mCRPC: Targeting resistance pathways

By Megan Lee

Earlier use of targeted therapies may help delay ARPI resistance and improve survival in mCRPC

Unmet needs in metastatic castration-resistant prostate cancer (mCRPC) demand new strategies as resistance to androgen receptor pathway inhibitors (ARPIs) remains a clinical challenge. What’s next for clinicians facing complex, evolving therapeutic choices? With resistance limiting the durability of current treatments, the focus is shifting toward earlier intervention, personalized approaches, and combination strategies that may help delay progression and improve survival. As the treatment landscape evolves, staying ahead of resistance is central to optimizing patient outcomes.

What are the main drivers of ARPI resistance in mCRPC?

Resistance in mCRPC stems from overlapping molecular mechanisms that complicate treatment decisions. These include:

• AR gene amplification
• AR splice variants
• Bypass signaling pathways
• Epigenetic alterations

How are PARP inhibitors being used to address resistance in mCRPC?

Poly (ADP-ribose) polymerase (PARP) inhibitors are being applied in several ways to help overcome ARPI resistance in mCRPC:

• As monotherapy in patients with homologous recombination repair (HRR) gene mutations, including BRCA1/2
• In combination with ARPIs to broaden clinical utility
• In earlier-line settings to preempt resistance and delay progression

What role do epigenetic agents play in overcoming ARPI resistance?

Epigenetic agents are being investigated as a novel strategy to overcome ARPI resistance by targeting molecular mechanisms associated with aggressive disease. Their potential role includes:

• Modulating EZH2 activity to disrupt resistance pathways
• Enhancing efficacy when combined with ARPIs
• Offering benefit in ARPI-exposed, resistant populations with limited options

What do TALAPRO-1 and TALAPRO-2 reveal about treatment sequencing?

The TALAPRO trials are investigating the role of talazoparib, a PARP inhibitor, in mCRPC.

• TALAPRO-1 (NCT03148795) evaluated talazoparib monotherapy in heavily pretreated patients with HRR gene mutations, showing meaningful clinical activity
• TALAPRO-2 (NCT03395197) is assessing talazoparib in combination with enzalutamide as first-line therapy and has demonstrated improved overall survival compared with enzalutamide alone

These findings support the potential for earlier use of PARP inhibitors in mCRPC treatment sequencing.

How early should clinicians consider introducing novel agents in mCRPC?

There is growing interest in introducing established and novel agents earlier in the mCRPC treatment pathway to delay resistance and improve outcomes. PARP inhibitors and epigenetic agents are being evaluated as first- or second-line options, including in patients naive and exposed to ARPIs. While guidelines support PARP inhibitor use, optimal timing and sequencing, particularly for investigative epigenetic approaches, remain undefined, leaving decisions to clinician discretion.

Key takeaways

• ARPI resistance is driven by complex molecular changes, making treatment decisions more challenging
• Using PARP inhibitor combinations earlier could help delay resistance and extend survival
• Targeted therapies may offer new possibilities, especially for patients with limited options. But with sequencing still undefined, clinicians need to weigh timing carefully based on individual patient profiles

Developed by EPG Health for Medthority, independently of any sponsor.