Clinical trial update on treatments for mCRPC

Watch: mCRPC management with Professors Merseburger and Agarwal

PARP inhibitors

PROfound compared the PARP (poly ADP ribose polymerase) inhibitor olaparib to physician’s choice of enzalutamide or abiraterone in mCRPC with one or more gene alterations with a role in HRR and progression on an androgen receptor pathway inhibitor (ARPI). Most patients were pretreated with one or two chemotherapies and up to two ARPIs.^2,3 The primary endpoint was radiographic progression-free survival (rPFS) in the population with BRCA1/2 or ATM mutations (cohort A). rPFS favoured olaparib for cohorts A and B (HR, 0.49; 95% CI, 0.38–0.63). For overall survival (OS), there was an improvement in cohort A (HR, 0.69; 95% CI, 0.50–0.97; P=0.0175).^2,3 For olaparib, the most common adverse events (AE) were anaemia, nausea, asthenia and fatigue; for the control treatment, asthenia, fatigue, decreased appetite and anaemia were the most common AEs.^2,3

Olaparib was US Food and Drug Administration (FDA) approved for patients with mCRPC and deleterious or suspected deleterious germline or somatic HRR mutations with progression following treatment with enzalutamide or abiraterone.⁴ The European Medicines Agency (EMA) approved olaparib for patients with mCRPC and BRCA1 and BRCA2 alterations.⁵

Abiraterone acetate plus prednisone or prednisolone (AAP) plus olaparib

The phase 3 trial PROpel investigated first-line AAP + olaparib (300 mg twice daily) or AAP + placebo in patients with mCRPC.^6,7 Imaging-based progression-free survival (ibPFS), the primary endpoint, was 24.8 months for AAP + olaparib versus 16.6 months for AAP + placebo (HR, 0.66; 95% CI, 0.54–0.81; P=0.001).

• For patients with HRRm+ status, the HR for rPFS was 0.50 (95% CI, 0.34–0.73)
• For patients with BRCA mutation (11% of the intent-to-treat [ITT] population), the HR for rPFS was 0.24 (95% CI, 0.12–0.45)

The HR for OS for patients with a BRCA mutation was 0.29 (95% CI, 0.14–0.56). These data indicate that the improved rPFS in the ITT population was driven by patients with a BRCA mutation.¹ Grade 3–4 anaemia occurred in 16% of patients in the AAP + olaparib group and 3% in the AAP + placebo group.^6,7

In 2023, the FDA approved this combination for patients with mCRPC with BRCA mutations.⁴ The EMA approved the combination in 2019 for adults with mCRPC in whom chemotherapy is not indicated.⁵

Enzalutamide plus talazoparib

TALAPRO-2 assessed the PARP inhibitor talazoparib (0.5 mg daily) + enzalutamide versus enzalutamide/placebo as first-line treatment in patients with mCRPC (unselected patients and selected patients with mutated HRR). Median rPFS (primary endpoint) favoured the study combination, irrespective of HRR status (the HR for rPFS was 0.63 [95% CI, 0.51–0.78; P<0.0001]).⁸ For subgroups of patients with HRR mutations, the benefit of talazoparib + enzalutamide was greater: median rPFS was 27.9 months (16.6–not reached), compared with 16.4 months (95% CI, 10.9–24.6) for placebo (HR, 0.46; 95% CI, 0.30–0.70; P=0.0003).⁸ The most common treatment-emergent AEs (TEAEs) with the addition of talazoparib were anaemia, neutropenia and fatigue; the most common grade 3–4 AE was anaemia (46%).⁸

The FDA approved talazoparib + enzalutamide for HRR-mutated mCRPC in 2023.⁹ In 2024, the EMA approved talazoparib + enzalutamide for patients with mCRPC (with or without gene mutations) in whom chemotherapy is not indicated.¹⁰

Rucaparib after ARPI

TRITON-3 included 405 patients with mCRPC with BRCA1, BRCA2, or ATM alterations and disease progression after second-generation ARPI treatment.¹¹ Participants were randomly assigned to receive oral rucaparib (600 mg twice daily) or a physician’s choice control (docetaxel or second-generation abiraterone acetate or enzalutamide). The primary endpoint of rPFS (ITT population) was significantly better with rucaparib (median 10.2 vs 6.4 months; HR, 0.61; 95% CI, 0.47–0.80; P<0.001). OS data are under analysis.¹¹ The most frequent AEs with rucaparib were fatigue, nausea and anaemia.^11,12 Rucaparib is FDA approved for mCRPC.¹³ It is not approved for mCRPC by the EMA.¹⁴

PSMA-based therapy

In the phase 2 TheraP trial, patients for whom cabazitaxel was the next appropriate standard treatment after docetaxel were randomised to receive ¹⁷⁷Lu-PSMA-617 (6.0–8.5 GBq intravenously, every 6 weeks, up to 6 cycles) or cabazitaxel (20 mg/m², up to 10 cycles). The primary endpoint was a prostate-specific antigen (PSA) reduction of ≥50%, which was met for the ITT population (66% for ¹⁷⁷Lu-PSMA-617 vs 37% for cabazitaxel; difference, 29%, 95% CI, 16–42%; P<0.0001).¹⁵ Grade 3–4 AEs occurred in 32 (33%) of 98 men in the ¹⁷⁷Lu-PSMA-617 group versus 45 (53%) of 85 men for cabazitaxel.¹⁵ At the 36-month follow-up, OS was similar for patients randomised to ¹⁷⁷Lu-PSMA versus cabazitaxel.¹⁶ No further safety signals were observed with longer follow-up.¹⁶

The phase 3 VISION trial compared ¹⁷⁷Lu-vipivotid tetraxetan (¹⁷⁷Lu-PSMA-617 radioligand therapy) with protocol-permitted standard of care (SOC) in patients with PSMA-expressing metastases on PET/CT previously treated with at least one ARPI and one or two taxanes. ibPFS and OS were the primary endpoints. ¹⁷⁷Lu-PSMA-617 + SOC significantly extended ibPFS and OS compared with SOC alone. Incidence of grade 3 AEs was higher with ¹⁷⁷Lu-PSMA-617 (52.7% vs 38.0%); however, quality of life was not adversely affected. Anaemia was the most common grade ≥3 A (12.9% vs 4.9%).^{17 177}Lu-PSMA-617 was FDA and EMA approved for mCRPC in 2022.^18,19

Read: mCRPC sequencing and intensification