Understanding Patient Selection and Management Strategies in a PARP Inhibitor Treatment of Advanced Prostate Cancer

Gain valuable insights into the importance of combination treatment in managing BRCA-mutated metastatic castration-resistant prostate cancer. 

Watch video 1 here and video 2 here. 

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 advanced prostate cancer. 

This final video in the series will focus on patient selection and management strategies with the PARP inhibitor olaparib in advanced prostate cancer and a comprehensive approach to safety management.  

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. 

SELECT SAFETY INFORMATION 

LYNPARZA is associated with serious, potentially fatal risks, including myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) and pneumonitis, and venous thromboembolism (VTE). LYNPARZA can also cause fetal harm.  

Please see additional Important Safety Information below at the end of the video. 

As a brief overview, PARP inhibitors are a class of drugs that block the action of PARP enzymes, which mediate repair of single-stranded DNA breaks. Inhibition of PARP by PARP inhibitors leads to accumulation of double-stranded breaks during DNA replication, making cancer cells with alterations in homologous recombination repair genes genomically unstable and more susceptible to cell death.^1-4  

Two pivotal trials established the clinical utility of olaparib in metastatic castration-resistant prostate cancer in patients with HRR mutations. 

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 (ARPi), such as enzalutamide or abiraterone.⁵  

The mCRPC patients 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 tablets orally twice daily or the investigator’s choice of enzalutamide or abiraterone.⁵  

The patients in the PROfound trial had a median age of 69 years. All patients had received a gonadotropin-releasing hormone, or GnRH, analog or had undergone prior bilateral orchiectomy.^5,6  

69% of patients across cohorts were White, 29% were Asian, and 1% were Black.⁶  

The primary endpoint for PROfound was radiographic progression-free survival, or rPFS, in Cohort A. 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.⁵ 

In the PROpel trial, olaparib was shown to have therapeutic benefit when used in combination with abiraterone plus prednisone or prednisolone in patients with mCRPC and HRR mutation.⁷  

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.⁷  

Patients were randomly assigned to receive 1000 mg abiraterone plus either 300 mg of olaparib or placebo.⁷  

About 70% of patients across cohorts were White, 17% to 18% were Asian, and 3% to 4% were Black.⁷ 

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.⁷  

While PROpel met its primary endpoint, the US Food and Drug Administration (FDA) approval was based on an exploratory BRCAm subgroup analysis that showed a 76% risk reduction.^7,8 

BRCAm status was not a stratification factor in PROpel, and analysis was not controlled for Type 1 error.⁹  

Currently, olaparib is the only PARP inhibitor recommended by NCCN Clinical Practice Guidelines in Oncology as both monotherapy and combination therapy for biomarker-selected patients with mCRPC.¹⁰  

BRCA1 and BRCA2 mutations are found in up to 40% of cases in patients with HRR mutation, which represents about 11% of all patients with mCRPC. Notably, BRCA2 mutations are the most common, accounting for 35% of identified HRR mutations and approximately 10% of all mCRPC cases.¹¹ Patients with BRCA mutation tend to have poor outcomes and prognoses following standard-of-care treatments compared to those without HRR mutation.¹²  

In an exploratory analysis of the PROfound data, olaparib showed antitumor activity as a monotherapy in patients with BRCA mutation and mCRPC.¹³  

Exploratory analyses are descriptive only. The PROfound trial was not designed to assess statistical significance in gene-by-gene subgroup analysis. Results should be interpreted with caution. Similarly, clinical benefit was observed in patients with BRCA mutation from PROpel, who received olaparib in combination with abiraterone.¹⁴  

Now, let’s discuss the role of genetic testing in the treatment of patients with mCRPC.  

As mentioned earlier, PARP inhibitors target cells with alterations in HRR genes, and approximately 28% of patients with mCRPC have deleterious mutations in HRR genes.¹¹  

To identify HRR mutations, genetic testing (both germline and somatic) is performed.  

The NCCN Guidelines recommend germline testing for patients with prostate cancer and any of the following¹⁵: 

• High-risk, very high-risk, node-positive or metastatic prostate cancer, regardless of family history  

• A positive family history,^* and 

• Ashkenazi Jewish ancestry  

The NCCN Guidelines^® also recommend somatic tumor testing for somatic HRR gene mutations for those with metastatic disease.¹⁰  

The American Urological Association, the American Society for Radiation Oncology, and the Society of Urologic Oncology recommend both germline and somatic testing for mutations in DNA damage repair genes in their 2020 guidelines.¹⁶  

For mCRPC, tumor tissue testing, paired with germline testing, is considered as the primary approach, with plasma circulating tumor DNA as a follow-up option in cases where tissue test fails or is unsuccessful.^17-20  

The overall effectiveness of plasma ctDNA to produce next-generation sequencing results was high in the PROfound trial, supporting ctDNA as an additional tool in identifying BRCA or ATM mutations in patients with mCRPC.¹⁸  

Based on the higher frequency of DNA repair alterations identified through matched tumor sample (germline + somatic) analysis, tumor genomic analysis is recommended for patients with advanced prostate cancer.¹⁷  

To define the optimal therapeutic strategy in patients most likely to respond to targeted treatments, as well as to inform familial risk and prognosis, diagnostic tests are crucial for identifying HRR mutations.²¹ While there are several diagnostic tests that can be used clinically, olaparib has 3 FDA-approved companion diagnostics, as listed here with their respective sample types and detectable alterations.^6,22  

Once the eligible patients are selected, patients can be started on the recommended dose of olaparib of 300 mg, taken orally twice daily with or without food, for both monotherapy and combination therapy.  

Treatment should be continued until disease progression or unacceptable toxicity.  

Additionally, patients should receive a gonadotropin-releasing hormone, or GnRH, analog concurrently or have had prior bilateral orchiectomy.  

Drug interactions to note include myelosuppressive anticancer agents and CYP3A inhibitors and inducers.⁶  

This is not all of the information related to olaparib dosing. Please see the Prescribing Information for more details. 

Once therapy is initiated, patients should be routinely monitored for potential adverse reactions. This includes a complete blood count at baseline and monthly thereafter as well as watching for signs and symptoms of venous thromboembolism.⁶  

Since its market introduction in 2014, olaparib has reported safety and tolerability data in different patient populations across indications, as evidenced in clinical trials as well as real-world data.^23-25  

For patients with mCRPC in both PROfound and PROpel, the most common adverse reactions reported were anemia, fatigue, and nausea or vomiting.⁶  

Adverse events associated with PARP inhibitors should be managed with standard supportive care measures.⁶ Dose reduction, interruptions, and discontinuations can also be used to manage adverse reactions in patients and will be discussed later in this presentation.  

In patients receiving abiraterone and olaparib compared with abiraterone and placebo, higher rates of venous embolic and thrombotic events were observed.⁷  

This was not unexpected given the FDA’s labeled warning for olaparib indicating a higher risk of venous thromboembolism.⁶  

Post-hoc analyses of clinical trial data for patients receiving olaparib in the PROfound and PROpel studies found that the median time to onset of adverse reactions was within the first 4 months, with the median duration of an adverse event lasting up to 2 months.²⁶  

Patients should contact their healthcare provider if they experience any of the following⁶: 

• Weakness, feeling tired, fever, weight loss, frequent infections, bruising, excessive bleeding easily, breathlessness, or blood in urine or stool 

• Any new or worsening respiratory symptoms 

• Any signs or symptoms of thromboembolism  

To manage adverse reactions, consider interruption of treatment or dose reduction. The recommended dose reduction is 250 mg twice daily. If a further dose reduction is required, then reduce to 200 mg twice daily.^6,27  

In PROfound and PROpel, 22% and 21% of patients, respectively, had a dose reduction due to an adverse reaction.⁶ 

In summary, olaparib is a PARP inhibitor recommended for treating patients with mCRPC and HRR mutation as a monotherapy or patients with mCRPC and BRCA mutation in combination with abiraterone, with a well-defined safety profile as seen from exposure to many patients across tumor types.⁶ 

Thank you for joining me for this video series on PARP inhibitors in advanced prostate cancer!  

*Please refer to the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate for a complete list of family history criteria

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: 

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3. 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   
4. 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   
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8. US Food & Drug Administration. FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. Published May 31, 2023. Accessed July 9, 2024. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-abiraterone-and-prednisone-or-prednisolone-brca-mutated-metastatic-castration   
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13. 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 
14. Canadian Journal of Health Technologies. Olaparib (Lynparza): CADTH Reimbursement Review. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2024.   
15. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate V.2.2025. ©National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed January 30, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org. 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.
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19. Armstrong AJ, Taylor A, Haffner MC, et al. Germline and somatic testing for homologous repair deficiency in patients with prostate cancer (part 1 of 2). Prostate Cancer Prostatic Dis. 2024. doi:10.1038/s41391-024-00901-4 
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22. US Food & Drug Administration. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). Updated November 15, 2024. Accessed December 2, 2024. https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools 
23. Bourien H, Lefevre LB, Mouret-Reynier MA, et al. Real-world data on olaparib in relapsed BRCA-mutated ovarian cancer: a multicenter GINECO RETROLA cohort study. Anticancer Res. 2023;43(2):653-662. doi:10.21873/anticanres.16202  
24. Ricci AD, Rizzo A, Novelli M, et al. Specific toxicity of maintenance olaparib versus placebo in advanced malignancies: a systematic review and meta-analysis. Anticancer Res. 2020;40(2):597-608. doi:10.21873/anticanres.13989   
25. Yang Y, Yang X, Li H, Tong X, Zhu X. Efficacy and safety of olaparib in advanced ovarian cancer: a meta-analysis. J Obstet Gynaecol. 2023;43(1):2151883. doi:10.1080/01443615.2022.2151883 
26. AstraZeneca. Select common adverse reactions for patients taking LYNPARZA. Updated November 2024. Accessed January 21, 2025. https://www.lynparzaarguide.com/lynparzaar/clinical-trials-onset-and-duration-prostate-cancer   
27. Moore KN, Monk BJ. Patient counseling and management of symptoms during olaparib therapy for recurrent ovarian cancer. Oncologist. 2016;21(8):954-963. doi:10.1634/theoncologist.2015-0268

US-97484  Last Updated 1/25