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Antibody-Drug Conjugates (ADCs) in Ovarian Cancer: A Detailed Overview

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1. Introduction and Background

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2. ADC Architecture and Mechanism of Action

2.1 Structural Components

2.2 Step-by-Step Mechanism of Action

┌─────────────────────────────────────────────────────────────────────────┐
│                    ADC MECHANISM OF ACTION                              │
│                                                                         │
│  1. ANTIGEN BINDING                                                     │
│     ADC (mAb + Linker + Payload) ──► Binds surface antigen on          │
│     tumor cell (e.g., FRα, HER2, NaPi2b)                              │
│                                                                         │
│  2. INTERNALIZATION (Receptor-Mediated Endocytosis)                     │
│     ADC-antigen complex ──► Clathrin-coated pit ──► Endosome           │
│                                                                         │
│  3. LYSOSOMAL PROCESSING                                                │
│     Endosome ──► Lysosome ──► Linker cleavage by                       │
│     low pH / cathepsin B / other proteases                              │
│                                                                         │
│  4. PAYLOAD RELEASE                                                     │
│     Free cytotoxin released into cytoplasm                              │
│     - DM4: binds tubulin → microtubule disruption → G2/M arrest → apoptosis│
│     - DXd: DNA topoisomerase I inhibition → DNA DSB → apoptosis         │
│                                                                         │
│  5. BYSTANDER EFFECT (cleavable linkers only)                           │
│     Membrane-permeable payload diffuses to adjacent                     │
│     antigen-negative tumor cells → additional cell kill                │
│     (particularly relevant for heterogeneous tumors)                    │
│                                                                         │
│  6. IMMUNE ACTIVATION (secondary)                                       │
│     Immunogenic cell death → release of DAMPs → DC activation           │
│     → T-cell priming (synergy with ICIs)                                │
└─────────────────────────────────────────────────────────────────────────┘

2.3 Key Differences Between Payload Classes

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3. Key Targets in Ovarian Cancer

3.1 Folate Receptor Alpha (FRα / FOLR1)

• Expressed in ~80% of high-grade serous ovarian cancer (HGSC)
• Markedly overexpressed on tumor surfaces vs. normal tissues (where expression is basolateral and inaccessible)
• Expression is inversely correlated with platinum sensitivity - higher in platinum-resistant disease
• Tested with MIRV, farletuzumab ecteribulin (MORAb-202), luveltamab tazevibulin (STRO-002)

3.2 HER2 (ERBB2)

• Overexpressed in ~15-30% of ovarian cancers (IHC 3+ or 2+/FISH+), much lower than breast cancer
• Tested with trastuzumab deruxtecan (T-DXd) - DESTINY-PanTumor02 showed activity
• Emerging target, not yet standard of care

3.3 Sodium-Dependent Phosphate Transport Protein 2b (NaPi2b / SLC34A2)

• Highly expressed in non-mucinous ovarian cancer (~90%)
• Tested with upifitamab rilsodotin (RC48-ADC) - Phase I/II data promising
• Specific to a subset of histologies

3.4 Other Targets

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4. Approved ADC: Mirvetuximab Soravtansine (MIRV)

4.1 Drug Profile

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5. Clinical Evidence: Platinum-Resistant Ovarian Cancer

5.1 Development Pathway

Phase I (Dose Finding)
    ↓
FORWARD I (Phase III - broader FRα) → NEGATIVE (overall)
    ↓                                      ↓ FRα-high subgroup: PFS 6.7 vs 3.9 mo ✓
Lessons learned: biomarker selection critical
    ↓
FORWARD II (Phase Ib - combinations)
    ↓
SORAYA (Phase II - single-arm, FRα-high, ≥prior bevacizumab)
  → ORR 32.4%, DoR 6.9 mo → Accelerated FDA Approval Nov 2022
    ↓
MIRASOL (Phase III - randomized, FRα-high vs chemo)
  → PFS 5.62 vs 3.98 mo (HR 0.65, p<0.001)
  → OS 16.46 vs 12.75 mo (HR 0.67, p=0.005) ← First OS benefit in platinum-resistant OC
  → ORR 42.3% vs 15.9% → Full FDA Approval March 2024

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5.2 FORWARD I (Phase III) - The Pivotal Learning Trial

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5.3 SORAYA (Phase II, Single-Arm) - Accelerated Approval Basis

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5.4 MIRASOL (Phase III, Randomized) - Full Approval Basis (THE LANDMARK TRIAL)

Landmark significance: MIRASOL is the FIRST trial to demonstrate an overall survival benefit specifically in platinum-resistant ovarian cancer.

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5.5 SORAYA Final Overall Survival

• Median OS: ~13 months in the heavily pre-treated FRα-high population
• Consistent efficacy regardless of number of prior lines or prior PARPi exposure

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5.6 Integrated Safety Profile (Across FORWARD I, FORWARD II, SORAYA, MIRASOL)

Ocular toxicity (blurred vision and keratopathy) is the hallmark toxicity of MIRV. All patients require baseline ophthalmology evaluation, and prophylactic steroid eye drops (dexamethasone 0.1%) should be used. Dose holds/reductions are required for grade ≥2 ocular events. A boxed warning exists in the FDA label for ocular toxicity.

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6. ADCs in Platinum-Sensitive Ovarian Cancer

6.1 Current Status: Investigational

6.2 MIRV + Carboplatin (Phase I/II)

• FORWARD II (Phase Ib, NCT02606305): MIRV combinations studied
  • MIRV + bevacizumab in PROC: ORR ~39% (Gilbert L et al., Gynecol Oncol 2023)
  • MIRV + carboplatin in platinum-sensitive recurrent OC: ORR ~83% (preliminary Phase I/II data, NCT04526691, 2024 data)
  • These data are very promising but require confirmatory Phase III studies

6.3 MIRV + Pembrolizumab in PROC

• Matulonis UA et al., Gynecol Oncol 2025 (PMID referenced in 2026 CME sources): Phase I/II combination
  • Active investigation; rationale based on immunogenic cell death from DM4
  • Pembrolizumab + MIRV FDA-approved for PROC as of February 2026 (KEYNOTE-B96 adjacent data)

6.4 Platinum-Sensitive Setting: Emerging Data

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7. Emerging ADCs in Ovarian Cancer

7.1 FRα-Targeting ADCs Beyond MIRV

Farletuzumab Ecteribulin (MORAb-202)

• Antibody: Farletuzumab (anti-FRα IgG1)
• Payload: Eribulin (microtubule inhibitor)
• Phase I/II (PAPILLON): ORR ~35% in platinum-resistant OC; DoR ~6 months
• Enrolled in meta-analysis (Kim ET et al., 2024): 45 patients, contributes to pooled ORR of 37%

Luveltamab Tazevibulin (STRO-002)

• Antibody: Anti-FRα
• Payload: SC209 (3-aminophenyl hemiasterlin derivative, tubulin inhibitor)
• Phase I (STRO-002-GM1): 36 patients in meta-analysis; ORR ~30%
• Distinct payload mechanism from MIRV

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7.2 HER2-Targeting ADCs

Trastuzumab Deruxtecan (T-DXd, DS-8201)

• DESTINY-PanTumor02 (2025 ESMO update, Makker V et al.): Ovarian cancer cohort with HER2 expression
  • ORR ~50.5% in IHC 3+ tumors
  • Being actively investigated in ovarian cancer
• T-DXd also shows activity in HER2-low ovarian cancer due to bystander effect
• Key toxicity: Interstitial lung disease (ILD) - requires monitoring; graded management protocol

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7.3 NaPi2b-Targeting ADCs

Upifitamab Rilsodotin (RC88 → IMGN151)

• Target: NaPi2b (sodium-dependent phosphate transporter 2b)
• Payload: Maytansinoid (tubulin inhibitor)
• Expression: ~90% of non-mucinous EOC
• Phase I/II (UPLIFT trial): Active investigation
• ORR in early data: Promising in platinum-resistant disease

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7.4 Cadherin-6 (CDH6) Targeting

Raludotatug Deruxtecan (R-DXd)

• Target: CDH6 (expressed in ~70% HGSC, also renal cell carcinoma)
• Payload: DXd (topoisomerase-I inhibitor) - same as T-DXd
• Strong preclinical activity in ovarian and kidney cancer models (Suzuki H et al., Mol Cancer Ther 2024 [PMID: 38205802])
• Phase I: NCT04676734; early promising clinical signals
• Listed as emerging ADC in 2026 CME materials alongside raludotatug-deruxtecan

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7.5 Trop-2 Targeting ADCs

Datopotamab Deruxtecan (Dato-DXd)

• Target: TROP-2
• Payload: DXd
• TROP-2 expression ~60-70% in EOC
• Phase I/II combination trials with durvalumab and carboplatin in progress
• Main development in lung/breast cancer; ovarian data emerging

Sacituzumab Govitecan (SG)

• Target: TROP-2
• Payload: SN-38 (irinotecan metabolite, topoisomerase-I inhibitor)
• Phase II data in recurrent EOC: ORR ~17% (limited data)

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7.6 Summary Table: ADCs in Development for Ovarian Cancer

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8. Meta-Analysis Evidence (Highest Level of Evidence)

• Pooled ORR (entire cohort): 37% (95% CI: 0.30-0.43)
• Pooled ORR (FRα-high subgroup): 34% (95% CI: 0.26-0.42)
• Grade ≥3 AEs: 27% (95% CI: 0.19-0.36)
• Agents included: MIRV (n=859), farletuzumab ecteribulin (n=45), luveltamab tazevibulin (n=36)
• Conclusion: FRα-targeting ADCs show definite efficacy with good safety as 2nd-line and beyond

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9. Resistance Mechanisms

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10. Current Guideline Recommendations

10.1 ESMO 2026 Guidelines (Updated January 28, 2026)

• FRα definition for ESMO: ≥75% viable tumor cells with ≥2+ staining intensity by validated assay
• Basis: MIRASOL trial data (first OS benefit in platinum-resistant OC)
• MIRV received EMA marketing authorization November 2024

10.2 NCCN v1.2026 Guidelines

• FRα testing requirement: VENTANA FOLR1 (SP213) IHC assay; ≥75% of viable cells at ≥2+ intensity = "FRα-high"
• MIRV is listed in NCCN as a preferred single-agent option for FRα-high platinum-resistant disease

10.3 FDA Approval Status

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11. Patient Selection and Biomarker Testing

11.1 FRα Testing Algorithm

┌─────────────────────────────────────────────────────────────────┐
│               FRα TESTING AND MIRV ELIGIBILITY                  │
│                                                                  │
│  Patient: Recurrent/Platinum-resistant EOC (HGSC, primary       │
│  peritoneal, fallopian tube)                                     │
│                         │                                        │
│                         ▼                                        │
│         FRα IHC Testing (VENTANA FOLR1 SP213 assay)             │
│         (archival or fresh tumor biopsy)                         │
│                         │                                        │
│          ┌──────────────┼──────────────┐                         │
│          ▼              ▼              ▼                         │
│    FRα-HIGH        FRα-MEDIUM      FRα-LOW/NEG                   │
│  (≥75% cells,      (25-74% cells,  (<25% cells at               │
│   ≥2+ IHC)          ≥2+ IHC)        ≥2+ IHC)                    │
│       │                  │               │                       │
│       ▼                  ▼               ▼                       │
│  ELIGIBLE for         Clinical        Standard                   │
│  MIRV (approved)      trial only      chemotherapy              │
│  (1-3 prior lines,                                               │
│   PFI <6 months)                                                 │
└─────────────────────────────────────────────────────────────────┘

11.2 FRα Prevalence in Ovarian Cancer Subtypes

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12. Treatment Algorithm: ADCs in the Context of Recurrent EOC

RECURRENT EPITHELIAL OVARIAN CANCER
             │
             ▼
   Determine Platinum-Free Interval (PFI)
             │
    ┌────────┴────────┐
    ▼                 ▼
PFI ≥6 months      PFI <6 months
(Platinum-         (Platinum-
 Sensitive)         Resistant)
    │                 │
    ▼                 ▼
Platinum-based    FRα IHC Testing
doublet ±         (VENTANA SP213)
bevacizumab            │
    │           ┌──────┴──────┐
    ▼           ▼             ▼
PARPi        FRα-HIGH      FRα-LOW/NEG
maintenance  (≥75%,≥2+)    (<75% ≥2+)
per BRCA/         │             │
HRD status        ▼             ▼
             MIRV*         Paclitaxel, PLD,
             (preferred)   Topotecan, Gemcitabine
                │          ± Bevacizumab
                │          ± Pembrolizumab
                ▼          (PD-L1 CPS ≥1)
         Progression
                │
                ▼
      Clinical trial / other agents
      (T-DXd if HER2+, emerging ADCs)

* 1-3 prior lines; HGSC/primary peritoneal/FT histology
* Prior bevacizumab not required (per MIRASOL eligibility)
* Dose: 6 mg/kg AIBW IV q3w
* Prophylactic steroid eye drops mandatory

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13. Combination Strategies

13.1 ADC + Bevacizumab

• MIRV + bevacizumab (FORWARD II): ORR ~39% in PROC; rational combination as bevacizumab may upregulate FRα
• Listed as an option in NCCN v1.2026

13.2 ADC + Immune Checkpoint Inhibitors

• MIRV + pembrolizumab: FDA approved February 2026 for PROC
• Rationale: DM4 payload induces immunogenic cell death (ICD) → enhances T-cell priming
• Phase I data: Matulonis UA et al., Gynecol Oncol 2025 (Safety/efficacy confirmed)
• DXd-based ADCs (T-DXd, R-DXd) also have strong ICD potential - ongoing combination trials

13.3 ADC + Chemotherapy / Targeted Agents

• MIRV + carboplatin: ORR ~83% in platinum-sensitive recurrent OC (Phase I/II)
• MIRV + PARPi: Under investigation
• Dato-DXd + durvalumab + carboplatin: Phase I/III ongoing (NSCLC primary; ovarian cohorts)

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14. Special Considerations and Future Directions

14.1 ADC Sequencing

• No established sequence for multiple ADCs currently
• Cross-resistance between FRα-targeting ADCs is expected (shared target) but payload resistance may differ
• CDH6, HER2, NaPi2b-targeting ADCs could follow MIRV progression
• Key question: Can non-FRα ADCs be used after MIRV failure?

14.2 Bystander Effect Significance

• DXd-based ADCs (T-DXd, R-DXd, Dato-DXd) have stronger bystander effects vs. DM4-based MIRV
• This is important for tumors with heterogeneous antigen expression (common in EOC)
• May explain broader activity of DXd-based ADCs at lower antigen expression levels

14.3 Platinum-Sensitive Setting: Unmet Need

• No ADC is currently approved in platinum-sensitive EOC
• MIRV + carboplatin showing ~83% ORR is compelling; Phase III needed
• The question of whether ADCs can replace/complement PARPis in platinum-sensitive relapse is being studied

14.4 ADC in First-Line (Emerging)

• MIRV + frontline platinum-based chemotherapy: Early investigations
• Rationale: FRα is expressed early in HGSC development (including serous tubal intraepithelial carcinoma/STIC)
• Kong B, Zheng W, J Hematol Oncol 2025 [PMID: 40102896]: Propose MIRV for STIC prevention in high-risk populations

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15. Ocular Toxicity Management Protocol (MIRV-Specific)

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16. Summary: Key Takeaways

1. MIRV is the only FDA/EMA-approved ADC for ovarian cancer (as of mid-2026), indicated for FRα-high, platinum-resistant HGSC/primary peritoneal/fallopian tube cancer after 1-3 prior lines.
2. MIRASOL (NEJM 2023) is the practice-defining trial - first Phase III RCT to demonstrate both PFS and OS benefit (OS HR 0.67, p=0.005) in platinum-resistant ovarian cancer.
3. Biomarker selection is critical - FRα-high definition (≥75% cells, ≥2+ by VENTANA SP213 IHC) identifies the population that benefits. ~30-40% of HGSC qualify.
4. Platinum-sensitive setting remains investigational - MIRV + carboplatin (ORR ~83%) shows promise but requires Phase III confirmation.
5. Emerging ADCs (T-DXd, R-DXd, upifitamab, farletuzumab ecteribulin) target HER2, CDH6, NaPi2b, and FRα respectively, and are in Phase I/II trials with encouraging early results.
6. DXd-payload ADCs (T-DXd, R-DXd, Dato-DXd) have strong bystander effects and immunogenic cell death properties - likely to complement or succeed MIRV in the future.
7. Ocular toxicity is the hallmark MIRV adverse effect; mandatory ophthalmology monitoring and prophylactic steroid eye drops are required.
8. Combination strategies (MIRV + pembrolizumab, MIRV + bevacizumab, MIRV + carboplatin) are approved or under active development.
9. Both NCCN v1.2026 and ESMO 2026 guidelines recommend MIRV for the FRα-high, platinum-resistant HGSC population.

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Key References

• Moore KN et al. Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer (MIRASOL). NEJM 2023 [PMID: 38055253]
• Matulonis UA et al. Efficacy and Safety of MIRV in PROC with High FRα Expression (SORAYA). JCO 2023 [PMID: 36716407]
• Kim ET et al. Efficacy and Safety of FRα-Targeted ADC Therapy - Systematic Review and Meta-Analysis. Cancer Med 2024 [PMID: 39526448]
• Coleman RL et al. MIRV in FRα-high PROC: Final OS from SORAYA. Int J Gynecol Cancer 2024 [PMID: 38858103]
• Moore KN et al. Integrated Safety of MIRV Monotherapy. Gynecol Oncol 2024 [PMID: 39461270]
• Kong B, Zheng W. Mirvetuximab soravtansine: current and future applications. J Hematol Oncol 2025 [PMID: 40102896]
• Barquin A et al. ADCs in gynecologic cancers. Cancer 2026 [PMID: 42226034]
• Van Gorp T et al. Patient-reported outcomes from MIRASOL. Lancet Oncol 2025 [PMID: 40179908]
• ESMO 2026 Guidelines (updated January 28, 2026): Recommend MIRV for FRα-high HGSC with PFI <6 months, 1-3 prior lines
• NCCN Guidelines v1.2026: MIRV as category 2A preferred single-agent for FRα-high PROC