Peptides in oncology: the approved drugs already treating cancer

The strongest proof that peptides are established medicine

When people debate whether peptides "work", the conversation usually centers on GLP-1 or research molecules. The hardest evidence, however, is in oncology: randomized phase 3 trials, survival outcomes and decades of hospital use. The general history of the class is in A hundred years of therapeutic peptides; here we review, with each trial's numbers, where peptides are already part of standard cancer treatment.

Prostate cancer: from leuprolide to degarelix

Leuprolide is a synthetic nonapeptide GnRH analog, with initial U.S. approval in 1985 according to its label². In the 1984 Leuprolide Study Group trial of 199 men with metastatic prostate cancer, objective response was 86% with leuprolide and 85% with diethylstilbestrol; the leuprolide group had less painful gynecomastia, nausea, vomiting and edema, and more hot flashes. The authors judged it therapeutically equivalent with fewer side effects¹.

Goserelin, another GnRH agonist, showed a survival benefit. In Bolla's EORTC trial of 415 patients with locally advanced prostate cancer, adding goserelin to radiotherapy was associated with 5-year overall survival of 79% vs 62% (P = 0.001), and a proportion of disease-free survivors of 85% vs 48%³.

Degarelix is a GnRH antagonist; its label describes it as a "synthetic linear decapeptide amide containing seven unnatural amino acids", with initial U.S. approval in 2008⁴. In its phase 3 trial of 610 patients, on day 3 testosterone was at castrate level (≤ 0.5 ng/mL) in 96.1% and 95.5% of the degarelix groups and in no leuprolide patient; at 1 year, suppression was maintained in 97.2%, 98.3% and 96.4%, respectively⁵.

Neuroendocrine tumors: octreotide and lanreotide

Octreotide is a cyclic octapeptide that mimics somatostatin, with initial U.S. approval in 1988 according to its label⁸. For years it was used to control hormonal symptoms; the PROMID trial tested whether it also slowed the tumor. In 85 patients with metastatic midgut neuroendocrine tumors, median time to progression was 14.3 months with octreotide LAR vs 6 months with placebo (HR 0.34)⁹.

The CLARINET trial did the same with lanreotide, another somatostatin analog, in 204 patients with grade 1 or 2 enteropancreatic tumors. Estimated progression-free survival at 24 months was 65.1% vs 33.0% with placebo (HR 0.47)¹⁰.

Peptides that carry radiation to the tumor: NETTER-1 and VISION

The next step was to use the peptide as a vehicle. 177Lu-dotatate is a radiolabeled somatostatin analog: according to its label, a cyclic peptide linked to a chelator that carries the radionuclide lutetium-177, with initial U.S. approval in 2018¹². In NETTER-1, with 229 patients with midgut neuroendocrine tumors progressing on octreotide, estimated progression-free survival at 20 months was 65.2% vs 10.8% with high-dose octreotide LAR, and the response rate was 18% vs 3%¹¹. It is the clearest clinical example of a peptide-drug conjugate: the peptide provides the aim and the isotope the effect.

In prostate cancer, 177Lu-PSMA-617 applies the same logic against prostate-specific membrane antigen (PSMA). Its chemistry deserves precision: the label defines it as a PSMA-binding ligand¹⁴, and the group that developed it describes it as a peptidomimetic structure synthesized by solid-phase peptide chemistry¹⁵. It is not a natural peptide but a small molecule designed from peptide-like building blocks. In VISION, with 831 men with metastatic castration-resistant prostate cancer, it prolonged imaging-based progression-free survival (median 8.7 vs 3.4 months) and overall survival (15.3 vs 11.3 months, HR 0.62)¹³. Its initial U.S. approval came in 2022¹⁴.

Multiple myeloma: proteasome inhibitors with a peptide backbone

Bortezomib is, according to its label, a "modified dipeptidyl boronic acid", with initial U.S. approval in 2003¹⁶. In the APEX trial of 669 patients with relapsed myeloma, response was 38% vs 18% with high-dose dexamethasone, median time to progression 6.22 vs 3.49 months, and 1-year survival 80% vs 66%¹⁷.

Carfilzomib descends from epoxomicin, a natural product; from it a synthetic tetrapeptide epoxyketone was designed that became the parent of the drug¹⁸. The FDA granted it accelerated approval on July 20, 2012¹⁹. In ASPIRE, with 792 patients, adding carfilzomib to lenalidomide and dexamethasone was associated with median progression-free survival of 26.3 vs 17.6 months (HR 0.69)²⁰.

Peptide vaccines: a real signal, not yet a standard

Peptides are also being studied as vaccines that teach the immune system to recognize the tumor. In a phase 3 trial of 185 patients with HLA-A*0201 advanced melanoma, the gp100 peptide vaccine added to interleukin-2 was associated with a clinical response of 16% vs 6% (P = 0.03) and progression-free survival of 2.2 vs 1.6 months; median overall survival was 17.8 vs 11.1 months, without reaching statistical significance (P = 0.06)²¹. It is a proof of concept, not a standard treatment.

Limits: what this evidence does not say

These are approved drugs, manufactured to pharmaceutical standards and tested in phase 3 trials. Their success shows that peptides are a validated therapeutic class; it does not show that every research peptide has the same efficacy or safety. Each molecule needs its own evidence.

Efficacy also does not mean absence of toxicity. In VISION, grade 3 or higher adverse events were 52.7% vs 38.0%¹³; in APEX, grade 3 or 4 events were 75% vs 60%¹⁷; degarelix caused injection-site reactions in 40% of patients⁵. And, as relugolix shows, a non-peptide molecule can outperform a peptide in the same trial⁷.

What it means for the physician

When a patient or a colleague questions peptides as a category, oncology provides the strongest answer: leuprolide, goserelin, degarelix, octreotide, lanreotide, 177Lu-dotatate and the proteasome inhibitors are part of hospital practice, with trials published in the leading journals^1359101117. Peptides are not a fad: they are a class with decades of use in cancer. For the arguments of peptide supporters beyond oncology, see The other side.