Oncology Drug Approval News Flash: FDA grants regular approval to rucaparib for BRCAm mCRPC and approves subcutaneous amivantamab and hyaluronidase-lpuj

FDA approval summary

On December 17, 2025, the U.S. Food and Drug Administration (FDA) granted regular approval to rucaparib (Rubraca, pharmaand GmbH) for adult patients with metastatic castration-resistant prostate cancer (mCRPC) associated with deleterious or suspected deleterious BRCA mutations (BRCAm), whether germline or somatic, who have been treated with an androgen receptor-directed therapy. Patients should be selected for therapy using an FDA-approved companion diagnostic.

Rucaparib previously received accelerated approval in 2020 for a similar indication. The current decision converts that accelerated approval to a regular approval based on confirmatory data from the TRITON3 trial.

In the same communication, FDA also approved amivantamab and hyaluronidase-lpuj (Rybrevant Faspro, Janssen Biotech, Inc.) for subcutaneous injection in adult patients across all indications currently approved for intravenous (IV) amivantamab (Rybrevant). The specific disease indications are unchanged and are described in the prescribing information for IV amivantamab.

TRITON3 trial (NCT02975934)

TRITON3 was the randomized, open-label trial required to confirm the clinical benefit supporting the 2020 accelerated approval of rucaparib.

• Population: 405 patients with mCRPC
  • BRCAm: 302 patients
  • ATMm: 103 patients
• Key eligibility criteria:
  • Radiographic progression on at least one prior androgen receptor pathway inhibitor (ARPI), such as enzalutamide or abiraterone
  • No prior chemotherapy in the castration-resistant setting
  • Maintenance of castrate levels of testosterone via ongoing androgen deprivation therapy or prior surgical castration
• Design: randomized 2:1 to:
  • Rucaparib
  • Physician’s choice of either an ARPI not previously received (enzalutamide or abiraterone acetate) or docetaxel
• Stratification factors: performance status, presence of hepatic metastases, and mutation type (BRCA1m, BRCA2m, or ATMm)

The major efficacy outcome was radiographic progression-free survival (rPFS) as assessed by independent radiology review in patients with BRCAm and in the overall population. Overall survival (OS) was an additional efficacy endpoint.

TRITON3 efficacy: benefit concentrated in BRCAm disease

Rucaparib demonstrated a statistically significant improvement in rPFS compared with physician’s choice of therapy in both the BRCAm subgroup and the overall population, with the effect driven primarily by patients with BRCAm.

• BRCA-mutated cohort (n = 302):
  • Median rPFS:
    • Rucaparib: 11.2 months (95% CI: 9.2, 13.8)
    • Physician’s choice: 6.4 months (95% CI: 5.4, 8.3)
  • Hazard ratio (HR) for rPFS: 0.50 (95% CI: 0.36, 0.69); p < 0.0001
• OS in the BRCA-mutated cohort:
  • Rucaparib: median 23.2 months (95% CI: 19.1, 25.2)
  • Physician’s choice: median 21.2 months (95% CI: 18.0, 23.1)
  • HR: 0.91 (95% CI: 0.68, 1.20); not statistically significant
• ATM-mutated cohort (n = 103; exploratory analysis):
  • HR for rPFS: 0.95 (95% CI: 0.59, 1.52)
  • HR for OS: 1.21 (95% CI: 0.77, 1.90)
  • These findings indicate that the overall efficacy benefit of rucaparib in TRITON3 is primarily attributable to patients with BRCAm rather than ATMm.

Rucaparib: safety profile and dosing

The prescribing information for Rubraca includes warnings and precautions for:

• Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML)
• Embryo-fetal toxicity

Recommended dosing:

• Rucaparib 600 mg orally twice daily (two 300 mg tablets per dose)
• May be taken with or without food
• Treatment is continued until disease progression or unacceptable toxicity

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The application was approved approximately one month ahead of the FDA goal date.

PALOMA-3 and subcutaneous amivantamab (Rybrevant Faspro)

The subcutaneous formulation of amivantamab and hyaluronidase-lpuj was evaluated in PALOMA-3, a randomized, open-label, multicenter, multiregional trial.

• Population: 418 adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations
• Design: 1:1 randomization to:
  • Subcutaneous amivantamab and hyaluronidase-lpuj plus lazertinib
  • Intravenous amivantamab plus lazertinib

The primary outcome measures were pharmacokinetic (PK) parameters: trough concentrations at steady state (C_trough on Cycle 4 Day 1) and area under the curve (AUC) in Cycle 2 (AUC_{Day 1–Day 15}). Additional descriptive outcomes included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).

• Every-2-week dosing (observed):
  • Geometric mean ratio (GMR, 90% CI) for Cycle 2 AUC_{Day 1–Day 15}: 1.03 (0.98, 1.09)
  • GMR (90% CI) for steady-state C_trough on Cycle 4 Day 1: 1.43 (1.27, 1.61)
• Every-3-week dosing (simulated):
  • GMR (90% CI) for average concentration over Cycle 2 Day 1–Day 21: 1.20 (1.15, 1.26)
  • GMR (90% CI) for steady-state C_trough: 1.32 (1.23, 1.42)
  • The lower bounds of the 90% CIs remained above the pre-specified threshold of 0.8, supporting PK comparability.

There were no notable differences in descriptive analyses of ORR and PFS, and no evidence of a potential detrimental effect on OS, between patients receiving subcutaneous versus intravenous amivantamab.

Subcutaneous amivantamab: safety and administration

The safety profile of the subcutaneous amivantamab arm in PALOMA-3 was generally similar to that of the intravenous arm, with one notable difference:

• Systemic administration-related reactions (ARRs):
  • Subcutaneous amivantamab: 13% (any grade)
  • Infusion-related reactions (IRRs) with intravenous amivantamab: 66% (any grade)
• This represents a substantial reduction in acute administration reactions with the subcutaneous formulation.

The prescribing information for subcutaneous amivantamab and hyaluronidase-lpuj includes warnings and precautions for:

• Hypersensitivity and administration-related reactions
• Interstitial lung disease (ILD)/pneumonitis
• Venous thromboembolic events when used concomitantly with lazertinib
• Dermatologic adverse reactions
• Ocular toxicity
• Embryo-fetal toxicity

The recommended dosage of subcutaneous amivantamab is based on baseline body weight and depends on the specific indication; detailed dosing tables are provided in the prescribing information.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence that enables concurrent submission and review of oncology drugs among international partners. For this application, FDA collaborated with the Australian Therapeutic Goods Administration (TGA) and Health Canada. The Assessment Aid was also used to facilitate FDA’s assessment.

Editorial perspective (Morningglorysciences)

Together, these approvals reflect two complementary trends in oncology: sharpening molecular precision on the one hand and improving treatment delivery and patient experience on the other.

For rucaparib, TRITON3 confirms that PARP inhibition delivers a clinically meaningful rPFS benefit in BRCAm mCRPC, while offering little advantage in ATM-mutated disease. This reinforces the view that the strongest rationale for PARP inhibitors in prostate cancer lies in BRCA-driven biology, particularly BRCA2, rather than a broad “HRR-mutated” label. With PARP-based intensification now moving into the metastatic castration-sensitive prostate cancer (mCSPC) setting—such as niraparib plus abiraterone—clinicians will increasingly face the strategic question of when to deploy PARP inhibition across the disease course.

For amivantamab, the subcutaneous formulation offers the prospect of maintaining PK exposure and antitumor efficacy while substantially reducing acute administration reactions. In EGFR-mutated NSCLC, where targeted therapies are administered over prolonged periods, route of administration can materially affect patient convenience, infusion chair time, and staffing burden. Broader availability of subcutaneous options may therefore support both patient-centered care and more efficient use of infusion resources.

Key questions going forward include:

• How best to position rucaparib relative to other PARP inhibitor regimens in BRCA-driven prostate cancer, including sequencing after or before mCSPC-stage combinations
• Whether expanding beyond BRCA to other DNA repair gene alterations will be clinically justified as more biomarker data accumulate
• How subcutaneous amivantamab will be adopted in real-world practice in terms of uptake, administration time, adverse reaction profiles, and overall cost-effectiveness

Overall, these approvals underscore the ongoing refinement of precision oncology—optimizing not only who receives targeted therapies, but also how those therapies are delivered in daily practice.

*This article is based on the AACR “FDA Approval Alert” and FDA source materials, summarized and edited by Morningglorysciences.*

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