Emerging serine-threonine kinase inhibitors for treating ovarian cancer

Abstract

Introduction

Ovarian cancer is the leading cause of gynecologic cancer death, owing to high rates of incurable, recurrent disease after initial treatment. Serine threonine kinases (STKs) have been proposed as potential therapeutic targets in ovarian cancer because of their role in the initiation and progression of cancers. Experience in non-ovarian cancers suggests that STK inhibitors are active against tumors with specific molecular alterations.

Areas covered

This review discusses STK inhibitors in active development in phase II/III clinical trials for ovarian cancer. PubMed and ClinicalTrials.gov were systematically searched to identify STK inhibitor trials for ovarian cancer; active development was confirmed via Pharmaprojects. Available data regarding the efficacy and safety of these compounds are explored.

Expert opinion

STK inhibitors currently in development have modest activity as single agents and are unlikely to achieve approval as monotherapy for unselected ovarian cancer patients. Combination trials of STK inhibitors with chemotherapy and/or targeted therapies have suggested an acceptable efficacy/toxicity ratio for certain combinations but confirmatory studies are needed. Carefully designed trials, especially those including somatic molecular analysis, may help identify the subsets of patients most likely to benefit from these therapeutic strategies and determine the role of STK inhibitors in the evolving landscape of precision oncology.

1. Background

Over 22,000 women in the United States will be diagnosed with ovarian cancer in 2019 and almost 14,000 will die of this disease. Ovarian cancer is the most lethal gynecologic malignancy and the 5^th most common cause of cancer death among women, accounting for approximately 5% of cancer mortality [1]. Ovarian cancer is comprised of multiple subtypes, the majority of which are epithelial, meaning related to the type of cells that cover surfaces in the human body; the remainder of this review discusses this subtype. Importantly, even epithelial carcinomas encompass a wide histologic and molecular diversity that results in differential tumor behavior and treatment response. The majority are diagnosed at a late stage with spread beyond the pelvis (stage III or IV), portending poor outcomes. Approximately 60% of stage III epithelial ovarian cancer patients and 80% of stage IV patients die of their disease within 5 years [2]. Standard first-line therapy includes debulking surgery combined with platinum-based cytotoxic chemotherapy. Despite remission after the above frontline treatment in 50–70% of the patients, 80% will recur [3,4], often with platinum-resistant disease, which is generally less responsive to all treatments [5].

Effective measures to prevent ovarian cancer are lacking. Potential preventative measures, including surgical removal of the fallopian tubes and ovaries, are recommended only for high-risk patients with known genetic predispositions to ovarian cancer, and screening modalities have not proven effective [2].

Ovarian cancer has significant financial implications for both the health-care system and individual patients. Within the first year of diagnosis, the median treatment cost is estimated at $100,000 per patient [6]. The addition of newer biological agents, including Bevacizumab, increases that estimate to $170,000. Out-of-pocket expenses for these patients pose significant financial toxicity, especially for patients enrolled in high-deductible health plans [7]. The last year of life for ovarian cancer patients is likewise associated with significant health-care spending [8]. Medical complications, including chronic bowel obstruction with dependency on intravenous nutrition, large volume fluid accumulation in the abdomen and chest, and debilitating pain, significantly affect the quality of life. Ovarian cancer also takes a toll on mental health with both patients and caregivers suffering from elevated rates of depression. Increased rates of anxiety have been noted in patients with higher symptom burden and less social support [9]. Quality of life, including self-reported mental and physical health, is affected by cancer recurrence [10], with caregiver burden and financial toxicity being common [11].

Given the above, major efforts are underway to change the therapeutic landscape for ovarian cancer [12]. These efforts have focused on the molecular mechanisms underlying ovarian cancer initiation and progression, as well as mechanisms of inherent and acquired resistance to standard therapy [12]. Additional systemic therapies have been approved for the treatment of ovarian cancer only in recent years. Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, was first approved for ovarian cancer in 2014 [13]. Bevacizumab targets angiogenesis, a process in which ovarian (and other) cancers form new blood vessels to support their growth and spread.

Molecular markers and analysis of genetic tumor mutations are increasingly utilized to guide treatment decisions, opening the door to new, more personalized therapies. The most successful class of targeted therapies in ovarian cancer has been Poly-ADP ribose polymerase (PARP) inhibitors, which target cancers lacking an important mechanism to repair DNA damage. In 2014, olaparib became the first drug in this class to obtain FDA approval [14]. Several other PARP inhibitors are now also approved with ongoing studies expanding their indications for use, including for first-line therapy of advanced ovarian cancer [15,16]. Immunotherapy for ovarian cancer is also being enthusiastically studied [12]. While harnessing the immune system to mediate an anti-tumor response shows efficacy in some cancers, it has yet to lead to an approval specifically for ovarian cancer [17]. Hence, additional therapeutic targets are needed to achieve better outcomes for ovarian cancer patients.

This review will cover serine-threonine kinase (STK) inhibitors in active development for the treatment of recurrent ovarian cancer. STKs are enzymes that modulate protein activity by phosphorylation of serine and threonine amino acid residues [18]. They are typically classified into groups and families based on the sequence similarity of their catalytic domains [19]. STKs represent the largest group of kinases that mediate cellular processes [19], although tyrosine kinases have been more successfully targeted pharmacologically [18]. STKs are part of the cell machinery that is involved in signal transduction pathways controlling metabolism, cell division, angiogenesis and other functions [20]. STKs are hyperactivated across multiple malignancies including ovarian cancer [21],making them attractive therapeutic targets [20]. STK inhibition has been attempted in various fashions, including orthosteric competitive inhibition at the catalytic domain, allosteric inhibition and irreversible inhibition [22–24]. Targeting the catalytic domain, however, can lead to decreased specificity because of the sequence homology of multiple kinases [22,23]. STK inhibitors have been grouped for the purpose of this review given the overarching common features of STKs and the challenges in translating their pharmacological effects into clinical benefit.

2. Medical need

Standard treatment for ovarian cancer includes surgical debulking followed by platinum and taxane therapy, resulting in high rates of remission, even in advanced-stage disease. Bevacizumab, which has shown modest benefit in frontline therapy, can be added to these modalities [2,5,25]. Given the frequency of recurrence, often incurable, the focus of research in novel ovarian cancer therapy has been on prolonging the progression-free interval – both by improving initial therapy and finding effective maintenance therapies – and on treating recurrent disease. To date, maintenance therapies with bevacizumab, liposomal doxorubicin, or PARP inhibitors prolong progression-free survival but have not been proven to increase overall survival [15,16,25–30]. PARP inhibitors are expected to be incorporated in first-line treatment for advanced ovarian cancer, given recent data demonstrating a clinically meaningful PFS benefit in this setting, including for patients without a BRCA 1/2 mutation. The implications of this change in practice for the treatment of recurrent disease and how this will affect overall survival is not known,

Recurrent disease has traditionally been described by anticipated responsiveness to platinum therapy. Those who progress through platinum therapy (10–15%) were deemed platinum refractory with a dismal median survival of less than 9 months. Thirty percent, deemed platinum-resistant, recur within 6 months of completing chemotherapy. The remainder of patients were considered platinum sensitive, which correlates to improved chemoresponsiveness and overall survival [5]. While these terms continue to be used in clinical research, including in trials covered in this review, there exists no biologically or clinically compelling argument to support a fixed cutoff at 6 months. Thus, these definitions have been discouraged by professional societies and with the changes in the frontline and maintenance therapeutic landscape for ovarian cancer [31], they may lose their relevance for guiding clinical decision-making and clinical trials. However, because these terms were used for the design and interpretation of the clinical trials reviewed in this paper, they will be used. Though several agents are FDA approved for the platinum-resistant disease, no standard treatment exists. Many approved regimens are associated with significant toxicity, with typical response rates only 10–25%. Median overall survival is often limited to less than 18 months [13,32–34].

Hence, there is a major need for improvement of the therapeutic landscape for platinum-recurrent and -refractory ovarian cancer in order to improve efficacy, reduce toxicity, prolong survival, and improve quality of life for patients.

3. Existing treatment

Decisions regarding management depend on tumor histology, platinum sensitivity, previous treatments, toxicities, molecular studies, and patient symptoms, preferences, and goals of care [35]. Due to their relative prevalence, most research has focused on high-grade serous carcinomas [5]. However, differential responses have been noted in other histologic subtypes. Hormonal therapy, while not particularly effective for high-grade serous ovarian carcinoma, is considered active for low-grade serous ovarian carcinoma and some cases of endometrioid ovarian carcinoma. Mucinous carcinomas are often treated with oxaliplatin and 5-fluorouracil, even in the upfront setting, as they are thought to behave more like gastrointestinal cancers [5]. There has also been an anecdotal success with immunotherapy in clear cell ovarian carcinoma [36].

Molecular markers, and germline and somatic genetic testing have also become increasingly important. BRCA1/2 status and homologous recombination deficiency (HRD) testing are important molecular studies to predict the benefit of PARP inhibitors. Microsatellite instability, a marker of deficient DNA mismatch repair (dMMR), can detect a minority of patients for whom immunotherapy is indicated based on the site-agnostic approval of immunotherapy for microsatellite unstable tumors [37].

Despite major advances achieved over the past decade, the limited efficacy of the available treatments for recurrent ovarian cancer, in conjunction with their potential side effects, underscores the importance of identifying new therapeutic strategies for this indication.

3.1. Existing treatment for platinum-sensitive recurrent ovarian cancer

The mainstay of treatment for recurrent platinum-sensitive disease consists of platinum-based combination chemotherapy and, in certain circumstances, secondary cytoreductive surgery [38]. As a general rule, the longer the platinum-free or disease-free interval between remission and recurrence, the better the response to all chemotherapies and the longer the overall survival [39,40]. In the platinum-sensitive setting, response rates to single-agent platinum range from 30% to 50% [41], and platinum-based regimens are the mainstay of treatment. Combination therapy increases the response rate to as much as 60–70% [42,43]. However, complete responses are uncommon and the chances of a second remission are much lower than with initial treatment, even with a long disease-free interval.

Common regimens include carboplatin/paclitaxel, carboplatin/gemcitabine and carboplatin/liposomal doxorubicin. Significant toxicities of these regimens include bone marrow suppression, allergic reactions, vomiting, stomatitis, hand-foot syndrome, neuropathy, and rarely, treatment-related death [44]. Carboplatin/paclitaxel conveys a higher risk of alopecia and severe neurotoxicity while carboplatin/liposomal doxorubicin conveys a higher risk of severe anemia, thrombocytopenia, and skin reactions [44]. Furthermore, retreatment with platinum agents increases the risk of a severe hypersensitivity reaction, which in rare cases can be fatal or debilitating [45]. Once a platinum reaction has been diagnosed, desensitization is typically required. The associated toxicities of platinum, especially its long-term effect on bone marrow, become dose-limiting if resistance or allergic reaction does not develop first.

The addition of bevacizumab to combination chemotherapy has also shown efficacy in this patient population, resulting in an overall survival of over 40 months [46]. The clinical benefit of bevacizumab is partially offset by a higher risk of adverse events such as hypertension and thromboembolism. It is also associated with delayed wound healing proteinuria, and, rarely, gastrointestinal perforation and/or fistulization [5,46].

PARP inhibitors are indicated as maintenance therapy after response to chemotherapy and have resulted in a dramatic improvement in progression-free-survival in the setting of platinum-sensitive recurrence. This benefit is more pronounced, but not limited, to patients with BRCA1/2 mutations or other HRD [47,48]. PARP inhibitors are generally well tolerated without detrimental effects on quality of life [49]. However, PARP inhibitors can cause fatigue, anemia, thrombocytopenia, nausea, diarrhea, and additional side effects that led to discontinuation in approximately 10% of the patients in clinical trials [28]. For a minority of patients whose tumor demonstrates dMMR or microsatellite instability [50], single-agent immunotherapy can be considered.

Overall, treatment for platinum-sensitive recurrent ovarian cancer relies on invasive and aggressive modalities that are typically non-curative and associated with significant, dose-limiting side effects. All patients in this setting are expected to eventually stop responding to currently available agents, so the development of alternative therapies for these patients is urgently needed.

3.2. Existing treatment for platinum-resistant recurrent ovarian cancer

Platinum-resistant recurrent ovarian cancer carries a dismal prognosis and is almost invariably fatal with a median overall survival of only 9–12 months [51]. In light of the palliative treatment intent, effective therapy with a tolerable side effect profile is needed. For this reason, treatment of platinum-resistant ovarian cancer often entails sequential single chemotherapy treatment, to which biologics or targeted therapies can be added. The optimal sequence of agents is unknown, and clinical trials of novel drugs are within the standard of care [52,53].

Commonly used agents include paclitaxel, pegylated liposomal doxorubicin, and topotecan, to which bevacizumab can be added [13]. Additional agents include gemcitabine, docetaxel, etoposide, cyclophosphamide, and other cytotoxic chemotherapies. The response rates to each of these drugs are low, ranging between 10%and 30% [53]. This results in poor progression-free-survival and overall-survival which are less than 6 and 18 months, respectively [53]. These agents also have significant toxicities. Neurotoxicity is a major dose-limiting side effect of paclitaxel [32], and previous neuropathy from paclitaxel may preclude its use in the setting of recurrence. Paclitaxel leads to alopecia in the majority of patients, including loss of the eyebrows and eyelashes, which can be distressing [32]. While alopecia is usually not seen with pegylated liposomal doxorubicin, it is associated with stomatitis, hand-foot syndrome, neutropenia or anemia in over a third of patients. Topotecan leads to severe cytopenias in over 70% of these patients. Neutropenic fever, treatment-related sepsis, and death have been reported with this agent [34]. Treatment delays, interruptions, and dose-reductions are also common with these agents and happen in more than 50% of the patients [34]. The full scope of adverse events for single-agent chemotherapy is outside the scope of this review but all cytotoxic agents are associated with toxicity that can often compromise the quality of life in this patient population [54].

Bevacizumab can be used in combination with chemotherapy or as a single agent in the platinum-resistant recurrent setting and is one of the most well-tolerated and active agents available. Response rates to monotherapy average about 10% with best response rates to dual therapy being around 30% [13]. However, risks of severe complications, such as bowel perforation, are increased in the setting of intestinal carcinomatosis, bowel obstruction, and recent surgery, which are commonly seen in recurrent ovarian cancer.

PARP inhibitors can be offered to patients with germline or somatic BRCA1/2 mutations who have progressed on two to three lines of therapy with response rates of 33% in platinum-resistant disease [14]. The toxicity profiles of these agents are described above, though the side effect profile differs depending on which of the three available agents is administered.

Hormonal therapies, including progestins, anti-estrogens, and GnRH analogs, have poor response rates and are not associated with improved survival in comparison with chemotherapy but are better tolerated and may be associated with improved quality of life [55,56]. While immunotherapy in combination with existing therapy is being explored and actively used in the hope of benefiting more patients, there is no current immunotherapeutic agent approved for platinum-resistant recurrent ovarian cancer.

Somatic molecular analysis is increasingly used in attempts to tailor individualized targeted therapies. Though targetable somatic alterations are occasionally found, this is the exception rather than the rule, and these treatments are infrequently successful.

Thus, current available therapies for platinum-resistant recurrent ovarian cancer have poor response rates and short-lived efficacy at best. There is an urgent need to improve treatment outcomes for this indication.

4. Current research goals

This review will address STK inhibitors that are currently being considered for ovarian cancer treatment, focusing on recurrent ovarian cancer, given that they have not been examined in the upfront setting. A systematic search of PubMed and ClinicalTrials.gov was performed including specific compounds and STK drug classes (see Table 1). STK inhibitors that are in Phase II or Phase III clinical trials and are actively being developed for ovarian cancer will be covered. Active development of individual drugs was confirmed via Pharmaprojects and ClinicalTrials.gov. Drugs not in active development or in other stages of development have been excluded and are not within the scope of this review.

Table 1.

Terms used for PubMed and ClinicalTrials.gov search.

mTOR pathway	MAPK pathway	Aurora kinase pathway	General/Other STK
mTOR inhibitor	MAPK inhibitor	Aurora kinase inhibitor	STK inhibitor
mammalian target of rapamycin inhibitor	mitogen-activated protein kinase inhibitor	Alisertib	serine-threonine kinase inhibitor
PI3K inhibitor	mitogen-activated protein kinase kinase inhibitor	AMG-900	Enzastaurin hydrochloride
AKT inhibitor	MEK inhibitor	Barasertib	Novonex
protein kinase B inhibitor	Raf inhibitor	Chiauranib	PF-06873600
phosphatidylinositol 3-kinase inhibitor	Binimetinib	Danusertib	Seliciclib
Afuresertib	Cobimetinib	Hesperadin	Thioureidobutyronitrile
Alpelisib	Cometinib	NMI-900	Vosaroxin
Apitolisib	Dabrafenib	Tozasertib	VX-970 (M6620)
Buparlisib	Encorafenib
Capivasertib (AZD5363)	ISIS 5132
CC-223	LTT462
Copanlisib	LXH254
Dactolisib	LYN00101
Everolimus	Pimasertib
Fimepinostat	Ralimetinib
Gedatolisib	Refametinib
GSK2636771	Regorafenib
Idelalisib	Selumetinib
Ipatasertib	Sorafenib
LYN00101	Trametinib
Metformin	Ulixertinib
Miltefosine	Vemurafenib
Miransertib
MK-2206
Perifosine
Pictilisib
Ridaforolimus
Sapanisertib
Silmitasertib
Taselisib
Temsirolimus
Triciribine
Uprosertib
Vistusertib
Voxtalisib

STK: serine-threonine kinase; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinase B; mTOR: mammalian target of rapamycin; MEK: mitogen-activated protein kinase kinase; MAPK: mitogen-activated protein kinase.

Scientific interest in STK inhibitors for ovarian cancer treatment has increased in recent years (Figure 1). Our previous systematic review of the data available for STK inhibitors in recurrent ovarian cancer showed limited efficacy and modest clinical benefit of these drugs for platinum-resistant recurrent ovarian cancer [20]. The median response rate was 8.4%, with a median progression-free survival of 3.4 months and a clinical benefit rate of 57.6%. However, specific patient populations derived greater clinical benefits that may be related to the histology and molecular features of their tumors [20].

Figure 1.

PubMed results for STK terms.

5. Scientific rationale

STKs comprise the majority of the human kinome [19] and play a role in a myriad of cellular processes. Genomic and epigenomic alterations in these pathways are among the most commonly encountered in ovarian and other cancers [20,21,57], rendering them attractive therapeutic targets. Alterations in cancer-driving STKs that have been previously characterized [58] can be found in at least 24% of the ovarian cancers [59,60] (Figure 2). STKs implicated as cancer-drivers include those critical to signaling pathways such as the MAPK (mitogen-activated protein kinase) and the related RAS-RAF-MEK-ERK/JNK (rat sarcoma oncogene/rapidly accelerated fibrosarcoma kinase/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase/c-Jun N-terminal kinase) pathways, in addition to the PI3K-AKT-mTOR (phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin) pathway [58]. These pathways regulate cell growth and arrest, proliferation, differentiation, survival, and apoptosis [20]. Aurora kinases and cyclin-dependent kinases (CDK), which regulate the cell cycle, are also targeted in ovarian cancer, as are the ataxia telangiectasia and Rad3-related (ATR) kinase, involved in the DNA damage response system [58,61,62].

Figure 2.

Genomic alterations in STK pathways.

Molecular profiles differ in each histologic ovarian cancer subtype. The PI3K-AKT-mTOR pathway is commonly altered in endometrioid (69.9%) and clear cell (59.6%) subtypes but is less often affected in high-grade serous carcinoma (24.7%) [59,60] (Figure 2). The RAS-RAF-MEK-ERK/JNK pathway is mutated in 78% of the mucinous ovarian carcinomas and 42% of low-grade serous ovarian carcinomas, in comparison with 13% of high-grade serous ovarian cancers [59,60] (Figure 2). These differences may partially explain disparate clinical responses to treatment [20,63,64] and underscore the importance of exploring STK inhibitor efficacy in the context of tumor profiling.

Preclinical data support the targeting of STKs in ovarian cancer [65–67] and clinical efficacy in other cancers lends further impetus to exploring their activity in ovarian cancer. FDA-approved STK inhibitors include cyclin-dependent kinase (CDK) 4/6 inhibitors for breast cancer, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors for melanoma, BRAF inhibitors for BRAF V600 mutated cancers, and mTOR inhibitors for breast and other cancers [68]. FDA-approved multi-kinase inhibitors, with activity against STKs and tyrosine kinases, have shown activity in ovarian cancer [69,70].

6. Competitive environment: a review of drugs in phase II & III development

Out of over 60 compounds with proposed STK inhibition activity (Table 1), nine drugs were found to have data confirming their current development in phase II or III clinical trials for ovarian cancer (Table 2). Only one compound (Trametinib) is being evaluated as monotherapy, for the less common ovarian cancer subtype of low-grade serous carcinoma. Other STK inhibitors are being evaluated in combination with chemotherapy, PARP inhibitors, anti-angiogenesis agents, immunotherapy and/or endocrine therapy. Out of 18 trials reported on ClinicalTrials.gov for these compounds (Table 3), 12 did not have a trial comparison arm without the STK under evaluation. Only one phase III trial was found.

Table 2.

Competitive environment characteristics of drugs with confirmed phase II/III activity for ovarian cancer are described in the table.

Compound	Company	Structure	Regimens	Indications	Molecular inclusion criteria	Stage of development	Mechanism of action
Afuresertib	Laekna	CN1C(= C(C = N1)Cl)C2 = C(SC(= C2)C(= 0) NC(CC3 = CC(= CC = C3)F)CN) Cl	Induction with Carboplatin (C) and Paclitaxel (C), followed by monotherapy maintenance	Recurrent, platinum resistant or refractory	Not specified	Phase II	AKT inhibitor
Alisertib	Takeda	COC1 = C(C(= CC = C1)F)C2 = NCC3 = CN = C (N = C3C4 = C2C = C(C = C4)Cl) NC5 = CC(= C (C = C5)C(= O)O)OC	Combination with Paclitaxel (C)	Recurrent, platinum sensitive, resistant or refractory	Not specified	Phase II	Aurora Kinase A inhibitor
Alpelisib	Novartis	CC1 = C(SC(= N1)NC(= O) N2CCCC2C(= O) N)C3 = CC(= NC = C3)C(C)(C) C(F)(F)F	Combination with Olaparib (P)	Recurrent	PIK3CA altered; BRCA1/2 mutated and wild type	Phase II	PIK3CA inhibitor
Chiauranib	Shenzhen Chipscreen Biosciences	O = C(C1 = C2C = CC(OC3 = CC = NC4 = CC (OC) = CC = C43) = CC2 = CC = C1)NC5 = CC = CC = C5N	Combination with Paclitaxel (C) or Etoposide (C)	Recurrent, platinum sensitive, resistant or refractory	Not specified	Phase II	Multi-kinase inhibitor, with activity against Aurora kinase B
Cobimetinib	Roche	C1CCNC(C1)C2(CN(C2)C(= O)C3 = C (C(= C(C = C3)F)F)NC4 = C(C = C(C = C4)I)F)O	Combination with Niraparib (P) with or without Atezolizumab (I); Combination with Bevacizumab (A) and Atezolizumab (I)	Recurrent, platinum sensitive, resistant or refractory	C1 mesenchymal molecular subtype	Phase II	MEK1/2
PF-068730600	Pfizer	O = C1C(C(F)F) = CC2 = CN = C (NC3CCN(S(= O)(C) = O)CC3) N = C2N1[C@H]4[C@](C)(O) CCC4	Monotherapy or combination with endocrine therapy (E)	Recurrent, platinum resistant	Not specified	Phase II	CDK inhibitor
Trametinib	Novartis	CC1 = C2C(= C(N(C1 = O)C)NC3 = C (C = C(C = C3)I)F)C(= O)N(C(= O)N2C4 = CC (= CC = C4)NC(= O)C)C5CC5	Monotherapy	Recurrent, low grade serous carcinoma	RAS or BRAF mutant	Phase II/III	MEK1/2 inhibitor
Triciribine phosphate	Prescient Therapeutics	CN1C2 = NC = NC3 = C2C(= CN3C4C (C(C(O4)COP(= O)(O)O)O)O)C(= N1)N	Combination with Carboplatin (C)	Recurrent, platinum resistant	Not specified	Phase II	AKT inhibitor
M6620	Merck	NC1 = NC = C(C2 = CC = C(S(= O) (C(C)C) = O)C = C2)N = C1C3 = CC(C4 = CC = C (CNC)C = C4) = NO3	Combination with Carboplatin (C) and Gemcitabine (C); combination with Gemcitabine (C); combination with Carboplatin (C) and Avelumab (I)	Recurrent, platinum sensitive or resistant; Recurrent, platinum sensitive progressing after maintenance PARP innhibitor	BRCA1/2	Phase II	ATR inhibitor

C: chemotherapy agent; P: PARP inhibitor; I: immunotherapy; A: anti-angiogenesis agent; AKT: protein kinase B; PIK3CA: phosphatidylinositol 3-kinase subunit alpha; MEK: mitogen-activated protein kinase kinase; CDK: cyclin-dependent kinase; PI3K: phosphatidylinositol 3-kinase; mTOR: mammalian target of rapamycin; ATR: ataxia telangiectasia and Rad3-related protein kinase

Table 3.

Clinical trials of STK inhibitors in active development for ovarian cancer active and completed clinical trials for drugs discussed in this review.

Drug	NCT ID	PMID	Phase	Country	Start date	Status	No.	Results on ClinicalTrials.gov	Condition	Interventions
mTOR pathway
afuresertib	NCT01653912	30,563,934	Phase I/II	Australia, Russia, UK	11/2012	Completed (11/2015)	59	4/2/2018	recurrent platinum-resistant	afuresertib + TC
alpelisib	NCT01623349	30,880,072	Phase I	USA	9/2012	Active not recruiting	118	none	recurrent	alpelisib + olaparib
alpelisib	NCT01708161	none	Phase I/II	Canada, Spain, USA	11/2012	Terminated	47	6/28/2018	advanced disease	alpelisib + ganitumab
triciribine	NCT01690468	none	Phase I/II	USA	9/2019	Recruiting	36	none	recurrent or persistent platinum-resistant	tricribine+ C
MAPK Pathway
cobimetinib	NCT03695380	none	Phase I	Multiple countriesa	11/2018	Recruiting	70	none	high grade serous/endometrioid; platinum-sensitive	Cobimetinib+ niraparib + atezolizumab
cobimetinib	NCT03363867	none	Phase II	Australia	7/2018	Recruiting	29	none	high grade serous; platinum-resistant or -refractory	cobimetinib+ bevacizumab+ atezolizumab
trametinib	NCT02101788	none	Phase II/III	UK, USA	2/2014	Active not recruiting	260	none	low-grade serous; recurrent or progressive	Trametinib vs. single-agent chemotherapy or ET
trametinib	NCT01155453	25,500,057	Phase I	Multiple countriesb	4/2010	Completed (11/2014)	113	none	RAS- or BRAF-mutant; advanced disease	trametinib+ buparlisib
Aurora kinase pathway
alisertib	NCT00853307	22,772,063	Phase II	France, Poland, USA	3/2009	Completed (11/2011)	31	3/27/2018	platinum-resistant or –- refractory	alisertib
alisertib	NCT02367352	none	Phase I	Korea, Japan	3/2015	Terminated	9	5/2/2019	East Asian ethnicity; relapsed or refractory	alisertib+T
alisertib	NCT01091428	30,347,019	Phase II	USA	4/2010	Completed (7/2017)	191	6/4/2018	progressive or recurrent	alisertib+T vs. T
chiauranib	NCT03166891	none	Phase I/II	China	12/2017	Active not recruiting	30	none	progressive or recurrent	chiauranib
chiauranib	NCT03901118	none	Phase II	China	6/2019	Not yet recruiting	40	none	platinum-resistant or -refractory	chiauranib + etoposide or T
General/Other STK
PF-06873600	NCT03519178	none	Phase I/II	USA	3/2018	Recruiting	220	none	advanced platinum-resistant	PF-06873600 + ET
M6620	NCT03704467	none	Phase II	Belgium, UK, USA	3/2019	Recruiting	81	none	recurrent, platinum-sensitive, PARPi-resistant	M6620 + C + avelumab vs. dual agent chemotherapy
M6620	NCT02595892	none	Phase II	USA	8/2016	Active, not recruiting	70	none	high grade serous; platinum-resistant	M6620 + G vs. G
M6620	NCT02627443	none	Phase I/II	USA	11/2016	Suspended	111	none	high grade serous; platinum-sensitive	M6620+ CG vs. CG
M6620	NCT02487095	none	Phase I/II	USA	6/2015	Recruiting	70	none	any	M6620, topotecan

NCT ID:ClinicalTrials.gov identifier; PMID: PubMed identification number; No.: number of patients enrolled; CG: carboplatin/gemcitabine; T: palcitaxel; C: carboplatin, G: gemcitabine; TC: paclitaxel/carboplatin; ET: endocrine therapy; PARPi: Poly ADP-ribose polymerase inhibitor

^aFrance, Italy, Spain, USA

^bBelgium, Canada, Spain, Switzerland, USA

Five trials had peer-reviewed published data available (Table 4), with two phase I trials. Only one trial with published results had a comparison arm consistent with current practice [71]. Figure 3 graphically represents the response rates and clinical benefit rates of the drugs in development presented below.

Table 4.

Published clinical trial for STK inhibitors in active development Efficacy and safety results for published trials (n = 5) are summarized.

Drug	NCT ID	PMID	Phase	Condition	Interventions	No.	CR n (%)	PR n (%)	SD n (%)	CA-125 ORR n (%)	PFS (mos.)	OS (mos.)	Grade 3 or 4 AE n (%)	AE leading to DC n (%)
afuresertib	01653912	30,563,934	I/II	platinum-resistant	afuresertib + TC	59	2 [3]	14 [24]	24 [41]	23 [39]	7.1*	NA	45 [76]	34 [58]
alisertib	00853307	22,772,063	II	platinum-resistant	alisertib	31	0	2 [6]	16 [52]	3 [10]	2.6#	NA	24 [77]	4 [13]
											1.2$
alisertib	01091428	30,347,019	II	recurrent platinum-sensitive or platinum- resistant/refractory	alisertib + T vs. T	73	7 [10]	23 [32]	25 [34]	40 [55]	6.7	NA	67 [92]	NA
alpelisib	01623349	30,880,072	I	recurrent, platinum-resistant with mut or WT BRCA	alpelisib + olaparib	28	0	10 [36]	14 [50]	NA	7.2	21.3	NA	3 [11]
trametinib	01155453	25,500,057	I	KRAS/BRAF mutated, low grade serous	trametinib + buparlisib	21	1 [5]	5 [24]	10 [48]	NA	7	not reached	NA	NA

NCT ID:ClinicalTrials.gov identifier; PMID: PubMed identification number; No. number of patients enrolled; CR: complete response; PR: partial response; SD: stable disease; ORR: overall response rate; PFS: progression-free survival; OS: overall survival; AE: adverse events; DC: discontinuation; TC: paclitaxel/carboplatin; T: paclitaxel; NA: not applicable

^*in expansion cohort, n = 30

^#platinum-resistant

^$platinum-refractory

Figure 3.

Published efficacy of emerging STK inhibitors for ovarian cancer.

6.1. Afuresertib

Afuresertib inhibits all three AKT isoforms. AKT is a key effector in the PI3K-AKT-mTOR pathway. AKT isoforms interact with mTOR and mTORC1 to promote cell growth, survival and angiogenesis [21,58]. Preclinical evidence suggests that AKT inhibition may restore platinum sensitivity in platinum-resistant ovarian cancer [72]. Afuresertib was evaluated in combination with carboplatin and paclitaxel, followed by afuresertib maintenance in a phase I/II trial for recurrent, predominantly platinum-resistant ovarian cancer [73]. Response rate for the single-arm expansion cohort (n = 30) of afuresertib plus double-agent chemotherapy was reported as 32%, which was below the hypothesized 40% response rate. Recruitment of patients with the platinum-refractory disease was stopped early because of slow accrual rate. PFS was 7.1 months and overall survival was not reported. However, the clinical benefit rate (rate of overall response and stable disease) was 71%. Over 70% of the patients had grade 3/4 AEs, and 17% discontinued the treatment regimen because of adverse events [73]. These side effects included rash, diarrhea, dyspepsia, and hyperglycemia and likely represent an additive effect to chemotherapy, as monotherapy with afureseritib was associated with a better toxicity profile in patients with hematologic malignancies [74] No molecular data were reported to support future patient selection for this STK inhibitor. Afuresertib has not yet proven an added clinical benefit to chemotherapy, nor an acceptable toxicity profile for the potential benefit that it provides when added to chemotherapy.

6.2. Alisertib

Alisertib is an Aurora Kinase A inhibitor. Aurora Kinase A plays an important role in cell cycle regulation by virtue of its role in the formation of the mitotic spindle which is necessary for accurate chromosomal segregation during mitosis [75,76]. Preclinically, alisertib has been shown to down-regulate PARP and BRCA1/2 and stimulate error-prone DNA repair [77]. Alisertib has been studied in combination with other drugs that inhibit DNA repair to induce synthetic lethality of ovarian cancer cells [78]. It has been known to have modest single-agent activity in platinum-resistant/refractory ovarian cancer (8% with partial response and 52%with disease stability), albeit with a significant toxicity profile [79]. Toxicities were thought to be related to cell cycle arrest [79] and grade 3/4 adverse events were reported in over 70% of the patients with a dose of 50mgdaily. However, clinical benefit may be obtained at a dose of 40 mg twice daily in combination with dose-reduced weekly paclitaxel (60 mg/m²). Alisertib and full dose paclitaxel (80 mg/m²) were not well tolerated and the maximally tolerated regimen was associated with approximately 80% grade 3/4 adverse events, including neutropenia, stomatitis, diarrhea, alopecia, and anemia [71,79]. Compared with full dose paclitaxel, alisertib with dose-reduced paclitaxel resulted in a non-significant PFS benefit that was worthy of further investigation based on pre-specified criteria, but no difference in response rate (PFS 6.7 vs 4.7 months, p = 0.14, overall response rate 48% vs 37%, p = 0.28). No overall survival data are available for this trial and quality of life was not changed with the addition of alisertib [71]. An additional trial demonstrated increased toxicities when alisertib was given with another taxane, docetaxel, requiring dose reductions of either alisertib or docetaxel to ensure tolerance of alisertib [80]. Alisertib is also being evaluated for the treatment of other solid and hematologic malignancies [81]. Despite initial encouraging results in peripheral T-cell lymphoma, a phase 3 trial was halted early because of the lack of benefit from alisertib as monotherapy [82].

A functional single nucleotide polymorphism has been proposed to predict response to alisertib [83], and these data can potentially be used for future patient selection. Pharmacokinetics of alisertib in the East Asian population may differ from those in predominantly white populations [84], and a study among this population was terminated prematurely (NCT02367352). Alisertib is one of the few STK inhibitors that has been compared in a combination regimen against a regimen used in the current practice and has shown encouraging preliminary results. However, its development is complicated by variable pharmacokinetics and a significant toxicity profile requiring dose reductions of alisertib or chemotherapy.

6.3. Alpelisib

Alpelisib is a PIK3CA inhibitor which is approved for certain PIK3CA-mutated breast cancer patients. PIK3CA transduces signals from cell membrane-bound receptors to downstream effectors of the PI3K-AKT-mTOR pathway by generating phospholipids [21] that recruit and activate AKT and other proteins. Preclinical work has suggested that alpelisib may induce an HRD phenotype in ovarian cancer, thus sensitizing tumors with proficient homologous recombination to PARP inhibition [85]. Results from a phase Ib clinical trial tested this hypothesis among a predominantly platinum-resistant ovarian cancer cohort. This trial included extensive preclinical and translational work. Subgroup analyses and comparison with historical cohorts suggested a potential benefit of the combination of olaparib with alpelisib for BRCA1/2 wild type, platinum-resistant ovarian cancer with a partial response rate of 36% and a 50% rate of disease stability (n = 34), with the conclusion that further studies are warranted. The combination had an acceptable toxicity profile with hyperglycemia being the most relevant added toxicity of alpelisib to PARP inhibition [85]. Alpelisib lacked the CNS toxicity caused by the pan-PI3K inhibitor buparlisib [86]. Alpelisib has an acceptable toxicity profile when added to PARP inhibitors, but confirmatory studies are needed to demonstrate its efficacy.

6.4. Chiauranib

Chiauranib is a multi-kinase inhibitor with activity against Aurora kinase B, which plays a role in the formation of the mitotic spindle during cell division; angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα, and c-Kit); and chronic inflammation-related kinase CSF-1R [87,88]. Common adverse events as a single agent include proteinuria, hematuria, hypothyroidism, hypertriglyceridemia, and hypertension [87]. Limited data is available regarding chiarunib. Preclinical data were first published in 2017; no safety or efficacy in ovarian cancer or regarding the combination of chiarunib with chemotherapy has been reported, and the development of chiauranib seems limited to China.

6.5. Cobimetinib

Cobimetinib is a MEK1/2 inhibitor that is approved, in combination with a BRAF inhibitor, for the treatment of certain BRAF mutated melanomas. MEK1/2 are components of the RAS-RAF-MEK-ERK/JNK pathway, which has many functions, including proliferation, survival, and differentiation of cells [58]. It has been extensively studied in melanoma but data in ovarian cancer is limited. Preclinical data suggest that a combination with other agents is necessary to achieve an anti-tumor activity in ovarian cancer [67]. Cobimetinib is being studied in combination with immunotherapy, anti-angiogenesis agents, and PARP inhibitors for ovarian cancer [89]. These trials are not expected to end until 2022/2023 and it may be difficult to discern the benefit of cobimetinib from the benefit of other agents in these combination regimens. Cobimetinib may be more active in RAS-RAF-MEK-ERK/JNK dysregulated ovarian cancers although its combination with immunotherapy has suggested activity regardless of KRAS/BRAF status [90]. Cobimetinib has a known and acceptable toxicity profile including dermatologic, gastrointestinal and retinal effects. Potential cardiac toxicity has been a concern but is rare [91,92].

6.6. PF-06873600

PF-06873600 is a CDK inhibitor with significant activity against CDK2, in addition to CDK4/6. CDK2 is involved in the regulation of the cell cycle and associated DNA-repair pathways [93]. The CDK2 pathway is associated with platinum and PARP inhibitor-resistant ovarian cancer, possibly involving co-alteration of the PI3K–AKT–mTOR pathway [62,65]. There is no available data regarding the safety or efficacy of this agent in any setting; an ongoing phase I/II trial is evaluating this drug with or without endocrine therapy for platinum-resistant/refractory ovarian cancer.

6.7. Trametinib

Trametinib is an extensively characterized MEK1/2 inhibitor, approved for the treatment of certain BRAF V600 mutated melanoma and NSCLC. It is commonly combined with dabrafenib, a BRAF inhibitor [94]. Trametinib has been evaluated in combination with a PI3K inhibitor, buparlisib, in a predominantly KRAS mutated ovarian cancer cohort with predominantly well-differentiated histology, demonstrating encouraging activity (76% disease control rate, 29% overall response rate with one complete response, and PFS 7 months; n = 21). Significant dose-limiting toxicity was noted in the overall cohort, with grade 3/4 adverse events occurring in over 65% of the patients and dose modifications or interruptions in 70% of the patients [95]. Molecular events were evaluated in this trial including specific KRAS, and PTEN, and PIK3CA mutations but the interpretation of these data was limited by sample size [95]. Anecdotal reports of encouraging response to trametinib with specific somatic alterations have also been reported [96–98]. Results of a trial of 260 patients with low-grade serous ovarian cancer (NCT02101788), often enriched with RAS-RAF-MEK-ERK/JNK alterations (Figure 2), were recently presented [99]. This Phase II/III trial evaluated trametinib monotherapy vs other standard of care agents, representing a very advanced stage of development for this indication. PFS was significantly improved with trametinib (13 vs 7.2 months) as was overall response rate (26.2% vs 6.2%) and duration of response (13.6 vs 5.9 months). Quality of life with trametinib was unchanged and overall survival was not statistically significantly different (37 vs 29.2 months) at a median follow up of 31.4 months. This trial may lead to the approval of trametininb for low-grade ovarian cancer. Though the low-grade serous subtype represents a minority of ovarian cancer patients, it lacks effective targeted treatment options. There were no active trials found of trametinib for unselected or high-grade ovarian cancer.

6.8. Triciribine

Triciribine is an AKT inhibitor being evaluated in combination with carboplatin for platinum-resistant recurrent or persistent ovarian cancer in one single-center, single-arm trial, at an early stage of development. This trial was initiated in 2014 and continues to recruit patients with a modified enrollment target of less than 40 patients, suggesting possible difficulties to recruit patients to this study. Triciribine phosphate is suggested to have a favorable tolerability profile as monotherapy [100].

6.9. M6620

M6620 is a first-in-class ataxia telangiectasia and Rad3-related (ATR) inhibitor. ATR has a major role in the DNA damage response system and its activity is related to BRCA1/2 and other genes that are commonly mutated in ovarian cancer, including p53, ARID1A, and ATM [61,101]. Inhibition of ATR is expected to induce synthetic lethality and its combination with platinum chemotherapy, topotecan and PARP inhibitors are being explored in ovarian and other cancers [61,101]. M6620 has shown an acceptable toxicity profile; data related to efficacy in ovarian cancer are limited and have anecdotally been reported as part of combination regimens [102,103]. A trial (NCT02627443) evaluating the added benefit of M6620 over standard combination gemcitabine and cisplatin for platinum-sensitive patients was suspended but results are not available. Results from a trial (NCT02595892) evaluating the added benefit of M6620 to gemcitabine in recurrent platinum-resistant disease have been presented in abstract form and suggest improvement in PFS; full results and overall survival data are awaited. PARP inhibitor-resistant ovarian cancer is being targeted with combination M6620, avelumab, and carboplatin. This combination will be compared with dualagent chemotherapy, but even if it is successful, further studies may be needed to clarify the importance of M6620 for the success of this combination. While the preclinical and safety data for M6620 are encouraging, further trials confirming its benefit in ovarian cancer are awaited.

7. Potential development issues

Though STKs comprise the majority of the human kinome, targeting their hyperactivation in ovarian cancer has been challenging [20]. Multikinase inhibitors with activity against STKs and tyrosine kinases, such as sorafenib, have been hypothesized to exert their effect mainly through tyrosine kinase inhibition [69,70].

Most of the STK inhibitors included in this review have not been tested in large, randomized phase III clinical trials and have not been compared to approved therapies in ongoing or completed clinical trials. As single agents, they have shown limited activity and are now largely being evaluated in combination regimens. Further trials will be needed to evaluate the benefit of adding these STK inhibitors to standard or novel treatments for recurrent ovarian cancer. None of the STK inhibitors included have shown an overall survival benefit or an improvement of quality of life. Future trials will need to balance progression-free-survival benefit with toxicity, quality of life and health-care expenses.

Because most STK inhibitors reviewed are now being evaluated as part of novel combination regimens, challenges may arise when trying to demonstrate their incremental benefit beyond other drugs in said combination regimens. The toxicity profile of individual drugs may vary or intensify when combined with other agents with similar adverse events, as has been shown with alisertib [71,79] and other compounds [104]. Some of the STK inhibitors, such as trametinib, are only being evaluated in uncommon subsets of ovarian cancer patients, limiting generalizability.

More convincing benefit has been suggested with STK inhibitors tested in ovarian cancers with specific molecular alterations, such as KRAS/BRAF mutated cancer and low-grade serous carcinomas [20,96–98,105]. However, most studies performed thus far lacked genomic and transcriptomic tumor profiling that would be sufficient to effectively guide patient selection. Further mechanistic studies are needed to clarify mechanisms of susceptibility and resistance to STK inhibitors.

Multiple STKs with similar mechanisms of action, such as PI3K inhibitors, have been trialled without success [106], and pre-clinical research has not generated sufficient data to predict response to these agents or prevent their toxicity as the accuracy of preclinical characterization of on-target and off-target effects is questionable [107]. Further preclinical and clinical research are needed to improve efficacy, specificity and tolerability of STK inhibitors.

Limited diversity of clinical trial patient population may also pose challenges to the development of STK inhibitors. The majority of clinical trial participants are white and reports of differing tolerated doses of alisertib among different ethnicities [84] raise the possibility that validation of pharmacokinetics may be required prior to obtaining regulatory approval. Similarly, confirmatory trials for drugs that are being developed only outside of the USA, such as chiauranib, may be required for approval in the USA and/or Europe.

8. Conclusion

The STK inhibitors discussed in this review demonstrate limited clinical benefits as single agents despite targeting commonly altered pathways in cancer. However, there have been some promising recent developments including the combination of afuresertib with platinum and paclitaxel, with a 32% response rate in platinum-resistant patients, and alpelisib and olaparib with a 36% response rate in platinum-resistant patients. Trametinib in combination with PI3K inhibitor, buparlisib, has also shown promise in a specific population with well-differentiated, KRAS-mutated ovarian carcinoma with response rate 29% including one patient with a complete response. Given response rates in these small, non-randomized studies, have been on par with, and sometimes higher than the typical response rates for the platinum-resistant disease, these combinations certainly warrant further investigation, including comparison with currently approved therapies. Furthermore, we anticipate the results of the remaining ongoing trials outlined in this manuscript and additional compounds that are beyond the scope of the current manuscript.

9. Expert opinion

This review summarizes the available data for a limited number of STK inhibitors that were included based on their advanced clinical development stage for the treatment of ovarian cancer. The main pathways targeted by these drugs include the PI3K-AKT-mTOR, the RAS-RAF-MEK, and the Aurora kinase pathways. The majority of the STK kinome has not been clinically targeted in ovarian cancer, and basic research continues to identify potential targetable STKs, such as those involved in DNA repair [108,109], including WEE1, CHK1, CHK2, and others. STK inhibitors reviewed here and previously [20] have yet to show a clear benefit in patient-centered outcomes of improving quality of life or overall survival, despite encouraging preclinical data. This suggests that oncogene addiction may not occur with these STKs and that intrinsic and acquired resistance to their inhibition is common. For such agents to be effective in multiple settings, primary, the recurrent and metastatic disease would need to demonstrate the same oncogenic pathway addiction.

The utility of STK inhibitors in ovarian cancer may lie in combination regimens, specifically in those designed or expected to have a molecular synergy that augments the efficacy of a second agent, and/or when the regimen targets a select population with specific histologies and somatic mutations.

Due to progressive chemoresistance, the main goal of therapy in this population is currently disease stability. Regression of disease is considered an added benefit but is the exception to the rule. Response rates of 32% and 36% (for the combinations of afuresertib with carboplatin and paclitaxel and for alpelisib with olaparib, respectively) are, in reality, quite high. These studies also noted clinical benefit rates of 71% and 86%, respectively, meaning that the majority of patients may derive benefit from these regimens. Because this datum has mostly been derived from small, phase I trials, further investigation in larger phase II and III trials, with randomized comparison to standard therapy should be pursued before drawing conclusions on the utility of these therapies.

The disease control rates using afuresertib with carboplatin and paclitaxel to induce platinum sensitivity did suggest efficacy, with a response rate of 30% and a clinical benefit rate of 71%. However, in platinum-resistant disease where complete remissions are exceedingly rare, clinicians should be wary of using multi-agent regimens, especially with three or more drugs, due to the potential for high toxicity with limited clinical benefit. Given the incurable nature of platinum-resistant ovarian carcinoma, treatment toxicities and maintaining quality of life are also of paramount concern. Given that few therapies impact overall survival, the toxicities of treatment must not outweigh those of the disease itself.

For those with low-grade carcinomas and KRAS/BRAF mutations, trametinib as monotherapy or in combination with mTOR pathway inhibitors has had encouraging outcomes. Low-grade ovarian carcinoma remains notoriously chemoresistant, even in the upfront setting.

Patient selection and companion diagnostics are needed in order to maximize clinical benefit, as has recently been demonstrated by the efficacy of alpelisib (a PI3Kα inhibitor) plus fulvesterant in PIK3CA-mutated breast cancer, and combination binimetinib (a MEK inhibitor), encorafenib (BRAF inhibitor) and cetuximab in BRAF V600 mutated colorectal cancer [63,64]. A phase III trial of binimetinib vs physician-choice chemotherapy in low-grade serous carcinoma did not meet its primary endpoint [110]. However, the encouraging results obtained with trametinib and post-hoc analyses that may improve patient selection may lead to additional studies of binimetinib.

Aside from PARP inhibitors, however, few ovarian cancer drugs targeting specific molecular pathways have demonstrated significant efficacy. Somatic testing for genetic alterations has become commonplace as well, with testing sometimes suggesting relevant clinical trials or off-label therapies. More often than not, though, the information gleaned from this testing is not clinically useful in the setting of ovarian cancer. Because STK inhibitors impact multiple metabolic pathways, however, these drugs are often implicated in such testing. The recently published WINTHER trial has suggested the relevance of STK inhibitors based on tumor molecular profiling; in fact, STK inhibitors were among the most common drugs prescribed based on tumor DNA profiling [111].

The PI3K-AKT-mTOR pathway is frequently altered in endometrioid and clear cell histologies, and these may be more attractive for this type of inhibition. Low-grade serous and endometrioid carcinomas more often harbor RAS-RAF-MEK-ERK/JNK pathway alterations. Thus, trials of STK inhibitors should correlate responses to somatic alterations and histologic subtypes whenever possible. Given the successful development of targeted therapies in other cancers, we continue to search and anticipate identifying additional relative predictive markers that may offer promise in this broad class of medications.