Personalized Treatment Plans for Certain Patients with BRCA-Mutated mCRPC

This article is sponsored by AstraZeneca. Dr George was compensated by AstraZeneca for his participation.

Metastatic castration-resistant prostate cancer (mCRPC) remains a challenging diagnosis, with limited long-term survival.^1,2 Despite the advances with taxane chemotherapy and novel hormone agents, there is still a significant unmet need, as survival remains poor.² In the U.S., approximately half of patients with mCRPC receive only one line of active therapy, underscoring the importance of having more treatment options in the first-line setting.¹ About 10% of men with prostate cancer have BRCA mutations, which are often associated with the risk of poor prognosis and outcomes.^3,4 For patients who present with BRCA-mutated disease, identifying targeted treatment options as early as possible is essential.^1,3

One of these targeted treatment options is LYNPARZA® (olaparib), a poly (ADP-ribose) polymerase (PARP) inhibitor, in combination with abiraterone and prednisone or prednisolone (abi/pred). This combination was approved by the U.S. Food and Drug Administration in 2023 for the first-line treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC).⁵ LYNPARZA targets PARP to disrupt the DNA-repair process and potentially kill tumor cells, while abiraterone targets CYP17 to disrupt androgen biosynthesis and potentially limit tumor growth.^5,6 Together, this combination therapy addresses two distinct pathways in prostate cancer biology, DNA damage repair and androgen signaling.^7,8 The exact mechanism of action of LYNPARZA remains a subject of research. Eligible patients can be selected for therapy based on an FDA-approved tissue or liquid biopsy companion diagnostic test.⁵

LYNPARZA is indicated for the treatment of patients with BRCAm* metastatic castration-resistant prostate cancer in combination with abiraterone and prednisone or prednisolone.⁵
*Select patients for this indication based on an FDA-approved companion diagnostic for LYNPARZA.

Select Safety Information⁵

• Serious and potentially fatal adverse events included:
  • Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML): Monitor patients for hematological toxicity at baseline and monthly thereafter. Discontinue if MDS/AML is confirmed
  • Pneumonitis: Interrupt treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed
  • Venous thromboembolism (VTE): Including severe or fatal pulmonary embolism (PE). Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism, and treat as medically appropriate
  • Hepatotoxicity, including drug-induced liver injury (DILI): Evaluate bilirubin and transaminases at baseline and throughout treatment with LYNPARZA. For patients who develop abnormal liver tests after LYNPARZA, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, interrupt LYNPARZA. If DILI is confirmed, discontinue treatment
• Advise patients of the potential risk of embryo-fetal toxicity and to use effective contraception
• Most common adverse reactions (≥10%) in clinical trials:
  • in combination with abiraterone and prednisone were anemia, fatigue, diarrhea, decreased appetite, lymphopenia, dizziness and abdominal pain

Please see the complete Important Safety Information and complete Prescribing Information, including Medication Guide.

The Role of Early Testing

In my practice, I emphasize the importance of genetic testing and counseling to newly diagnosed patients. This includes BRCA testing as early as possible so that results are available at the point of treatment decision-making.³ Because there is no clinical phenotype that reliably predicts a BRCA mutation, every patient with advanced prostate cancer should be considered for testing.⁹

Timely results allow us to make informed choices about treatment.¹⁰ They also help ensure we can integrate the appropriate approach as soon as patients meet criteria for mCRPC, without delay.¹⁰ This requires collaboration between members of a multi-disciplinary team to make testing systematic and to support patients throughout the process.¹¹

Three Clinical Scenarios in Practice

In my experience, I often consider three scenarios in which patients with BRCAm mCRPC may be appropriate for treatment with LYNPARZA in combination with abiraterone and prednisone or prednisolone:

1. Patients initially managed with androgen-deprivation therapy (ADT) alone. There is a subset of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with ADT alone.¹² If these patients progress to castration resistance and test positive for a BRCA mutation, the LYNPARZA combination regimen is an approved treatment option.⁵
2. Patients who receive ADT and radiation for high-risk localized disease.¹³ These men may be on extended hormonal therapy.¹³ If their disease progresses to mCRPC during this period and they harbor a BRCA mutation, they may be considered for the approved LYNPARZA combination.⁵
3. Patients who discontinue an AR pathway inhibitor after a deep response. Some patients experience near-complete remission with ADT plus abiraterone or enzalutamide and later stop therapy.^10,14 If they meet the definition of castration resistance while on a planned treatment interruption and are BRCA positive, the LYNPARZA combination is an option.⁵

These scenarios illustrate how systematic testing and close monitoring allow us to help identify patients who may be appropriate candidates for targeted therapy with LYNPARZA in combination with abi/pred in BRCAm mCRPC.

Evidence from the PROpel Trial

The approval of LYNPARZA in combination with abiraterone and prednisone or prednisolone in BRCAm mCRPC was based on results from an exploratory BRCAm subgroup of the Phase III PROpel trial. In an exploratory subgroup analysis of patients with BRCAm, treatment with the combination showed a clinically meaningful improvement with a risk reduction of 76% in radiographic progression-free survival (rPFS) compared with placebo + abi/pred (HR 0.24; 95% CI, 0.12–0.45).⁵ Overall survival (OS) results in an exploratory BRCAm subgroup (n=85) showed a 70% reduction in risk of death (HR 0.30; 95% CI, 0.15–0.59) compared with placebo + abi/pred.⁵ Median rPFS and median OS were not reached for LYNPARZA + abi/pred, compared with 8 months and 23 months, respectively, for placebo + abi/pred.⁵

The safety of LYNPARZA in combination with abiraterone and prednisone or prednisolone was also evaluated in PROpel. The most common adverse reactions of any grade (≥10%) were anemia (48%), fatigue (38%) (including asthenia), nausea (30%), diarrhea (19%), decreased appetite (16%), lymphopenia (14%), dizziness (14%) and abdominal pain (13%).⁵ Please see the complete Important Safety Information and complete Prescribing Information, including Medication Guide.

Moving Toward Multidisciplinary Care

Integrating a genomic biomarker-driven treatment into practice requires coordinated care. Urologists can help initiate the testing conversation at diagnosis.¹⁵ Medical oncologists play a role in interpreting results and guiding treatment planning.¹⁶ Genetic counselors provide support to patients and their families when germline findings are identified.¹⁷ This collaboration may help ensure that patients receive the most appropriate treatment in a timely manner.¹¹

Conclusion

For patients with BRCAm mCRPC, early testing, timely treatment and multidisciplinary collaboration are essential.^3,11 The FDA-approved combination of LYNPARZA with abiraterone and prednisone or prednisolone provides an important treatment option supported by the PROpel trial. By making testing routine and engaging the full care team, we can help ensure eligible patients can make informed treatment decisions tailored to their disease biology.^9,11

LYNPARZA is indicated for the treatment of patients with BRCAm* metastatic castration-resistant prostate cancer in combination with abiraterone and prednisone or prednisolone.
*Select patients for this indication 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 approximately 1.2% of patients (26/2219) with various BRCAm, gBRCAm, HRR gene-mutated or HRD-positive cancers who received LYNPARZA in clinical studies 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 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 counts 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: Including severe and fatal cases, has occurred in patients treated with LYNPARZA. In clinical studies, among patients who received LYNPARZA as a single agent or as part of a combination regimen, the incidence of pneumonitis, including fatal cases, was 1.0% (29/2851). If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and promptly assess the source of the symptoms. If pneumonitis is confirmed, discontinue LYNPARZA treatment and treat the 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.

Hepatotoxicity, including Drug-Induced Liver Injury (DILI): Hepatotoxicity, including severe and potentially fatal cases of DILI has occurred in patients treated with LYNPARZA. Evaluate bilirubin and transaminases at baseline and throughout treatment with LYNPARZA. For patients who develop abnormal liver tests after LYNPARZA, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold LYNPARZA. Upon confirmation of DILI, discontinue LYNPARZA.

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.

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—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/abiraterone 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).

INDICATION

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

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.

You may report side effects related to AstraZeneca products (Opens new window).

References

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3. Na R, et al. Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death. Eur Urol. 2017;71(5):740-747.
4. de Bono JS, et al. Central, prospective detection of homologous recombination repair gene mutations (HRRm) in tumour tissue from >4000 men with metastatic castration-resistant prostate cancer (mCRPC) screened for the PROfound study. Presented at: ESMO Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract 847PD.
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