Beyond the PARP inhibition: what is the future of ovarian cancer treatment?

In the February, 2024 issue of the Journal of Clinical Oncology, Lorusso and colleagues presented the results of a phase 3 trial (1) assessing the efficacy of trabectedin, an alkylating agent with multiple mechanisms of action coming from the sea squirt species Ecteinascidia turbinata. Trabectedin is the first marine natural product to be used clinically as a drug—for the treatment of advanced soft tissue sarcoma and ovarian cancer (OC). In the latter indication, it was approved in combination with pegylated liposomal doxorubicin (PLD), in patients with intermediate sensitivity to platinum at relapse (2).

Its mechanism of action, as well as the results of previous studies, suggested a particular activity in tumors with BRCAness phenotype, as defined by either a BRCA 1/2 mutation, or a response to repeated lines of platinum-based chemotherapy (3). Such a phenotype is strongly linked to the presence of homologous recombination deficiency (HRD) status.

The current treatment of first-line, advanced OC relies on surgery, platinum-based chemotherapy and maintenance treatment, in order to lower the probability of relapse. Poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib, niraparib and rucaparib, have demonstrated a particular activity on tumors with genomic instability. Those tumors have genomic alterations, such as BRCA 1/2 mutations and HRD. For those tumors, which account for around half of all high-grade carcinomas, a PARP inhibitor is the reference treatment in maintenance, either alone or in combination with bevacizumab (4,5). In case of relapse, the tumor is considered platinum-resistant if relapse has occurred within 6 months after the last administration of platinum, and platinum-sensitive after 6 months (5).

In the present study, trabectedin was compared to the investigator’s choice of monochemotherapy in both platinum-resistant and platinum-sensitive settings. Eligible patients were adult females (age 18 years and older) with histologically documented invasive epithelial OC, primary peritoneal carcinoma, or fallopian tube cancer. All patients had recurrent platinum-resistant [with a platinum-free interval (PFI) of <6 months] or platinum-sensitive (with a PFI of ≥6 months) disease with either a BRCA1 or 2 mutation or BRCAness phenotype who either had responded to at least two previous platinum-based chemotherapy lines, or were platinum-sensitive. There were no limits in the number of previous chemotherapy lines or previous treatment with PARP inhibitors.

The study was powered to detect a 33% reduction of the risk of death in favor of trabectedin, as compared to weekly paclitaxel, pegylated liposomal doxorubicin (PLD), or topotecan, with an alpha risk of 5%. Under this hypothesis, the trial had to enroll 244 patients, who were indeed included on a 20-month period, in 21 Italian centers.

Monochemotherapy is a reasonable standard in the resistant setting, nevertheless it produces low progression-free survival (PFS) rates and a median overall survival (OS) of around 15 months (6). Decades of research have failed to demonstrate any efficacy gain by adding another chemotherapeutic agent. Bevacizumab was shown to improve PFS in the AURELIA trial, without measurable impact on OS. Whether a platinum-based combination would remain beneficial in patients who already received multiple lines of platinum, but remain platinum sensitive, is still unknown.

In the MITO-23 trial, the authors chose OS as their principal endpoint, which is certainly the most meaningful one in patients with heavily pretreated and/or rapidly-progressive disease, who can no longer receive multiple lines of therapy. But in our opinion, the most important limitation of the statistical hypothesis was the choice of 10 months as the estimated OS in the control arm, considering the lack of data in this particular setting.

At the end, the study was negative, partly because the results obtained in the control arm were superior to those expected in the statistical assumptions. The authors hypothesize that PLD in the control arm might be responsible for this unexpectedly high efficacy. The results obtained in term of OS—median between 15 and 17 months—suggest that the target population was close to a platinum-resistant one, as compared to those observed for instance in the CALYPSO trial—33 months—where carboplatin + PLD were given at first relapse (7).

It is noteworthy that only one third of the included patients had previously received a PARP inhibitor, which made no difference for the final results, nor did platinum resistance and the number of previous lines of chemotherapy.

At the current era where the PARP inhibitors are fully prescribed in first line, the MITO-23 study already belongs to the past and probably shows that chemotherapy is not a reliable basis for the development of precision oncology.

However, the question addressed by the authors remains accurate: what can we do to improve the outcome of our patients with genetically unstable tumors at relapse?

The OREO trial suggested that re-challenging olaparib after platinum-based chemotherapy re-induction resulted in a small, but clinically debatable PFS benefit (8).

However, some data suggest that a relapse occurring under PARP inhibitor given in maintenance has a low probability of response to chemotherapy (9). In this case, drugs with other mechanisms of action are required to overcome resistance.

Drugs with various mechanisms of action can be combined to PARP inhibitors. Antiangiogenic agents such as bevacizumab and cediranib have been tested in combination with drugs such as niraparib and olaparib, both in first-line and relapse, suggesting an additive effect (4). There is also a biologic rationale for combining immune checkpoint inhibitors with PARP inhibitors, which can sensitize the tumor to immunotherapy by increasing the tumor mutational load (5). Encouraging results have been obtained in preliminary studies, but the results coming from randomized studies have not yet confirmed our expectations (4,5).

Interesting results have also been obtained with the Wee-1 kinase adavosertib in a population of patients with high-grade serous ovarian carcinoma with CCNE1 overexpression, after progression under a PARP inhibitor (10). The Wee-1 kinase is linked to the G2-M cell-cycle checkpoint. Its inhibition produces a cell-cycle acceleration which results in the so-called “mitotic catastrophe” and ultimately in cell death.

Another potential target is PIK3CA, which is involved in DNA replication and cell cycle regulation. Inhibition of the PIK3CA may lead to genomic instability and mitotic catastrophe through a decrease of the activity of the spindle assembly checkpoint protein Aurora kinase B and consequently increase of the occurrence of lagging chromosomes during prometaphase (11). A synergistic effect would be expected from the combination of a PARP inhibitor and a PIK3CA inhibitor. In the EPIK-O randomized trial, the combination of olaparib and alpelisib—a selective alpha-inhibitor of PIK3CA—was compared to chemotherapy of the investigator’s choice in non BRCA-mutated patients with platinum resistant relapse. However, the study failed to show any additional benefit of the combination (12).

Beyond targeting the homologous recombinational repair (HRR) system, non-specific agents such as antibody drug conjugates (ADCs) should also play a role in the treatment of the platinum resistant relapse. In the MIRASOL study, mirvetuximab soravtansine, a folate receptor targeting antibody with a monomethyl auristatin E (MMAE) payload, was shown superior to the chemotherapy of the investigator’s choice, leading to an OS benefit of around 4 months (13). Multiple other ADC and BITES (bispecific antibodies engaging both cancer cell structures and immune cell receptors) are now under development, such as ubamatamab, an anti-MUC16 (the other denomination for CA 125) and CD3—a T lymphocyte receptor—antibody (14). In a recently-presented early-phase trial, the authors reported an 18% response rate in platinum-resistant tumors, with a median duration of 9 months. An ongoing trial (NCT03564340) is investigating the efficacy of ubamatamab alone or in combination with cemiplimab in relapsing OC with CA 125 increase.

The currently evolving therapeutic landscape in OC should be completed by mentioning the role of cellular therapy [engineered T-cells and tumor-infiltrating lymphocyte (TILs)] and vaccines, which has to be further assessed (15).

We are reaching the end of the chemotherapy era, at least in the OC relapse setting.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-91/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-91/coif). G.F. received consulting fees from Lilly France, Genomic Health; payment or honoraria from MSD, Astrazeneca, Pfizer, Lilly, GSK, Pierre Fabre, Novartis, Menarini; and support for attending meetings and/or travel from Novartis, GSK, MSD. T.R. received payment or honoraria from Lilly, Grunenthal, Menarini; payment for expert testimony from Astrazeneca, Novartis; support for attending meetings and/or travel from GSK, DaiichiSanko. The other author has no conflicts of interest to declare.

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