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Advances in mCRPC

CE / CME

Advances in Metastatic Castration-Resistant Prostate Cancer: Biomarker-Driven Treatment Strategies and Emerging Therapeutic Approaches

ABIM MOC: maximum of 0.50 Medical Knowledge MOC point

Physicians: Maximum of 0.50 AMA PRA Category 1 Credit™

Released: July 20, 2026

Expiration: January 19, 2027

Neal D. Shore
Neal D. Shore, MD, FACS
CME/CE Information

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BRCA-Related Synthetic Lethality With PARP Inhibition

This slide illustrates BRCA-related synthetic lethality with PARP inhibition. In normal cells, DNA damage can be repaired through multiple pathways. PARP enzymes help repair single-strand DNA breaks, while BRCA and other HRR proteins repair double-strand DNA breaks. When a BRCA mutation is present, the HRR pathway is impaired, but the cell can often survive by relying on alternative repair mechanisms, including PARP-mediated repair.

When a PARP inhibitor is introduced, this backup repair pathway is also blocked. As DNA damage accumulates, double-strand breaks can no longer be repaired effectively. In cells with BRCA or other selected HRR mutations, the inability to repair DNA ultimately leads to cell death. This is the concept of synthetic lethality.

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Rationale for PARP Inhibitor + ARPI Combinations

PARP inhibition may help attenuate resistance to ARPI therapy in certain tumor clones. For example, RB1 loss may upregulate AR-mediated transcription.

Conversely, ARPI therapy may increase sensitivity to PARP inhibition by downregulating AR target genes and other HRR genes. As a result, some tumors that do not initially appear sensitive to PARP inhibition may become more susceptible to PARP inhibitor therapy.

This biologic rationale formed the basis for evaluating PARP inhibitor plus ARPI combinations in broader patient populations, not just those with known HRR mutations. This strategy was evaluated in the phase III MAGNITUDE, TALAPRO-2, and PROpel trials.

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Approvals of Existing PARP Inhibitors in mCRPC (APMR)

For mCRPC, olaparib and rucaparib are approved as monotherapy in biomarker-defined settings.7,8 Niraparib and talazoparib are not approved as monotherapies in prostate cancer; they are approved as combination regimens. Niraparib is approved in combination with abiraterone acetate and prednisone for BRCA-mutated mCRPC, and talazoparib is approved in combination with enzalutamide for HRR gene–mutated mCRPC.9,10

FDA indications and companion diagnostic requirements differ by agent and regimen. These differences make timely germline and somatic testing essential for matching eligible patients with the right PARP inhibitor strategy.

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PROpel: First-line Olaparib vs Placebo in Combination With AAP in mCRPC

The phase III PROpel trial evaluated olaparib plus abiraterone acetate and prednisone/prednisolone vs placebo plus abiraterone acetate and prednisone/prednisolone in 796 patients with mCRPC. Patients had not received prior therapy for mCRPC, and HRR testing was not required for enrollment. The primary endpoint was radiographic progression-free survival (rPFS) by investigator assessment.

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PROpel: rPFS in Asymptomatic/Mildly Symptomatic Disease

This was a successful trial in which the addition of olaparib resulted in a statistically significant improvement in rPFS and a numerical improvement in OS. Post hoc exploratory analyses in patients with asymptomatic or mildly symptomatic disease showed that olaparib plus abiraterone demonstrated improved median rPFS (27.6 months) vs placebo and abiraterone (19.1 months), with an HR of 0.59, and further separation of curves over time.11

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TALAPRO-2: Enzalutamide ± Talazoparib in Patients With Newly Diagnosed mCRPC

The phase III TALAPRO-2 study evaluated talazoparib plus enzalutamide vs placebo plus enzalutamide in patients with newly diagnosed mCRPC. Participant samples were prospectively assessed for somatic and germline HRR gene alterations. The primary endpoint was rPFS by blinded independent central review (BICR), and OS was a key secondary endpoint.

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TALAPRO-2: Efficacy Outcomes

TALAPRO-2 showed a statistically significant rPFS improvement with talazoparib plus enzalutamide. With longer follow-up, the median rPFS was 33.1 months vs 19.5 months with placebo plus enzalutamide, with an HR of 0.667. Final OS was also improved, with median OS of 45.8 vs 37.0 months and an HR of 0.796.12

The key takeaway is that biomarker definitions and approved panels differ across regions and regimens. In clinical practice, careful attention to the approved indication, the companion diagnostic, and the patient’s HRR alteration is essential when selecting a PARP inhibitor combination.

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MAGNITUDE: First-line Niraparib vs Placebo in Combination With AAP in mCRPC

MAGNITUDE was a phase III trial in patients with mCRPC with and without alterations in HRR genes, particularly BRCA1/2. However, a prespecified futility analysis showed no benefit in the HRR-negative population, leading to early discontinuation of that cohort. Subsequent analyses therefore focused primarily on patients with HRR alterations.

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MAGNITUDE: Final OS Analysis in BRCA+ Subgroup

In the unadjusted final OS analysis in the BRCA-positive subgroup, median OS was 30.4 months with niraparib plus AAP vs 28.6 months with placebo plus AAP, with an HR of 0.788. In a preplanned multivariable analysis incorporating prognostic factors, OS favored niraparib plus AAP, with an HR of 0.663.13

The key takeaway is that comprehensive genomic testing is essential in patients with mCRPC. Ideally, testing should be performed earlier in the disease course, including in patients with mHSPC. Identifying BRCA alterations and other selected HRR mutations can help inform treatment decisions and provide opportunities to leverage targeted therapies if the disease progresses to a castration-resistant state.

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Conclusion: PARP Inhibitors in Prostate Cancer

PARP inhibitors have a clear role in selected patients with DNA damage repair alterations. BRCA2 is the most predictive alteration and is associated with clinically meaningful benefit. Patients with BRCA1, PALB2, and CDK12 may also derive benefit, although the magnitude of benefit varies by gene, regimen, and disease setting.

PARP inhibitors are effective therapies, although there continues to be discussion regarding the balance between benefit and risk in certain patient populations. As a class, PARP inhibitors can cause myelosuppression and, in some cases, gastrointestinal toxicity, which are generally manageable with monitoring and dose modification. With long-term use, there is a small risk of bone marrow disorders, including myelodysplastic syndrome and acute myeloid leukemia, occurring in approximately 1% of patients.7

The key message is the importance of testing. Both germline and somatic genetic testing are essential to identify patients who may benefit from these therapies.

Ongoing studies are evaluating PARP inhibitors in earlier prostate cancer settings. These include PETRANHA, a phase I/II study of saruparib/AZD5305 in combination with new hormonal agents in metastatic prostate cancer (NCT05367440), and the phase III EvoPAR-Prostate01 study of saruparib plus physician’s choice of new hormonal agent in metastatic castration-sensitive prostate cancer (NCT06120491). EvoPAR-Prostate02 is evaluating adjuvant saruparib in patients with BRCA-mutated localized or locally advanced high-risk prostate cancer receiving radiotherapy with ADT (NCT06952803).

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