Ovarian cancer is a significant gynecological malignancy, often diagnosed at an advanced stage. Initial treatment involves cytoreductive surgery followed by platinum-based chemotherapy, typically carboplatin combined with paclitaxel. This standard approach yields a high initial response rate, often exceeding 80%. However, the majority of patients with advanced disease will experience a recurrence. The subsequent treatment strategy for recurrent disease is determined by the Platinum-Free Interval (PFI), which reflects the cancer cells’ ability to overcome the effects of platinum drugs.
Defining Platinum Resistance
Oncologists classify recurrent ovarian cancer based on the Platinum-Free Interval (PFI), the time elapsed between the completion of the last platinum-based therapy and recurrence. This interval determines the next course of treatment. Platinum-sensitive disease is defined by recurrence occurring six months or more after completing treatment, suggesting the cancer remains responsive to re-treatment with a platinum-based regimen.
Platinum-resistant ovarian cancer (PROC) is designated when the cancer returns or progresses between one and six months after the last dose of a platinum drug. Platinum-refractory tumors progress during initial platinum treatment or within one month of its completion. For PROC and refractory cases, the standard approach shifts away from reintroducing platinum agents, leading to the use of non-platinum systemic therapies.
Molecular Mechanisms Driving Resistance
Platinum resistance involves multiple adaptive changes within the cancer cell. Platinum drugs, such as carboplatin, damage DNA by forming crosslinks that prevent replication and ultimately trigger cell death. Resistant cells overcome this by enhancing their DNA repair machinery, significantly increasing the capacity for DNA damage response pathways to effectively fix platinum-induced lesions.
Another mechanism is the altered accumulation of the drug within the cell. Cancer cells may overexpress efflux pumps, specialized proteins that actively transport the chemotherapy drug out before it reaches its DNA target, reducing its intracellular concentration and effectiveness. Resistant cells also often have alterations in their apoptotic pathways, the signaling cascades that regulate programmed cell death. These alterations allow the cancer cell to ignore damage signals and refuse to die, even in the presence of the drug.
Current Systemic Treatment Strategies
Once platinum resistance is confirmed, systemic treatment shifts to non-platinum options, primarily aiming for disease control and symptom management. Single-agent non-platinum chemotherapy is the standard, utilizing drugs that work through different mechanisms than platinum agents.
Commonly used options include liposomal doxorubicin (a formulation encapsulated in fat bubbles to reduce toxicity), gemcitabine, weekly paclitaxel, and topotecan. These agents are associated with lower response rates, typically ranging from 10% to 30%, compared to initial platinum therapy.
Targeted therapy is frequently incorporated into the treatment plan for platinum-resistant disease. Bevacizumab, an antibody that targets Vascular Endothelial Growth Factor (VEGF), is often combined with single-agent chemotherapy.
By inhibiting VEGF, bevacizumab blocks the formation of new blood vessels, thereby starving the tumor and hindering its growth (anti-angiogenesis). Clinical trials have shown that adding bevacizumab improves Progression-Free Survival compared to chemotherapy alone.
Poly(ADP-ribose) polymerase (PARP) inhibitors, including olaparib, niraparib, and rucaparib, have a defined role in the platinum-resistant setting for patients with specific genetic markers. These targeted drugs interfere with DNA repair in cells that already have a defect in their homologous recombination repair (HRR) pathway, such as those with a BRCA gene mutation.
Although their primary role is maintenance therapy in platinum-sensitive disease, PARP inhibitors can be utilized in the platinum-resistant setting if the tumor has a BRCA mutation or is Homologous Recombination Deficient (HRD). This offers a non-chemotherapy option with demonstrated response rates.
Investigational Therapies and Novel Approaches
The landscape of treatment for platinum-resistant ovarian cancer is rapidly evolving, particularly with the use of Antibody-Drug Conjugates (ADCs). An ADC is a targeted delivery system linking a potent chemotherapy agent to an antibody recognizing a specific protein on the cancer cell surface, allowing the payload to be delivered directly to the tumor.
Mirvetuximab soravtansine is the first ADC approved for PROC, targeting the Folate Receptor Alpha (FRα) protein, which is highly expressed on many ovarian cancer cells. This drug provides a new standard of care for this subgroup, showing a notable response rate in patients whose tumors express high levels of FRα. Next-generation ADCs targeting markers such as NaPi2b and HER2 are also being explored.
Immunotherapy is another area of intense research. Checkpoint inhibitors (e.g., PD-1/PD-L1 blockers) have had limited success as single agents but are being investigated extensively in combination strategies. Combining these inhibitors with anti-angiogenic drugs or novel ADCs is a major focus, suggesting improved activity over monotherapy. The continued development of these novel agents and combination strategies through clinical trials offers hope for improving outcomes for patients with platinum-resistant ovarian cancer.