PROfound: A PHASE 3 trial of a PARPi in mCRPC1,6

PROfound assessed the efficacy of LYNPARZA vs an active comparator (retreatment with enzalutamide or abiraterone) in men with mCRPC with HRR gene mutations

PROfound assessment chart of LYNPARZA vs an active comparator
PATIENT POPULATION

mCRPC
Metastatic castration-resistant prostate cancer

prior enzalutamide or abiraterone
Progression on prior enzalutamide or abiraterone treatment for metastatic prostate cancer and/or CRPC

HRR mutation
A tumor mutation in at least 1 of 15 genes involved in the HRR pathway

COHORT A

BRCA1/2 or ATM gene mutation (n=245)‡§

Randomization was stratified by prior receipt of taxane chemotherapy and presence of measurable disease by RECIST 1.1

COHORT B

Other HRR gene mutations
(N=142)§||

LYNPARZA
300 mg BID§
(n=162)

Primary endpoint:

  • Radiological progression-free survival (rPFS) in Cohort A as determined by BICR using RECIST v.1.1 and PCWG3 (bone) criteria

2:1 randomization
Open label

Retreatment with investigator's choice of enzalutamide or abiraterone§¶ (n=83)

Select secondary endpoints (tested sequentially):

  • Confirmed objective response rate (ORR) in Cohort A
  • rPFS in Cohorts A+B as assessed by BICR
  • Overall survival (OS) in Cohort A
  • PROfound included additional secondary endpoints not presented here.

Select secondary endpoint:

  • rPFS in Cohorts A+B as assessed by BICR
  • PROfound included additional secondary endpoints not presented here.

LYNPARZA
300 mg BID§
(n=94)

2:1 randomization
Open label

Retreatment with investigator's choice of enzalutamide or abiraterone§¶ (n=48)

Patients with mCRPC were eligible for PROfound regardless of previous taxane use.

Although patients with PPP2R2A gene mutations were enrolled in the trial, LYNPARZA is not indicated for the treatment of patients with this gene mutation due to unfavorable risk-benefit ratio.

HRR gene mutations (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and/or RAD54L) were identified by tissue-based testing using the Foundation Medicine FoundationOne® clinical trial HRR assay performed at a central laboratory. No patients were enrolled who had mutations in 2 of the 15 prespecified HRR genes: FANCL and RAD51C.

Patients with co-mutations (BRCA1, BRCA2, or ATM plus a Cohort B gene) were assigned to Cohort A.

§All patients received a GnRH analog or had prior bilateral orchiectomy.

||BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L.

Upon radiological progression confirmed by BICR, patients randomized to enzalutamide or abiraterone were given the option to switch to LYNPARZA.

BICR=blinded independent central review; BID=twice a day; CRPC=castration-resistant prostate cancer; mCRPC=metastatic castration-resistant prostate cancer; ORR=objective response rate; PCWG3=Prostate Cancer Working Group 3; RECIST=Response Evaluation Criteria in Solid Tumors; rPFS=radiological progression-free survival.

Among men with BRCA1/2- or ATM-mutated mCRPC following progression on enzalutamide or abiraterone

LYNPARZA more than doubled median rPFS vs retreatment with enzalutamide or abiraterone1

From The New England Journal of Medicine, de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. Published online April 28, 2020. doi:10.1056/NEJMoa1911440. Copyright © 2020 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

CI=confidence interval; HR=hazard ratio; mo=months.

rPFS in Cohort A was determined by BICR using RECIST version 1.1 and PCWG3 (bone) criteria.

Consistent results were observed in exploratory analyses of rPFS:

  • For patients who received or did not receive prior taxane therapy
  • For those with germline BRCA mutations identified using the Myriad BRACAnalysis CDx® assay compared with those with BRCA mutations identified using the Foundation Medicine F1CDx assay

rPFS in Cohort A was determined by BICR using RECIST version 1.1 and PCWG3 (bone) criteria.
Consistent results were observed in exploratory analyses of rPFS:

  • For patients who received or did not receive prior taxane therapy
  • For those with germline BRCA mutations identified using the Myriad BRACAnalysis CDx® assay compared with those with BRCA mutations identified using the Foundation Medicine F1CDx assay

Among men with BRCA1/2- or ATM-mutated mCRPC following progression on enzalutamide or abiraterone

Secondary endpoint: LYNPARZA demonstrated an OS benefit and reduced risk of death by 31% vs retreatment with enzalutamide or abiraterone1,6

LYNPARZA demonstrated a statistically significant improvement in overall survival

From The New England Journal of Medicine, de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. Published online April 28, 2020. doi:10.1056/NEJMoa1911440. Copyright © 2020 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

PROfound was powered to evaluate OS in Cohort A within a hierarchical statistical analysis.

Additional secondary endpoints1,6

  • LYNPARZA significantly improved confirmed ORR by BICR vs retreatment with enzalutamide or abiraterone for patients with measurable disease at baseline in Cohort A: 33% (n=28) with LYNPARZA (95% CI: 23–45, P<0.0001; n=84) vs 2% (n=1) with enzalutamide or abiraterone retreatment (95% CI: 0–12, P<0.0001; n=43)
  • LYNPARZA improved median rPFS vs retreatment with enzalutamide or abiraterone (Cohorts A+B): 5.8 months median rPFS with LYNPARZA (95% CI: 5.5–7.4; n=256) vs 3.5 months median rPFS with enzalutamide or abiraterone retreatment (95% CI: 2.2–3.7; n=131). rPFS in Cohorts A+B was assessed by BICR

    PROfound was powered to evaluate ORR in Cohort A and rPFS in Cohort A+B within a hierarchical statistical analysis.

Adverse reactions# reported in ≥10% of patients in PROfound1

#Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.

**Includes anemia and hemoglobin decreased.

††Includes platelet count decreased and thrombocytopenia.

  • Fatal adverse reactions occurred in 4% of patients treated with LYNPARZA. These included pneumonia (1.2%), cardiopulmonary failure (0.4%), aspiration pneumonia (0.4%), intestinal diverticulum (0.4%), septic shock (0.4%), Budd-Chiari Syndrome (0.4%), sudden death (0.4%), and acute cardiac failure (0.4%)
  • Serious adverse reactions occurred in 36% of patients receiving LYNPARZA. The most frequent serious adverse reactions (≥2%) were anemia (9%), pneumonia (4%), pulmonary embolism (2%), fatigue/asthenia (2%), and urinary tract infection (2%)
  • Venous thromboembolic events, including pulmonary embolism, occurred in 7% of patients with metastatic castration resistant prostate cancer who received LYNPARZA plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study

Laboratory abnormalities reported in ≥25% of patients in PROfound1

‡‡This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.

§§Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

Dose modifications and discontinuations in PROfound (n=256)

>8 out of 10 men remained on LYNPARZA without discontinuing due to ARs1

AR=adverse reaction.

Test all patients with advanced prostate cancer for HRR gene mutations at metastatic diagnosis or upon progression with enzalutamide or abiraterone1,7-11

NCCN recommend evaluation of HRR mutations in patients with mCRPC

Olaparib (LYNPARZA) is the only PARPi included in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) as a Category 1|||| recommended option for men with HRRm mCRPC adenocarcinoma who have progressed on prior treatment with enzalutamide and/or abiraterone, regardless of prior docetaxel therapy.7

The NCCN Guidelines® recommend tumor testing for HRRm for any patient with mCRPC.7

||||Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

FOUNDATIONONE® CDx logo

Tissue biopsy test

  • Requires archived or fresh biopsy tissue from primary or metastatic tumor
  • Uses DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens
  • Can detect both somatic and germline alterations but does not distinguish between them

IF TISSUE IS UNAVAILABLE OR IF THE TEST FAILS

BRCAAnalysisCDx logo

Germline test from Myriad Genetics

  • Requires blood sample
  • Detects germline mutations in BRCA1, BRCA2
  • Consider for those who test positive on tissue test to assess hereditary risk

FoundationOne® CDx is a registered trademark of Foundation Medicine, Inc. BRACAnalysis CDx® is a registered trademark of Myriad Genetics, Inc.

Tissue biopsy test icon
FOUNDATIONONE® CDx logo

Tissue biopsy test

  • Requires archived or fresh biopsy tissue from primary or metastatic tumor
  • Uses DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens
  • Can detect both somatic and germline alterations but does not distinguish between them

IF TISSUE IS UNAVAILABLE OR IF THE TEST FAILS

Germline test from Myriad Genetics
BRCAAnalysisCDx logo

Germline test from Myriad Genetics

  • Requires blood sample
  • Detects germline mutations in BRCA1, BRCA2
  • Consider for those who test positive on tissue test to assess hereditary risk

FoundationOne® CDx is a registered trademark of Foundation Medicine, Inc. BRACAnalysis CDx® is a registered trademark of Myriad Genetics, Inc.

Choose LYNPARZA: The ONLY PARPi approved with phase 3 data for men with HRRm¶¶ mCRPC following progression on enzalutamide or abiraterone1-4

¶¶Based on an FDA-approved companion diagnostic for LYNPARZA.1

HRRm=homologous recombination repair gene–mutated; NCCN=National Comprehensive Cancer Network.

IMPORTANT SAFETY INFORMATION

INDICATION

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

INDICATION

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

There are no contraindications for LYNPARZA.

WARNINGS AND PRECAUTIONS

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.

Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males

Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

Venous Thromboembolic Events: Including pulmonary embolism, occurred in 7% of patients with metastatic castration-resistant prostate cancer who received LYNPARZA plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. Patients receiving LYNPARZA and ADT had a 6% incidence of pulmonary embolism compared to 0.8% of patients treated with ADT plus either enzalutamide or abiraterone. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism, and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated.

ADVERSE REACTIONS—HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA for PROfound were: anemia (46%), fatigue (including asthenia) (41%), nausea (41%), decreased appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia (12%), cough (11%), and dyspnea (10%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for PROfound were: decrease in hemoglobin (98%), decrease in lymphocytes (62%), decrease in leukocytes (53%), and decrease in absolute neutrophil count (34%).

DRUG INTERACTIONS

Anticancer Agents: Clinical studies of LYNPARZA with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

CYP3A Inhibitors: Avoid coadministration of strong or moderate CYP3A inhibitors when using LYNPARZA. If a strong or moderate CYP3A inhibitor must be coadministered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid coadministration of strong or moderate CYP3A inducers when using LYNPARZA.

USE IN SPECIFIC POPULATIONS

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C).

Renal Impairment: No dosage modification is recommended in patients with mild renal impairment (CLcr 51-80 mL/min estimated by Cockcroft-Gault). In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the dose of LYNPARZA to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

Please click here for complete Prescribing Information, including Patient Information (Medication Guide).

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References: 1. LYNPARZA® (olaparib) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020. 2. Zejula® (niraparib) [prescribing information]. Waltham, MA: TESARO, Inc.; 2020. 3. Rubraca® (rucaparib) [prescribing information]. Boulder, CO: Clovis Oncology, Inc.; 2020. 4. Talzenna® (talazoparib) [prescribing information]. New York, NY: Pfizer Inc.; 2020. 5. Teo MY, Rathkopf DE, Kantoff P. Treatment of advanced prostate cancer. Annu Rev Med. 2019;70:479-499. 6. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. Published online April 28, 2020. doi:10.1056/NEJMoa1911440 7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.2.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed May 21, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org. 8. Data available on request from Merck & Co., Inc., Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package US-39159. 9. FoundationOne CDx Technical Information. Foundation Medicine, Inc. Accessed May 12, 2020. https://assets.ctfassets.net/vhribv12lmne/6Rt6csmCPuaguuqmgi2iY8/d9ddc283ec250ad771c3e4d31f2f2d34/F1CDx_Updated_Label.Technical_Info.050620.pdf 10. BRACAnalysis CDx Executive Summary. Myriad Genetics Laboratories. Accessed March 13, 2020. https://myriad.com/managed-care/bracanalysis-cdx/ 11. Frey MK, Pothuri B. Homologous recombination deficiency (HRD) testing in ovarian cancer clinical practice: a review of the literature. Gynecol Oncol Res Pract. 2017;4:4.