PARP Inhibitors as Treatment Options for Monotherapy and Combination Therapy in HRRm or BRCAm Prostate Cancer
Transcript:
Hi, I’m Dr Tanya Dorff, a medical oncologist and the division chief of the Genitourinary Disease Program at City of Hope in Duarte, California.
This video series examines the importance of poly (ADP-ribose) polymerase, or PARP, inhibitors in elevating the treatment of certain types of advanced prostate cancer.
This second video will delve into the registrational trials for olaparib, a PARP inhibitor, and the types of patients who may benefit from this therapy.
There are other PARP inhibitor agents for metastatic castration-resistant prostate cancer that have been approved by the US Food and Drug Administration, including rucaparib as monotherapy, niraparib in combination with abiraterone, and talazoparib in combination with enzalutamide, but this video will focus on the olaparib registrational trials.
Up to about a quarter of patients with mCRPC have certain mutations in homologous recombination repair genes, also known as HRRm.1 For these patients, PARP inhibitors, which trigger cell death in HRR-deficient cancer cells by preventing repair of double-strand DNA breaks, are a treatment option.1-5
Olaparib is a PARP inhibitor approved:
• for the treatment of adult patients with deleterious or suspected deleterious germline or somatic HRR mutations with mCRPC that has progressed following prior treatment with enzalutamide or abiraterone; and
• in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated mCRPC.
To shed light on the patient types most likely to benefit from the PARP inhibitor olaparib, let’s explore the clinical studies that led to its approval.
The first is the PROfound study, a phase 3 trial that evaluated the efficacy and safety of olaparib as monotherapy for men with mCRPC and at least 1 of 15 HRR gene mutations. This trial included patients who progressed on a prior androgen receptor pathway inhibitor, such as enzalutamide or abiraterone.5
The patients with mCRPC were categorized into 2 cohorts based on their gene alterations: Cohort A, which included patients with at least 1 alteration in BRCA1, BRCA2, or ATM, or Cohort B, which consisted of patients with alterations in any of the other 12 genes. Patients were then randomly assigned to receive either 300 mg of olaparib orally twice daily or the investigator’s choice of enzalutamide or
abiraterone.5-7
The baseline characteristics of patients in the PROfound trial are shown here. Overall, these patients had a median age of 68 years. All patients had received a gonadotropin-releasing hormone, or GnRH, analog or had undergone prior bilateral orchiectomy.6,8
In terms of racial diversity, 69% of patients across cohorts were White, 29% were Asian, and 1% were Black.8
The primary endpoint for PROfound was radiographic progression-free survival, or rPFS, in Cohort A, patients with at least 1 alteration in BRCA1, BRCA2, or ATM. The risk of disease progression or death was 66% lower in patients who received olaparib when compared to the control group, patients receiving investigator’s choice of enzalutamide or abiraterone.6-8
In Cohort A, the median overall survival was 19.1 months across all patients who received olaparib and 14.7 months in those who received the control treatment, a reduction in risk of death with a hazard ratio of 0.69.7
An analysis of the BRCA-mutated mCRPC subgroup showed 78% lower risk of disease progression or death and 37% lower risk of death.9
Exploratory analyses are descriptive only. The PROfound trial was not designed to assess statistical significance in gene-by-gene subgroup analysis, and results should be interpreted with caution.
PROfound was powered to evaluate several secondary endpoints within a hierarchical statistical analysis including objective response rate in Cohort A, rPFS in Cohorts A and B, and overall survival in Cohort A.6,8
In terms of safety and tolerability, the most common adverse reactions of any grade reported in patients taking olaparib in PROfound were anemia, nausea, and fatigue or asthenia. Anemia was the most common serious (grade 3 to 4) reaction.
Laboratory abnormalities reported in over 25% of patients included decreases in hemoglobin, lymphocytes, leukocytes, and absolute neutrophil count.
In this trial, there were no reports of myelodysplastic syndromes or acute myeloid leukemia.6-8
The PROfound trial supported the approval of olaparib monotherapy as treatment for adult patients with germline or somatic HRR gene-mutated mCRPC, specifically those who have previously been treated with enzalutamide or abiraterone.
Next, let’s look at olaparib combination therapy.
PROpel was a phase 3 trial evaluating the efficacy and safety of olaparib in combination with abiraterone as first-line therapy for biomarker-unselected men with mCRPC. Patients who received prior treatment with abiraterone were excluded.10
Patients were randomly assigned to receive a 1000 mg abiraterone plus either 300 mg of olaparib or placebo.10
The baseline characteristics of patients in the PROpel trial are shown here.10
We also see that in the exploratory BRCA mutation subgroup, patients had similar baseline characteristics. Approximately 25% had received prior docetaxel treatment.8,11
This international multicenter trial was able to recruit half of the expected representative number of Black patients from the United States. About 70% of patients across cohorts were White, 17% to 18% were Asian, and 3% to 4% were Black.10
The primary endpoint of rPFS in all patients found a 34% decreased risk of disease progression or death for the olaparib and abiraterone arm compared to the placebo plus abiraterone arm.8,10
While PROpel met its primary endpoint, the FDA approval was based on an exploratory BRCA mutation subgroup analysis that showed a 76% risk reduction.10
BRCA mutation status was not a stratification factor in PROpel, and analysis was not controlled for Type 1 error.
In terms of overall survival in the BRCA-mutated subgroup, median overall survival was not reached during the study in patients receiving olaparib vs 23 months in those receiving placebo + abiraterone and prednisone or prednisolone, representing a reduced risk of death, as indicated by a hazard ratio of 0.3.8
The most commonly reported adverse reactions of any grade with olaparib plus abiraterone in the PROpel trial were anemia, fatigue or asthenia, and nausea.8,10 Anemia was the most common serious (grade 3 to 4) reaction from the safety analysis data from October 2018 through the data cutoff in July 2021.8,10,11
Laboratory abnormalities reported in over 20% of patients included decreases in hemoglobin, lymphocytes, leukocytes, and absolute neutrophil count.8
Based on PROpel, olaparib is indicated in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA mutations in mCRPC.8
In summary, the PROfound and PROpel studies helped define patients with HRR mutation and BRCA mutation as specific mCRPC populations for which olaparib demonstrated efficacy as monotherapy and combination therapy, respectively.6,10 Both trials showed meaningful clinical benefits of olaparib in BRCA-mutated patients with mCRPC, a group with aggressive disease.
The results of PROfound and PROpel underscore the importance of identifying the genomic characteristics of the patient and the cancer to guide the selection of the most appropriate treatment for a specific patient type.
PARP inhibitors are an important option for patients with mCRPC and are available as monotherapy for patients who have progressed on an AR Pathway inhibitor such as enzalutamide or abiraterone, or in combination with an AR Pathway inhibitor in patients with mCRPC who have not progressed on an AR Pathway inhibitor previously.6,7,9,10
Thank you for joining me today! To learn more, please watch the other videos in the series.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
There are no contraindications for LYNPARZA.
WARNINGS AND PRECAUTIONS
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in approximately 1.2% of patients with various BRCAm, gBRCAm, HRR gene-mutated or HRD-positive cancers who received LYNPARZA as a single agent or as part of a combination regimen, consistent with the approved indications, and the majority of events had a fatal outcome. The median duration of therapy in patients who developed MDS/AML was approximately 2 years (range: <6 months to >4 years). All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy.
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 0.8% of patients exposed to LYNPARZA monotherapy, 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.
Venous Thromboembolism (VTE): Including severe or fatal pulmonary embolism (PE) occurred in patients treated with LYNPARZA. In the combined data of two randomized, placebo-controlled clinical studies (PROfound and PROpel) in patients with metastatic castration-resistant prostate cancer (N=1180), VTE occurred in 8% of patients who received LYNPARZA, including pulmonary embolism in 6%. In the control arms, VTE occurred in 2.5%, including pulmonary embolism in 1.5%. 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.
Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. Verify pregnancy status in 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.
ADVERSE REACTIONS—HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients who received 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 who received LYNPARZA for PROfound were: decrease in hemoglobin (98%), decrease in lymphocytes (62%), decrease in leukocytes (53%), and decrease in absolute neutrophil count (34%).
ADVERSE REACTIONS—Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone
Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA/abiraterone with a difference of ≥5% compared to placebo for PROpel were: anemia (48%), fatigue (including asthenia) (38%), nausea (30%), diarrhea (19%), decreased appetite (16%), lymphopenia (14%), dizziness (14%), and abdominal pain (13%).
Most common laboratory abnormalities (Grades 1-4) in ≥20% of patients who received LYNPARZA/abiraterone for PROpel were: decrease in hemoglobin (97%), decrease in lymphocytes (70%), decrease in platelets (23%), and decrease in absolute neutrophil count (23%).
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).
INDICATIONS
LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:
HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer
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.
BRCAm Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone
In combination with abiraterone and prednisone or prednisolone (abi/pred) for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
Please see complete Prescribing Information, including Medication Guide.
References:
- Antonarakis ES, Gomella LG, Petrylak DP. When and how to use PARP inhibitors in prostate cancer: a systematic review of the literature with an update on on-going trials. Eur Urol Oncol. 2020;3(5):594-611. doi:10.1016/j.euo.2020.07.005
- O'Connor MJ. Targeting the DNA damage response in cancer. Mol Cell. 2015;60(4):547-560. doi:10.1016/j.molcel.2015.10.040
- Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature. 2012;481(7381):287-294. doi:10.1038/nature10760
- Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697-1708. doi:10.1056/NEJMoa1506859
- Pilié PG, Gay CM, Byers LA, O'Connor MJ, Yap TA. PARP inhibitors: extending benefit beyond BRCA-mutant cancers. Clin Cancer Res. 2019;25(13):3759-3771. doi:10.1158/1078-0432.CCR-18-0968
- de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440
- Hussain M, Mateo J, Fizazi K, et al; PROfound Trial Investigators. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020;383(24):2345-2357. doi:10.1056/NEJMoa2022485
- LYNPARZA® (olaparib) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2023.
- Mateo J, de Bono JS, Fizazi K, et al. Olaparib for the treatment of patients with metastatic castration-resistant prostate cancer and alterations in BRCA1 and/or BRCA2 in the PROfound trial. J Clin Oncol. 2024;42(5):571-583. doi:10.1200/JCO.23.00339
- Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. 2022;1(9):EVIDoa2200043. doi:10.1056/EVIDoa2200043
- Canadian Journal of Health Technologies. Olaparib (Lynparza): CADTH Reimbursement Review. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2024.
US-97484 Last Updated 1/25
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