worst pain) at least once during the 7-day baseline period and is presented as an average.

†Investigators could select more than one site of disease. Entries for ‘Other locally advanced sites’, ‘Other distant sites’ and ‘Other’ have been excluded. 

‡Prior to mCRPC, treatment with next-generation hormonal agents (except abiraterone) was allowed, provided patients had not had PSA, clinical or imaging-based progression during the treatment and the treatment was stopped at least 12 months before randomisation.

§HRRm: Any deleterious or suspected deleterious HRR gene mutation detected; non-HRRm: no deleterious or suspected deleterious HRR gene mutation detected; HRRm unknown: patients for whom mutation testing was not performed or where mutation testing failed due to insufficient quantity or quality of the sample, or technical failure at sequencing or post-sequencing steps on analysis. Use of aggregate test data was considered the favoured method for assignment of PROpel patients to HRRm subgroups to maximise the proportion of patients with assigned HRRm status and minimise potential false-negative results.

In PROpel, molecular testing to determine HRRm status was not done prospectively5

  • HRRm status determination for all study eligible patients is complicated by sample and testing challenges
  • Requiring determination of HRRm status pre-enrolment risks biasing patient enrolment to those with sufficient tumour, and/or detectable ctDNA

  • It was anticipated that due to the size of the study, the population baseline factors would be balanced
  • Therefore, retrospective patient assignment to biomarker subgroups was expected to give balanced representation of HRR subgroups in the study arms

Discover the efficacy outcomes for LYNPARZA combination therapy
 

  

 

 

LYNPARZA combination therapy demonstrated an 8.2-month improvement in median rPFS and a 34% reduction in the risk of progression or death vs in the placebo + abiraterone arm*5,7

 

Primary endpoint: rPFS by investigator assessment (ITT) at DCO1


Adapted from Clarke NW et al. 20225 and Saad F et al. 2022.7

DCO1: 30 July 2021. Events: 394; 49.5% maturity.

*Patients in both treatment arms also received prednisone/prednisolone 5 mg BID

 

BICR-assessed analysis at DCO1 and investigator-assessed analysis at DCO2 supported the above findings.5,7,8

 

 

rPFS benefit was generally consistent irrespective of HRRm status7
Post hoc exploratory analysis*

 

Forest plot with subgroup categories
Forest plot with subgroup categories


Adapted from Saad F et al. 2022.7

DCO1: 30 July 2021.

Patients in both treatment arms also received prednisone/prednisolone 5 mg BID.

*The HRRm status of patients in PROpel was determined retrospectively using results from tumour tissue and plasma ctDNA HRRm tests. Patients
were classified as HRRm if (one or more) HRR gene mutation was detected by either test; patients were classified as non-HRRm patients if no HRR gene
mutation was detected by either test; patients were classified as unknown HRRm if no valid HRR test result from either test was achieved. 18 patients did
not have a valid HRR testing result from either a tumour tissue or ctDNA test and were excluded from the subgroup analysis.

†Global interaction test not significant at 10% level.

 

 

LYNPARZA combination therapy presented 42.1-month median OS vs 34.7 months
in the placebo + abiraterone arm*9

Final OS analysis; P=0.054* (not statistically significant)

 

Median OS (ITT) at final pre-specified analysis​


Adapted from Clarke NW et al. 2023.9

DCO3: 12 October 2022.

*Patients in both treatment arms also received prednisone/prednisolone 5 mg BID

†Median duration of follow-up for censored patients at DCO3 was 36.6 months (range 8.3–47.0) in the LYNPARZA arm and 36.5 months (range 2.9–45.3)
in the placebo + abiraterone arm.

 

 

LYNPARZA combination therapy allows more progression-free survival with no clinically meaningful detriment to HRQoL5,10

The secondary endpoint of HRQoL was similar between treatment arms, with no clinically meaningful detriment to HRQoL5,10
 

P not tested

 

LS mean change from baseline in FACT-P total score*​

Least-square mean graph with descending purple and yellow lines
Least-square mean graph with descending purple and yellow lines


Adapted from Armstrong AJ et al. 2023.10

DCO3: 12 October 2022.

*Plot includes 95% confidence limits. FACT-P total score change from baseline values can be a minimum of -156 and a maximum of 156. A clinically
meaningful change in FACT-P total score is 10.

†Patients in both treatment arms also received prednisone/prednisolone 5mg BID

  

8 out of 10 patients remain on LYNPARZA combination therapy without discontinuing due to AEs*9

Table containing PROpel adverse events in LYNPARZA treatment group and placebo group
Table containing PROpel adverse events in LYNPARZA treatment group and placebo group

 

Data cut-off 3: 12 October 2022.

 

Two pie charts - left: No dose reduction pie chart with 77% in the middle right: No discontinuations pie chart with 83% in the middle
Two pie charts - left: No dose reduction pie chart with 77% in the middle right: No discontinuations pie chart with 83% in the middle

 

Data cut-off 3: 12 October 2022.

 

4 out of 5 patients remain on LYNPARZA combination therapy without discontinuation due to AEs, however 49% of patients did require a dose interruption.9

The AE profile in PROpel was consistent with the known toxicity profiles for the individual drugs (olaparib and abiraterone)3,9

Pathway chart of the different options available when referring patients with prostate cancer for BRCA testing
Pathway chart of the different options available when referring patients with prostate cancer for BRCA testing

Adapted from Clarke NW et al. 2023.9

DCO3: 12 October 2022.

 

Safety was assessed through the reporting of AEs according to the NCI CTCAE v4.03 and laboratory assessments. Patients in both treatment arms also received prednisone/prednisolone 5 mg BID.

*Anaemia category 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

Two cases of MDS/AML were observed with LYNPARZA combination therapy vs the placebo and abiraterone arm in PROpel9


VTEs

In PROpel, VTE events occurred in 8.5% vs 4% (at DCO3) in the LYNPARZA combination therapy and placebo and abraterone arm, respectively.9 This is consistent with other observations in other PARPi studies in mCRPC.3,9,11 The majority of PE events were asymptomatic and incidental on imaging3,9


Pneumonitis

Incidence of pneumonitis was balanced between the LYNPARZA combination therapy and placebo and abiraterone arm (5 vs 3 cases, respectively)9

 

Please refer to the SmPC for a full list of adverse events and special warnings.

Discover the dosing regimen for LYNPARZA combination therapy

Challenge NHA-naive mCRPC with LYNPARZA combination therapy


Learn how to manage possible adverse events in patients receiving LYNPARZA

Discover how LYNPARZA monotherapy could benefit patients with BRCAm mCRPC
Please refer to the SmPC for further information to minimise the risks associated with the use of the medicine before making any prescribing decisions.

References

  1. Olaparib with abiraterone for untreated hormone relapsed metastatic prostate cancer. NICE TA951. February 2024. Available at https://www.nice.org.uk/guidance/ta951/resources/olaparib-with-abiraterone-for-untreated-hormonerelapsed-metastatic-prostate-cancer-pdf-82615723963333. Accessed February 2025.
  2. Scottish Medicines Consortium. Olaparib (Lynparza) March 2024. Available at: https://www.scottishmedicines.org.uk/medicines-advice/olaparib-lynparza-mcrpc-full-smc2617/. Accessed February 2025.
  3. LYNPARZA (olaparib). Summary of Product Characteristics. https://www.medicines.org.uk/emc/product/9488. Accessed February 2025.
  4. Clinicaltrials.gov. NCT03732820. Available at: https://clinicaltrials.gov/ct2/show/NCT03732820 Accessed February 2025.
  5. Clarke NW, et al. NEJM Evid. 2022. doi:https://doi.org/10.1056/EVIDoa2200043. Accessed February 2025.
  6. Clarke NW, et al. NEJM Evid. 2022. doi:https://doi.org/10.1056/EVIDoa2200043. Supplementary data. Accessed February 2025.
  7. Saad F, et al. Presented at ASCO GU Annual Meeting 2022. 17–19 February. San Francisco, CA, USA. Oral Abstract. 
  8. Saad F, et al. Presented at ESMO Annual Congress 2022. 9–13 September. Paris, France. Abstract #13570.
  9. Clarke N, et al. Presented at ASCO GU 2023. 16–18 February. San Francisco, US. Abstract #LBA16.
  10. Armstrong AJ, et al. Presented at ASCO GU Annual Meeting 2023. 02–06 June. Chicago, IL, US. Abstract 5012; Poster 106.
  11. Chi KN, et al. Ann Oncol. 2023;34(9):772-782.

 

Abbreviations

1L=first-line; abi=abiraterone; AE=adverse event; AML=acute myeloid leukaemia; BICR=blinded independent central review; BID=twice a day; BPI-SF=Brief Pain Inventory - Short Form; BRCAm=breast cancer gene mutation; CBC=complete blood count; CI=confidence interval; CTC=circulating tumour cell; CTCAE=Common Terminology Criteria for Adverse Events; ctDNA=circulating tumour DNA; DCO=data cut-off; ECOG=Eastern Cooperative Oncology Group; FACT-P=Functional Assessment of Cancer Therapy-Prostate; HR=hazard ratio; HRQoL=health-related quality of life; HRR=homologous recombination repair; HRRm=homologous recombination repair mutation; IQR=interquartile range; ITT=intention-to-treat; LFT=liver function test; LS=least squares; mCRPC=metastatic castration-resistant prostate cancer; MDS=myelodysplastic syndrome; mHSPC=metastatic hormone-sensitive prostate cancer; NICE=National Institute for Health and Care Excellence; NHA=novel hormonal agent; NS=not significant; ORR=objective response rate; OS=overall survival; PARPi=poly (ADP-ribose) polymerase inhibitor; PFS=progression-free survival; PFS2=time to second objective disease progression; pre=prednisone/prednisolone; PSA=prostate-specific antigen; rPFS=radiographic PFS; SE=standard error; SMC=Scottish Medicines Consortium; SSRE=symptomatic skeletal-related event; TFST=time to first subsequent therapy; VTE=venous thromboembolism.

February 2025 | Job code: GB-63540

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