Rechallenging Ovarian Cancer patients with triplet regimen in MEDIOLA clinical Trial

Ovarian cancer often goes undetected until it is metastasized to the proximate tissue sites in the pelvis and stomach. At this late stage, the cancer is more difficult to treat and can be fatal. The current treatment largely constitutes of surgery, radiation therapy, and chemo radiation. Platinum based chemotherapy have been main stream treatment for patients who are unfit of surgical resection, to delay progression of the disease and maintain the patient’s quality of life with the intent of achieving complete remission. Evolution of biomarker based treatment like bevacizumab has been remarkable in the OC treatment landscape. Bevacizumab has become ubiquitous treatment, whether prescribed as therapeutic agent or maintenance therapy, across the lines of treatment. A new class of drug “PARP Inhibitors” has significantly transformed the treatment of ovarian cancer landscape over the past few years. PARP Inhibitors perform antineoplastic action by blocking enzymes involved in DNA repair processes that cancer cells reap as they multiply. PARP inhibitors are mostly being used to treat people who have been newly diagnosed, as maintenance therapy to sustain remission. But, hardly being used as salvage treatment after other therapies have failed. Even after much therapeutic advancement, the recurrence rates are high in Ovarian Cancer and there is a dire need for newer and more effective treatment options. Within three years of initial treatment approximately half of the patients experience recurrence. Resistance to the main stream therapy has been in the middle of main causes of recurrence in Ovarian Cancer. Few subtypes of ovarian cancers like clear cell, mucinous cell etc. are innately resistance towards platinum based chemotherapy. Since both platinum based chemo therapy and PARP inhibitors exert antineoplastic effect by synthetic lethality, resistance to platinum based chemotherapy may resonate for PARP inhibitors also. Moreover, BRCA reversion mutation, a secondary mutation that restores the wild-type BRCA2 reading frame, could be a major mediator of acquired resistance to platinum-based chemotherapy and PARP inhibitors.  In therapeutically resistant patients, finding rational and efficacious, combination have been a significant challenge. Since patients are heavily pretreated and TEAEs might be major deterring factor, to prescribe combination therapy again, which are more or less was part of initial treatment regimen. 

So far, stratification outlook of treatment therapies across the line are also not impressive, by and large care givers have to revolve around changing combination regimen mostly which is used  in  initial line of therapy.  High recurrence rates and limited treatment modalities have been clearly reflecting unmet need for novel, more efficacious options, which can fill therapeutic gaps and sustain remission especially in initial line of therapies. Periodical screening are also necessitated, since it could help in early detection of OC. Early detection coupled with novel therapeutic approach, if it’s done, would be huge relief for both patients and physician. 

AstraZeneca’s Triplet regimen elicits therapeutic response by collective inhibition of PD-1, PARP, and VEGF receptors. AstraZeneca Presented updated interim results of Phase I/II, clinical study (MEDIOLA), evaluating efficacy and safety of the triplet regimen (durvalumab + Olaparib + Bevacizumab) vs. doublet (olaparib plus durvalumab) regimen in non gBRCA mutated (wild type), platinum-sensitive ovarian cancer patients, at ESMO 2022 :

• Median overall survival (OS), in triplet regimen (durvalumab + olaparib + bevacizumab) arm vs. doublet (olaparib plus durvalumab) regimen arm, were found to be 31.9 months and 26.1 months, respectively, which reflects median OS favored the triplet therapy arm
• Disease control rate (DCR) at 56 weeks, in triplet regimen (durvalumab + olaparib + bevacizumab) arm vs. doublet (olaparib plus durvalumab) regimen arm, were found to be 38.7% and 9.4%, respectively
• Median progression-free survival (PFS) in in triplet regimen (durvalumab + olaparib + bevacizumab) arm vs. doublet (olaparib plus durvalumab) regimen arm, were found to be 14.7 months and 5.5 months, respectively 
• Safety profile were consistent with known safety profiles of the single agents          

So far updated efficacy and safety results from MEDIOLA clinical study reflects, the triplet regimen (durvalumab + Olaparib + Bevacizumab) bested over doublet regimen, for Second and later line in non gBRCA mutated, platinum-sensitive ovarian cancer patients. Going forward it could be a new breakthrough for subset of ovarian cancer patients.

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