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INNOSC Theranostics and
Pharmacological Sciences Precision medicine and beyond in oncology

analyze differences in their drug profiles and how these such as anemia, are conveniently managed with dose
relate to patient characteristics and medical history. modifications. 109
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For example, sotorasib was observed to be associated In contrast, olaparib carries a higher risk than talazoparib
with significantly lower rates of gastrointestinal adverse in terms of drug–drug interactions, as it is primarily
effects such as diarrhea and nausea (around 40% and 55% metabolized by cytochrome P450; thus, it is less preferred
lower prevalence of each, respectively), when compared as an option in patients taking multiple medications. In
to adagrasib. Hepatotoxicity with increased alanine addition, the recommended oral dosage of talazoparib
aminotransferase levels was also found to be associated (1 mg) is lower than olaparib (300 mg) and is taken only
more with adagrasib use than sotorasib, suggesting once daily, whereas olaparib is often prescribed to be taken
that sotorasib is a better option in patients with prior twice a day. In different trials observing drug efficacy, the
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gastrointestinal or liver-related health issues. For example, EMBRACA trial (for talazoparib) determined a slightly
the prevalence of diarrhea and nausea associated with longer median PFS than the OlympiAD trial (for olaparib)
adagrasib (70.7% and 69.8%, respectively) was higher than in similar patient populations. However, in terms of
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in sotorasib (34% and 14%). Moreover, the overall Grade 3
adverse effects were 89.1% with adagrasib and 20% with safety profiles, olaparib has less severe adverse effects, but
sotorasib. In addition, although adagrasib was found to with more gastrointestinal changes like vomiting, whereas
have a slightly higher therapeutic efficacy in sustaining talazoparib is associated with hematological toxicity,
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cancer control, most studies suggested similar efficacies including more severe forms of anemia and neutropenia.
between the two drugs. The choice between them often Overall, both olaparib and talazoparib are being studied and
hinges on patient group-specific considerations regarding have so far been determined to be effective PARP inhibitor
adverse effects profiles. Importantly, the efficacy of both therapies for BRCA 1/2-mutated cancers, with carefully
drugs overall was partially dependent on wild-type RAS monitored dose management and symptom monitoring.
feedback reactivation induced by Src homology-2 domain- 4.5. TME
containing protein tyrosine phosphatase-2, known to be
the primary resistance mechanism of KRAS inhibitors. 106 TME plays a pivotal role in tumor progression, therapeutic
resistance, and immune evasion. Composed of immune
4.4. Poly(ADP-ribose) polymerase inhibitors in PDAC cells, stromal components, vasculature, signaling
In cancers with BRCA mutations, including some pancreatic molecules, and extracellular matrix, the TME interacts
adenocarcinomas, poly-ADP-ribose polymerase (PARP) dynamically with tumor cells to influence treatment
inhibitors such as olaparib and talazoparib are being outcomes. As a result, strategies aimed at remodeling
investigated as potentially effective therapies. Olaparib the TME have emerged as a critical complement to
(Lynparza®) was studied in Phase II trials with results conventional and targeted therapies.
suggesting a well-tolerated response in patients with long- 4.5.1. Modulating the TME through immunogenic
standing ovarian, breast, pancreatic, and prostate cancers, vaccines
with a significant efficacy (about a 26.2% tumor response
rate overall) in genetically targeting PARP enzymes One of the primary approaches to overcoming TME-
in BRCA 1/2-mutated circumstances. Upon further associated immunosuppression is the use of cancer
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investigation of DNA damage repair genes in trials with vaccines in combination with ICIs.
olaparib, cross-resistance with platinum analogues was Vaccines can also be combined with ICI to potentiate
identified. However, after modifying the study accordingly, their efficacy. For instance, combining the alpha-
the drug was ultimately determined to be consistent in fetoprotein vaccine with ICIs has been shown to elicit
its efficacy, supported by parallel studies in Israel and the strong CD8 cytotoxic T-cell responses and hinder
+
United States, with only minor expected toxic effects such HCC progression in pre-clinical models. Interestingly,
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as anemia, fatigue, anorexia, and nausea. 108 engineered oncolytic viruses capable of inducing
Another PARP inhibitor of newfound importance hyperacute rejection were administered in 20 patients
in cancers with BRCA 1/2 mutations is talazoparib with refractory cancer and reached a 90% response
(Talzenna®), with a significant improvement in PFS without any Grade 4 adverse event. Neoantigen-based
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and efficacy compared to other chemotherapies. The vaccines, personalized formulations derived from somatic
results of the recent controlled Phase 3 EMBRACA mutations identified through whole-exome or RNA
trial demonstrated a double response rate and 46% risk sequencing, have demonstrated the ability to provoke
reduction for cancer progression or death with talazoparib. highly specific antitumor immunity when combined with
Minor myelotoxicity and hematological complications, ICI therapy. 115

Volume 8 Issue 3 (2025) 47 doi: 10.36922/ITPS025140018