Hello fellow warriors!!

It has been almost a year since I created and started publishing on this site, actually, it will be a year in November 2025, and I wanted to take advantage of a ‘slow’ month like August (at least in the Northern Hemisphere) to take stock of the situation. Over the past year, we have had many new developments concerning both clinical and preclinical research. In this article, I will try to list everything I have talked about during this year as a reminder. But before starting with the list of new drugs and trials (which fortunately is not short at all!), let’s try to understand broadly in which direction we are moving.
We are actually moving quite fast. When I was diagnosed in August 2023 (which, as it turns out, is not always a slow month!), the statistics gave me about a 30% chance of being alive in 5 years. Now, with most doctors using the most advanced androgen receptor signaling inhibitors and various combination therapies that have become the standard of care, that figure is being raised to above 50%.

Remember one thing: in less than a year, I have published articles on about 150 drugs and drug combinations currently in clinical testing. We know that roughly 5% of cancer drugs that enter phase 1 trials successfully complete phase 3. So, if the statistics don’t lie, we can expect at least around 7 new successful drugs hidden on the site (considering this year alone)!

The Direction of Research: A Future of Precision and Synergy

Over the past year, the research landscape for advanced prostate cancer has demonstrated several clear trends, all pointing towards a future of more effective and personalized patient care:

• Precision Targeting: The dominant theme is the development of therapies that precisely target cancer cells while minimizing harm to healthy tissue. This includes Antibody-Drug Conjugates (ADCs), Radioligand Therapies (RLTs), and PROteolysis TArgeting Chimeras (PROTACs). These approaches leverage specific proteins on cancer cells (like PSMA, B7-H3, DLL3, Nectin-4, STEAP1, CD138, AR-V7, FAP, ACP3, ROR1, GRPr, ERG, CD46) to deliver potent agents directly to the tumor. And if my “nose” is right, PSMA won’t remain the king for long!
• Immune System Activation: A significant push is to “wake up” the immune system against prostate cancer, often considered a “cold” tumor. This involves T-cell engagers, oncolytic viruses, and strategies to modulate the tumor microenvironment (TME) to enhance immune responses.
• Overcoming Resistance: A core challenge is how prostate cancer adapts and becomes resistant to therapies. Research is focusing on novel mechanisms of resistance, including AR mutations and splice variants, DNA repair deficiencies (HRR), and other pathways like PI3K/AKT/mTOR, MYC, EZH2, and HSPs. Overcoming resistance is important because it allows us to gain precious time while something better gets developed!
• Neuroendocrine Prostate Cancer (NEPC): There’s a dedicated effort to find treatments for this aggressive, often treatment-induced, variant of prostate cancer, utilizing targets like DLL3, TROP2, and epigenetic regulators.
• Combination Therapies: There is a strong trend towards combining multiple drugs with different mechanisms of action (e.g., ARPIs with PARP inhibitors, RLTs with immunotherapies, ADCs with chemotherapy) to achieve synergistic effects and overcome tumor heterogeneity and resistance.
• Drug Repurposing: Leveraging existing FDA-approved drugs for new indications, like metformin, pioglitazone, pimitespib, and aspirin, offers a faster path to patient benefit with known safety profiles. This is a huge market! It is very important for healthcare systems to reduce costs, and drug repurposing helps cut both costs and development time, leading to better therapies.
• Advances in Diagnostics & Delivery: New imaging agents and blood tests (like AR-ctDETECT and multi-tracer PET imaging) are refining patient selection and monitoring, while innovative drug delivery platforms (nanoparticles, hydrogels, PROTACs, gene editing tools like ENVLPE) aim to make therapies more efficient and less toxic.
• Role of AI: Artificial intelligence is fundamentally transforming how drugs are discovered, designed, and optimized, significantly accelerating the pipeline from lab to clinic and enhancing personalized medicine. These AI-driven advancements are also expected to improve the traditionally low success rate, that 5% I mentioned, of therapies that are currently entering phase 1 clinical trials.

We are not close to a cure for metastatic prostate cancer, but we are not far from making it a chronic disease. We must resist!

Now, let’s go into more detail. You can use this as a reference list. It is not a complete list (there has been research ongoing for more than a year!), and I am not sure I have included everything I have written about in the past year, but… more or less.

A Year of Progress: Key Areas in Advanced Prostate Cancer Research

I. Next-Generation Targeted Therapies

A major focus has been on developing highly precise therapies that can deliver potent anti-cancer agents directly to tumor cells while sparing healthy tissue.

Antibody-Drug Conjugates (ADCs)

These are “smart bombs” that combine an antibody to target specific proteins on cancer cells with a potent chemotherapy payload.

• MHB088C (B7-H3-targeted): Showed promising anti-tumor activity (14.3% objective response rate, 95.2% disease control rate, 87% 6-month radiographic progression-free survival) in heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) patients in a Phase 1/2 study.
• Ifinatamab Deruxtecan (MK-2400) (B7-H3-targeted, TROP2-targeted): Entered a Phase 3 trial (IDeate-Prostate01) for mCRPC, comparing it to docetaxel. Earlier Phase 1/2 trials showed promising response rates in heavily pretreated mCRPC. A separate Phase 1 trial for TROP2-targeted MK-2400 in mCRPC is expected to enroll soon.
• DS-3939a (TA-MUC1-targeted): A promising treatment for advanced prostate cancer where tumor-associated MUC1 is overexpressed (found in ~90% of advanced cases).
• GSK5764227 (B7-H3-targeted): This ADC is in a global Phase 1 study for advanced solid tumors, including mCRPC, with earlier studies showing promising activity.
• ABBV-969 (STEAP1 and PSMA-targeted): A novel bispecific ADC in a Phase 1 trial, targeting two proteins highly expressed in prostate tumors to improve precision.
• CRB-701 (Nectin-4-targeted): A Phase 1 investigational ADC targeting Nectin-4, a protein overexpressed in various cancers including prostate cancer.
• BR111 (ROR1-targeted): An ADC designed to target ROR1, which is expressed in advanced prostate cancer, especially castration-resistant small cell and neuroendocrine PCa. Clinical research is ongoing but not for PCa at the moment.
• ADRX-0405 (STEAP1-targeted): A Phase 1 ADC that showed significant efficacy in preclinical models for STEAP1-expressing cancers, including prostate cancer.
• SDV2102 (PSMA-targeted): Preclinical studies suggest this ADC, which uses a novel antibody and MMAE payload, could be a game-changer for mCRPC.
• TD001 (PSMA-targeted): A novel ADC that uses exatecan to induce DNA damage, showing dramatic tumor shrinkage in preclinical mCRPC models, even those with intermediate PSMA expression.
• FOR46 (FG-3246) (CD46-targeted): A novel ADC showing manageable safety and significant clinical activity (20% objective response rate, 8.7 months median rPFS) in mCRPC in a Phase 1 trial. It’s advancing to a Phase 2 trial.
• ARX517 (PSMA-targeted): Demonstrated promising efficacy in mCRPC (52% PSA50 response, 26% PSA90 response) in Phase 1/2 trials, with a favorable safety profile.

Radioligand Therapies (RLTs)

These therapies deliver targeted radiation to cancer cells by binding to specific proteins.

• 177Lu-PSMA-617 (Pluvicto): A Phase 3 study (PSMAfore trial) showed it significantly delayed radiographic progression (59% lower risk) and improved quality of life compared to switching ARPIs in taxane-naive mCRPC. The PSMAddition trial met its primary endpoint for mHSPC, significantly extending radiographic progression-free survival (rPFS) when combined with standard treatments.
• 225Ac-ETN029 (DLL3-targeted): A new Phase 1 trial is investigating this alpha-emitting radiopharmaceutical for neuroendocrine prostate cancer (NEPC).
• 225Ac-LNC1011 (PSMA-targeted): Showed encouraging results in a Phase 1 trial for PSMA-positive prostate cancer, with a 50% objective response rate (75% by PET-based criteria) and significant PSA declines.
• ART-101 (PSMA-targeted): An investigational radiopharmaceutical agent targeting PSMA with potential for enhanced treatment effectiveness and fewer side effects due to higher tumor uptake and retention. Phase 1 trial is starting.
• 177Lu-PSMA-I&T: A Swiss registry study (EKNZ 2021-01271) confirmed its safety and efficacy as an alternative to 177Lu-PSMA-617. The ECLIPSE trial also showed it significantly prolonged rPFS in mCRPC patients.
• 161Tb-PSMA-I&T: A novel RLT using Terbium-161, which emits beta particles and Auger electrons, potentially enhancing destruction of micrometastases. Phase 1/2 VIOLET trial showed promising results with 70% PSA50-RR and 40% PSA90-RR in mCRPC.
• 177Lu-JH020002 (PSMA-targeted): An ongoing Phase 1/2 trial shows a favorable safety profile and robust antitumor activity in advanced prostate cancer, with 67% of patients achieving PSA decline ≥50%.
• 67Cu-SAR-bisPSMA: Received FDA Fast Track Designation for mCRPC. The SECuRE trial showed a 92% response rate among pre-chemotherapy participants after a single dose and a complete response in one heavily pretreated patient, highlighting its potential for earlier intervention.
• 225Ac-PSMA-617 (AAA817): A Phase 3 trial is underway to evaluate this targeted alpha therapy in combination with ARPIs for mCRPC, aiming for improved rPFS. Earlier Phase 1 studies showed promising PSA declines and survival.
• 177Lu rhPSMA-10.1: Positive Phase 1 data support a Phase 2 trial. This novel RLT showed high tumor absorption and minimal radiation to organs like kidneys and salivary glands in mCRPC patients.
• FC705: A new PSMA-targeted RLT that demonstrated superior therapeutic effects compared to Pluvicto in Phase 2 clinical trials, with 60% of patients achieving ≥50% PSA reduction and three experiencing complete PSA elimination.
• TLX591 (177Lu-DOTA-rosopatamab): A novel radiopharmaceutical using a PSMA-targeting antibody (rosopatamab/J591) combined with Lutetium-177. It’s now in a global Phase 3 trial (ProstACT Global) for advanced mCRPC, building on promising early-phase data.
• Iodine-131-LNTH-1095 (PSMA-targeted): The ARROW trial in mCRPC showed 62.9% of patients achieved a ≥50% PSA decline when combined with enzalutamide, nearly doubling the response of enzalutamide alone.
• Thorium-227 conjugates (PSMA-TTC): Preclinical studies showed this targeted alpha therapy (TTC) effectively killed prostate cancer cells, including those resistant to anti-androgen treatments, and reduced bone metastases. A Phase 1 trial combined with darolutamide is nearing completion.
• OncoACP3 (ACP3-targeted): A small-molecule ligand targeting Acid Phosphatase 3 (ACP3), an enzyme highly expressed in prostate cancer (way more targeted than PSMA = less side effects!), is moving to a therapeutic clinical trial after successful Phase 1 imaging data.
• 225Ac-Macropa-PEG4-YS5 (CD46-targeted): Preclinical tests using this Actinium-225 therapy for CD46-rich tumors showed it eradicated small tumors and boosted survival in animal models, especially for PSMA-negative tumors.
• 67Cu-SAR-bisFAP and 67Cu-SAR-Bombesin: Emerging radiopharmaceuticals for patients with low or absent PSMA expression. 67Cu-SAR-bisFAP targets Fibroblast Activation Protein (FAP) in the tumor microenvironment, while 67Cu-SAR-Bombesin targets the Gastrin-Releasing Peptide receptor (GRPr). Both are in or moving towards clinical trials.
• Sn-117m-DTPA: A theranostic agent for bone metastases in Phase 1/2 trials, with production improvements after an earlier trial termination.
• Cu-67 NuriPro: Expected to enter clinical trials in early 2026 as a therapeutic counterpart to the diagnostic imaging agent Cu-61 NuriPro, targeting PSMA.

PROteolysis TArgeting Chimeras (PROTACs)

These novel drugs “tag” disease-causing proteins for destruction by the cell’s natural disposal system, rather than just inhibiting their activity.

• LYA914 (AR-targeted): A novel oral PROTAC designed to degrade both full-length androgen receptors (AR) and resistant splice variants like AR-V7, showing greater tumor growth inhibition than enzalutamide in preclinical studies.
• JSB462 (luxdegalutamide) (AR-targeted): A PROTAC in a Phase 2 trial combined with abiraterone for mHSPC. It degrades the AR, including resistant mutants, and early mCRPC data showed promising PSA50 response rates.
• SHR3591 (AR-targeted): An oral AR PROTAC showing powerful activity against wildtype AR and various AR mutations in preclinical studies, heading for Phase 1/1b clinical trials.
• GDC-2992 (RO7656594) (AR-targeted): A dual-action PROTAC that degrades and antagonizes the AR, including resistant mutants. It’s in a Phase 1 study for advanced prostate cancer.
• Protac NP18: Preclinical research shows this PROTAC offers new hope for overcoming anti-androgen therapy resistance in CRPC by degrading the androgen receptor.
• HLD-0915 (Regulated Induced Proximity Targeting Chimera – RIPTAC): An orally bioavailable RIPTAC for mCRPC that has shown superior anti-tumor activity compared to enzalutamide in preclinical studies. The first patient was dosed in a Phase 1 trial.
• ERG-targeted protein degrader: A first-in-class PROTAC targeting ERG gene fusions (present in 40-50% of prostate cancers) is advancing toward clinical trials.
• CTS2190 (PRMT1 inhibitor): This oral small molecule significantly degrades the AR, including AR-V7 variants, and outperformed standard treatments in preclinical models. It’s in a Phase 1/2 trial for ARPI-resistant mCRPC.

T-Cell Engagers & Bispecific Antibodies

These therapies redirect a patient’s own T cells to attack cancer cells.

• Tarlatamab (DLL3-targeted): A bispecific T-cell engager in a Phase 2 trial for neuroendocrine prostate cancer (NEPC), showing preliminary higher objective response rates in DLL3-positive tumors.
• ZG006 (DLL3- and CD3-targeted): A trispecific T cell engager in a Phase 2 trial for advanced neuroendocrine carcinoma, including NEPC. It aims to activate T cells to destroy tumor cells.
• Pasritamig (JNJ-78278343) (KLK2- and CD3-targeted): A bispecific antibody in a Phase 1 study for mCRPC, showing promising anti-tumor activity by simultaneously binding KLK2 on cancer cells and CD3 on T cells. It’s also part of a combination trial with JNJ-87189401.
• DR-0202 (CLEC7A/Dectin-1 bispecific antibody): A first-in-class bispecific antibody in a Phase 1 trial for advanced solid tumors, including mCRPC, that leverages myeloid cells to destroy malignancies.
• JNJ-87189401 (PSMA-targeted): Being evaluated in combination with JNJ-78278343 (KLK2-targeted) in a Phase 1 trial for advanced prostate cancer, aiming for enhanced T-cell activation.
• VIR-5500 (PSMA-targeted): A dual-masked T-cell engager in an ongoing Phase 1 trial for mCRPC, showing 100% PSA reduction and 58% PSA50 response, with minimal side effects.
• NRM-823: A first-in-class T-cell engager targeting a novel tumor antigen, with preclinical studies showing promise. Clinical trials are planned for the second half of 2025.
• APVO442 (PSMA- and CD3-targeted): A preclinical bispecific antibody designed for precise tumor targeting and enhanced immune response against prostate cancer, minimizing harm to healthy cells.
• GEN1057 (DuoBody-FAPαxDR4): A bispecific antibody in a Phase 1 trial for advanced solid tumors, including prostate cancer. It conditionally activates DR4 (death receptor 4) on cancer cells only when FAPα (fibroblast activation protein alpha) is nearby, promoting targeted cell death.
• QXL138AM (CD138-targeted): A masked immuno-cytokine (MIC) in Phase 1 trials for CD138-expressing tumors, including prostate cancer, showing 69% tumor growth inhibition in preclinical prostate cancer models.

II. Immune-Modulating Strategies

Boosting the body’s own immune system to fight cancer is a promising area, especially for “cold” tumors like prostate cancer.

Checkpoint Inhibitors & Combinations

• The KEYNOTE-641 study found that adding pembrolizumab (an immunotherapy) to enzalutamide did not improve outcomes for chemotherapy-naive mCRPC and increased toxicity, leading to the trial’s discontinuation. This highlights the ongoing challenge of making immunotherapies work effectively in prostate cancer as single agents or simple combinations.
• Gotistobart (BNT316/ONC-392) (anti-CTLA-4 antibody) combined with 177Lu (Pluvicto): The PRESERVE-006 Phase 1/2 trial showed manageable safety and encouraging antitumor activity in mCRPC, suggesting that depleting regulatory T cells (Tregs) in the tumor microenvironment may amplify 177Lu’s activity.
• Ciforadenant (adenosine pathway inhibitor): Early clinical trial data in mCRPC showed that combining ciforadenant with atezolizumab (an immunotherapy) resulted in a 21% partial response rate, suggesting it can make “cold” prostate tumors more susceptible to immunotherapy by reversing adenosine-induced immunosuppression.
• IMGS-101 (evofosfamide): A hypoxia-modifying agent entering Phase 1/2 trials in combination with checkpoint inhibitors for advanced cancers, including mCRPC. It aims to counteract tumor hypoxia, which hinders T-cell infiltration, thereby boosting immunotherapy efficacy.
• PIM1 Kinase Inhibition: A study found that inhibiting PIM1 kinase could make previously ineffective immunotherapy for prostate cancer viable, by enhancing immune checkpoint inhibitors.

Novel Immunotherapies

• 2141-V11: A CD40 agonist antibody that showed systemic tumor remission, including distant lesions, in a Phase 2 trial with reduced toxicity via intratumoral injection. Now being tested in prostate, bladder, and brain cancers (≈200 patients enrolled)
• INKmune: A Phase 1/2 clinical trial for mCRPC met its primary and secondary endpoints, demonstrating a favorable safety profile and signs of biological activity by priming natural killer (NK) cells into memory-like NK cells capable of targeting tumors. Plans are underway to advance it to a randomized Phase 2b trial. The trial has also expanded to include U.S. military veterans.
• MDNA113: A first-in-class immunotherapy that combines an anti-PD1 antibody and an IL-2 Superkine, designed to activate only within the tumor microenvironment by targeting IL-13Rα2, which is overexpressed in aggressive prostate cancers.
• CD-001: A promising new immunotherapy combining two immune-boosting strategies (blocking inhibitory signals and stimulating T cells) into a single drug, aiming to overcome the immunosuppressive environment of prostate tumors. A Phase 1 trial is beginning.
• KCL-HO-1i: Preclinical studies suggest this drug can convert an immunologically “cold” tumor microenvironment into a “hot” one, making it highly relevant for prostate cancer by increasing effector CD8+ T cells and enhancing chemotherapy efficacy.
• BA1106 (anti-CD25 monoclonal antibody): A Phase 1 trial for advanced solid tumors showed it was well-tolerated and confirmed CD25’s presence in prostate cancer (linked to poor prognosis), suggesting potential for this therapy to enhance immune responses.
• Q702 (Axl, Mer, CSF1R blocker): A Phase 1 trial in advanced solid tumors showed promising results. By blocking proteins tumors use to grow, spread, and evade the immune system, Q702 could be a game-changer for mCRPC, potentially enhancing existing prostate cancer drugs or immunotherapies.
• NEU-002 (ELANE Pathway target): Preclinical data for this pan-cancer therapeutic show it selectively triggers immunogenic cell death in cancer cells, regardless of their genetic makeup or immune status. While not yet including prostate cancer in Phase 1, its broad applicability offers future hope.

Personalized Cancer Vaccines

• PGV001: A personalized multi-peptide neoantigen cancer vaccine that induced strong immune responses across various cancer types in a Phase 1 trial. While not yet in prostate cancer trials, the technology is highly relevant.
• AI-guided cancer vaccines: A new partnership aims to revolutionize cancer treatment through personalized peptide vaccines, leveraging AI to craft tailored treatments based on the unique genetic makeup of each patient’s tumor.
• CancerVax’s Smart mRNA technology: Has shown success in developing a universal cancer treatment platform that leverages the immune system, with potential for various cancer types.
• Hydrogel-based vaccine delivery: A new hydrogel breakthrough may improve cancer vaccines by enhancing immune cell activation and sustained presence of cancer-fighting peptides, with significant promise for prostate cancer.

Oncolytic Viruses & Gene Therapy

• CAN-2409: A novel viral immunotherapy that induces immunogenic cell death. A Phase 3 trial for intermediate-to-high-risk localized prostate cancer showed a significant 30% reduction in recurrence or death risk and a 14.5% relative improvement in disease-free survival. It received Regenerative Medicine Advanced Therapy (RMAT) designation, expediting its development.
• SVV-001: An oncolytic virus being investigated in a Phase 1 trial for high-grade neuroendocrine tumors.

III. Addressing Treatment Resistance & Novel Pathways

A key challenge in advanced prostate cancer is the development of resistance to therapies. Researchers are exploring various mechanisms to overcome this.

Cell Cycle & DNA Repair Inhibitors

• TYK-00540: A novel oral small-molecule inhibitor targeting CDK2/4/6 to overcome resistance mechanisms seen with existing CDK4/6 inhibitors. It’s in a Phase 1b/2 trial combined with enzalutamide for mCRPC.
• TY-302 (CDK4/6 inhibitor): In a Phase 1b/2 study combined with Abiraterone acetate for mCRPC, aiming to address both cell cycle and androgen signaling pathways.
• Talazoparib (PARP inhibitor): The TALAPRO-2 trial showed that combining talazoparib with enzalutamide significantly improved overall survival (median OS of 45.1 months vs. 31.1 months) and radiographic progression-free survival for mCRPC patients with homologous recombination repair (HRR) gene alterations, especially BRCA1/2 mutations. It also showed overall survival benefit in the “all-comers” population. A comparison suggested TALA+ENZA offers improved outcomes compared to other PARP inhibitor combinations (olaparib + abiraterone, niraparib + abiraterone).
• Niraparib (PARP-1/2 inhibitor): The AMPLITUDE trial (Phase 3) showed that combining niraparib and abiraterone acetate with prednisone significantly improved outcomes for mCSPC patients with HRR gene alterations, aiming to move PARP inhibitors to earlier stages of the disease.
• SYN608 (PARG inhibitor): A new molecule being studied in a Phase 1 trial for advanced solid tumors, including prostate cancer, in patients with homologous recombination repair (HRR) deficiencies.
• EIK1004 (IMP1707) (PARP1 inhibitor): A Phase 1/2 trial is open for patients with advanced solid tumors, including prostate cancer, aiming for greater precision by targeting only PARP1 to reduce side effects. It has brain-penetrating ability, filling a critical gap.
• EIK1003 (IMP1734) (PARP1-selective inhibitor): A Phase 1/2 study is testing this novel PARP1-selective inhibitor in advanced prostate cancer, aiming to maintain strong antitumor effects while reducing blood-related toxicities seen with earlier PARP inhibitors.
• XL309 (USP1 inhibitor): A potent and selective inhibitor of ubiquitin-specific protease 1 (USP1) now in a Phase 1 first-in-human trial for BRCA1/2 mutated solid tumors (including mCRPC), introducing a novel therapeutic strategy for DNA repair deficiencies.
• SYN818 (POLQ inhibitor): A new investigational drug showing early promise in Phase 1 trials for advanced cancers, particularly for prostate cancer patients with HRR gene deficiencies (BRCA1, BRCA2, ATM) by inhibiting DNA polymerase theta (POLQ).
• Polynucleotide Kinase/Phosphatase (PNKP) inhibitor: A new PNKP inhibitor is scheduled to begin Phase 1 clinical trials in 2025. Inhibiting PNKP can sensitize prostate cancer cells to DNA-damaging therapies, especially in ATM and BRCA mutated tumors.
• Targeting LIG1 with PARP Inhibitors: New research (pre-print) used CRISPR/Cas9 to identify that LIG1, EME1, and FAAP24 losses act as PARP inhibitor sensitizers, suggesting new targets for CRPC patients beyond known HRR genes.

Androgen Receptor Pathway Modulators (beyond PROTACs)

• HSK46575 (CYP11A1 inhibitor): A new oral small molecule in early clinical trials for mCRPC. It targets CYP11A1, an enzyme starting steroid hormone production, aiming to reduce androgens and limit tumor growth.
• ACE-232 (CYP11A1 inhibitor): A novel oral CYP11A1 inhibitor entering Phase 1 trials for mCRPC, demonstrating the ability to overcome resistance to ARPIs caused by AR-LBD mutations or amplification in preclinical studies.
• OST11098 (CYP11A1 inhibitor): A newly developed, orally bioavailable, and highly selective CYP11A1 inhibitor showing strong potential for CRPC, especially in models resistant to standard hormonal therapies.
• BMS-986365: An investigational oral drug in a pivotal Phase 3 study for mCRPC. It has a dual mechanism of action, degrading and antagonizing the androgen receptor, including mutated forms, with early trials showing PSA declines in up to 70% of patients.
• ORIC-944 (PRC2 inhibitor): A potent and selective allosteric inhibitor of PRC2, showing early promise in mCRPC in Phase 1b trials. When combined with apalutamide, it resulted in deep (50-90% or more) and sustained PSA reductions with a manageable safety profile. Registrational trials are planned for early 2026.
• APG-5918 (EED inhibitor): A novel small molecule inhibiting EED (a component of PRC2), showing strong antiproliferative activity against prostate cancer cells and synergistic effects with enzalutamide in preclinical studies. It has entered a Phase 1 trial for advanced solid tumors, including prostate cancer.
• KPG-121 (cereblon modulator): A novel oral drug that showed promising synergy with existing ARPIs (abiraterone, enzalutamide, apalutamide, darolutamide) in a Phase 1 study for mCRPC patients already on stable ARPIs.

Other Novel Targets

• NSD2 inhibitor (KTX-2001): The first clinical trial of an NSD2 inhibitor in mCRPC (STRIKE-001, Phase 1) has been cleared. NSD2 is a powerful driver of aggressive prostate cancer, contributing to immune suppression and resistance.
• MYC inhibitors:
  • UTRxM1-18: A novel mRNA destabilizing therapy targeting the c-MYC oncogene. While initial trials focus on other cancers, its potential for aggressive, treatment-resistant prostate cancer (where c-MYC overexpression is a key driver) is considerable.
  • PMR-116: Preclinical studies show this drug disrupts a downstream pathway MYC depends on, resulting in an 85% reduction in cancer lesions in MYC-driven prostate cancer mouse models and reducing spread by 50% in 12 hours.
  • Metformin: A recent study from Northwestern Medicine provided direct evidence that metformin lowers blood sugar by interfering with mitochondria, the cell’s “powerhouse”. This could tie into its potential as a MYC-driven cancer therapy.
• PI3K/AKT/mTOR inhibitors:
  • Gedatolisib: A Phase 1/1b/2 clinical trial (CELC-G-201) is exploring combining gedatolisib (a PI3K/AKT/mTOR pathway inhibitor) with darolutamide for mCRPC, showing a 6-month radiographic progression-free survival rate of 66%.
  • STX-478: A mutant-selective PI3Kα inhibitor in a Phase 1 trial for PI3K-mutated solid tumors. It shows clinical activity with reduced toxicities compared to other PI3K inhibitors, making it valuable for prostate cancer where PI3K mutations play a role in resistance.
  • MTX-531: A novel dual-target cancer drug simultaneously targeting EGFR and PI3K, aiming to overcome treatment resistance in prostate cancer by disrupting two complementary survival pathways.
• QED-203 (TRPV6 inhibitor): A novel small molecule targeting a previously unexploited mechanism in cancer cells, showing superior potency over enzalutamide and darolutamide against AR-V7 splice variants in preclinical studies. It induces endoplasmic reticulum stress and programmed cell death.
• ASH1L: Researchers identified this protein as a crucial epigenetic driver that primes cancer cells to invade and colonize bone tissue, offering a promising new target for therapies to prevent bone metastasis.
• Acyl–coenzyme A binding protein (ACBP): Identified using CRISPR, ACBP is a key player in cancer metastasis to bones, with higher levels associated with increased likelihood of spread.
• GCN2 inhibition: Researchers discovered a new vulnerability in prostate cancer: targeting GCN2 to starve tumors of amino acids, particularly in p53-deficient tumors.
• SREBP inhibition: A new study found that inhibiting sterol regulatory element-binding protein (SREBP) can reinduce sensitivity to docetaxel in prostate cancer, suggesting a path to overcome docetaxel resistance by affecting cholesterol and lipid biosynthesis.
• HSP60 inhibition: Researchers identified mitochondrial HSP60 as a potential new treatment target for neuroendocrine prostate cancer (NEPC), and targeting it could leverage existing drugs.
• RPT04402 (PP2A reactivator): A first-in-class molecular glue that activates Protein Phosphatase 2A (PP2A), a tumor suppressor enzyme, to suppress oncogenic signaling pathways. An IND filing is expected by end of 2025.
• STAT3 inhibition: VVD-130850, an oral STAT3 inhibitor, is in a Phase 1 trial for advanced solid tumors, including prostate cancer, as STAT3 hyperactivation drives tumor progression.
• TACC3 inhibitor (A0-252): Preclinical studies indicate potential efficacy of this innovative TACC3 inhibitor in prostate cancer, focusing on ovarian, triple-negative breast, and endometrial cancers in early trials.
• NXP900: In a Phase 1 trial for advanced solid tumors, preclinical studies suggest NXP900, especially when combined with osimertinib and enzalutamide, could reverse acquired resistance in mCRPC models.
• Evexomostat: A novel drug targeting metabolic and molecular pathways in aggressive variant prostate cancer (AVPC), including neuroendocrine and AR-independent forms. Preclinical models show promise in halting tumor progression and overcoming resistance to AR-targeted therapies.
• NXP800: A novel drug discovered by ICR showing potential in overcoming hormone therapy resistance by targeting heat shock proteins (HSPs). Preclinical studies showed up to 70% tumor growth reduction and delayed progression in resistant prostate cancers.
• Pocenbrodib (p300/CBP inhibitor): The first patient has been dosed in a Phase 1 clinical trial for this AI-designed experimental therapy for mCRPC, targeting epigenetic regulators involved in cancer cell growth and survival. A separate Phase 1 trial will explore it alone and in combination with other agents.
• (R)-9bMS (ACK1 inhibitor): The PHAROS trial is exploring this drug for mCRPC patients who failed prior enzalutamide or abiraterone. It aims to lower AR-V7 levels and re-sensitize cancer cells to therapies.

IV. Neuroendocrine Prostate Cancer (NEPC)

NEPC is an aggressive form of prostate cancer with limited options, and targeted research is critical.

• Tarlatamab (DLL3-targeted): We already mentioned it, it’s a bispecific T-cell engager in a Phase 2 trial for NEPC, showing preliminary response rates.
• 225Ac-ETN029 (DLL3-targeted): A Phase 1 clinical trial for NEPC, using an alpha-emitting isotope to target DLL3, found in 77% of NEPC cases.
• BL-M14D1 (TROP2-targeted ADC): An experimental ADC currently in Phase 1 trials for neuroendocrine tumors, including NEPC.
• CCS1477 (CBP and p300 epigenetic regulators target): Scientists uncovered genetic mechanisms driving NEPC evolution and successfully blocked the neuroendocrine shift in lab and animal models using CCS1477 (a drug in early-phase trials).
• ZG006 (DLL3- and CD3-targeted): A trispecific T cell engager in a Phase 2 trial for NEPC.
• MT-4561 (BRD4 degrader): A new drug being tested in a Phase 1/2 trial for advanced solid tumors, including its neuroendocrine variant.
• Combination of pembrolizumab and chemotherapy: A study found this combination significantly improved outcomes for patients with small cell bladder cancer and small cell/neuroendocrine prostate cancer, with many patients living for two years after starting treatment.
• HSP60 inhibition: Researchers identified mitochondrial HSP60 as a potential new treatment target for NEPC, with potential to leverage existing drugs.
• PT217 (DLL3- and CD47-targeted bispecific antibody): Received Fast Track Designation for NEPC, underscoring its potential for this aggressive cancer.

V. Drug Repurposing & Combination Strategies

Finding new uses for existing drugs, and combining therapies, continues to offer practical avenues for treatment.

Metformin

• A review in The Lancet discussed metformin’s impact on prostate cancer patients from the STAMPEDE trial. The trial showed metformin reduced weight gain (~2kg less) and lowered blood sugar/harmful fats in men with advanced prostate cancer on hormone therapy, suggesting a role in managing long-term side effects and comorbidities.

Other Repurposed Drugs

• Pioglitazone (PPARγ agonist): A diabetes drug showing promise against prostate cancer by activating the PPARγ protein, altering tumor cell metabolism and inhibiting growth in preclinical studies. Initial patient data correlated PPARγ agonist use with no cancer relapse.
• Pimitespib: An approved drug in Japan for GI tumors, found in preclinical studies to help overcome resistance to enzalutamide, darolutamide, and abiraterone in mCRPC by blocking AR and GR from entering the cell nucleus.
• Nodularin-R: Preclinical studies showed this compound enhanced abiraterone’s effectiveness against CRPC by inhibiting tumor growth and reducing resistance genes.
• Aspirin: A study suggests aspirin may help delay biochemical recurrence (BCR) after radical prostatectomy, likely by inhibiting cell proliferation and angiogenesis. Another study in Nature offers insight into how aspirin boosts the immune system to stop cancer spreading.
• Kaempferol: A key ingredient in a traditional Chinese medicine, shown to suppress emotional stress-aggravated prostate cancer metastasis by targeting the GR/PER1 pathway and modulating lipid metabolism in tumor-associated macrophages (TAMs).
• Digoxin: Preclinical research suggests targeting tumor cell clusters with repurposed drugs like digoxin could combat metastasis in prostate cancer, among other cancer types.
• Dinuclear Platinum(II) Complexes: Preclinical research explored these complexes as alternatives to cisplatin, showing promising antiproliferative effects in prostate cancer cell lines with minimal toxicity, and an ability to inhibit AR signaling.

Combination Therapies

• Darolutamide + ADT: The ARANOTE trial (Phase 3) showed this combination significantly improved radiographic progression-free survival (rPFS) in mHSPC (46% reduction in progression or death risk) and led to high rates of undetectable PSA responses, with a favorable safety profile.
• Darolutamide + ADT + docetaxel (triplet therapy): The ARASENS trial (Phase 3) for mHSPC patients with metastases, this triplet therapy offers the greatest chance for extended survival. If you are fit and you have an high volume of metastatic lesions, this is the protocol to follow. ARANOTE is also a very good protocol but less beneficial in case of high volume.
• STAMPEDE trial analysis: Suggests transdermal estradiol (tE2) patches may be a safer and equally effective alternative to traditional LHRHa for hormone suppression in metastatic prostate cancer patients receiving ARPIs, showing comparable PSA reductions.
• Masitinib + docetaxel: A new Phase 3 trial for mCRPC is evaluating this combination, building on previous Phase 3 data showing improved progression-free survival in patients with lower alkaline phosphatase (ALP) levels.
• Abiraterone with low-fat meal: A Phase 1 trial suggests a model-informed 500 mg daily dose of Abiraterone acetate taken with a low-fat meal may offer comparable efficacy and safety to the 1000 mg fasted dose, potentially reducing cost and improving access.
• ENV105 + apalutamide: A Phase 2 trial for mCRPC is exploring this combination to overcome resistance by targeting CD105, showing a 62% clinical benefit rate in an earlier study. Safety data are expected soon.
• SX-682 + Apalutamide/Enzalutamide: Phase 1/2 trials (ASpiRE and SYNERGY-201) are combining this CXCR1/2 inhibitor with AR inhibitors to re-educate the tumor microenvironment and overcome resistance in mCRPC.
• Opaganib (ABC294640) + darolutamide: A Phase 2 clinical trial is set to evaluate this combination for mCRPC, targeting specific pathways to potentially overcome ARPI resistance.
• Capivasertib (Truqap) + abiraterone + ADT: The CAPItello-281 Phase 3 trial showed promising results for PTEN-deficient mHSPC, with significant improvement in rPFS. However, the CAPItello-280 trial combining capivasertib with docetaxel and ADT for mCRPC was terminated due to futility in meeting primary endpoints.
• QED-203 with enzalutamide/darolutamide: Preclinical data showed QED-203 retained its power against enzalutamide-resistant cells and showed superior potency over enzalutamide and darolutamide against ARV7 splice variants.
• Pimitespib + ARPIs: Preclinical studies suggest pimitespib could be repurposed to overcome resistance to enzalutamide, darolutamide, and abiraterone by boosting their effects.
• Rifaximin + existing therapies: Repurposing rifaximin as a PIM-1 inhibitor holds promise for prostate cancer, especially when combined with existing therapies to target multiple tumor survival pathways simultaneously.
• CDK4/6 inhibitors + senolytics/PARP inhibitors (sequential): Preclinical research shows prostate cancer cells develop senescence (dormant state) after CDK4/6 inhibition, which can then be targeted by senolytic compounds, suggesting a sequential combination therapy approach for resistance.
• 177Lu-PSMA-I&T, olaparib, and pembrolizumab (triple combination): The “LumOnate” Phase 1b trial is investigating this combination for mCRPC, targeting cancer through direct radiation, DNA repair inhibition, and immune activation.
• FPI-2265 (225Ac-PSMA-I&T) + olaparib: A Phase 2 trial is combining this targeted alpha therapy with a PARP inhibitor for mCRPC, hoping to enhance anti-tumor effects.
• CBP-1018 (bi-ligand–drug conjugate): A Phase 1/2 trial shows manageable side effects and promising disease control (20% ORR, 88% DCR) in heavily pre-treated mCRPC patients.
• Adaptive ADT with docetaxel: A Phase 2 study is expanding on a successful Phase 1b trial that used adaptive, intermittent ADT based on PSA responses. This trial aims to prolong the castration-sensitive phase by adding docetaxel.
• Bipolar Androgen Therapy (BAT): The WOMBAT Trial (Phase 2) is investigating BAT in combination with darolutamide for M0 castration-resistant prostate cancer to extend metastasis-free survival. The COSMYC trial (Phase 2) is also investigating BAT with ZEN-3694 and then enzalutamide for mCRPC to shrink tumors and delay progression.
• KCL-HO-1i + chemotherapy/immunotherapy: Its mechanism suggests it could enhance chemotherapy or immunotherapy efficacy in prostate cancer.
• Intermittent Fasting + Enzalutamide:In mouse models, alternate-day fasting enhanced enzalutamide efficacy by reducing AR signaling and protein synthesis in tumors. Based on these results, a clinical trial in prostate cancer patients on hormone therapy is now being launched.

VI. Advances in Diagnostics & Delivery

Improved ways to detect and monitor prostate cancer, and deliver drugs more effectively, are crucial for personalized care.

• AR-ctDETECT: A new blood test that analyzes circulating tumor DNA (ctDNA) to distinguish between patients with good and poor prognoses in advanced prostate cancer. It detected ctDNA in 59% of mCRPC patients in a Phase 3 trial, linked to worse overall survival.
• Multi-tracer PET Imaging: A new approach using 18F-FDG, 68Ga-PSMA-617, and 68Ga-DOTATATE PET/CT scans to identify intrapatient intermetastatic heterogeneity (IIH) in mCRPC. High prevalence of IIH (82.7%) was linked to decreased survival rates (median OS of 9.5 months).
• 61Cu-NODAGA-PSMA: A novel Copper-61 radiotracer in a Phase 1 clinical trial for prostate cancer imaging. Its longer half-life (3.3 hours) could overcome limitations of other isotopes, making technology more accessible.
• Nanoparticles for dual drug delivery: A breakthrough in cancer treatment, these biodegradable nanoparticles deliver two drugs simultaneously to tumors by targeting P-selectin, which is overexpressed on tumor cells and blood vessels. This could address brain metastases and improve efficacy with lower doses.
• Hydrogel-based vaccine delivery: A breakthrough for cancer vaccines by improving activation of immune cells and ensuring sustained presence of cancer-fighting peptides.
• ENVLPE (Engineered Nucleocytosolic Vehicles for Loading of Programmable Editors): A system highlighted for its remarkable ability to deliver gene-editing tools like CRISPR/Cas9 into living cells with unprecedented efficiency and safety, holding potential for gene-level interventions in advanced prostate cancer.
• 4armPEG-DD: A PSMA-targeted drug delivery vehicle designed for enhanced prostate cancer treatment, using a PEG polymer to bind docetaxel and release it only within tumor cells, aiming for precision and reduced side effects.
• Targeted nanoparticles for in vivo CAR-T production: A method to produce CAR-T cells directly inside the body using targeted nanoparticles, potentially reducing the complexity and cost of CAR-T therapy, with implications for cancer and autoimmune conditions.

VII. Real-World Evidence & Practice Changes

Studies based on real-world patient data provide valuable insights into how treatments perform outside of controlled clinical trials, often showing even greater benefits. But remember: they are more prone to biases! So let’s take them with a pinch of salt.

• Sipuleucel-T: A retrospective study analyzing over 11,000 mCRPC patients showed a median overall survival (OS) of 44 months for those treated with sipuleucel-T, compared to 24 months for those not treated, suggesting a substantial survival benefit in real-world settings.
• Apalutamide vs. Abiraterone/Enzalutamide: Real-world studies suggest apalutamide may offer a survival advantage for mCSPC patients, showing a 26% reduction in death risk compared to abiraterone and 23% compared to enzalutamide at 24 months. Another real-world study showed APA+ADT led to significantly better outcomes than ENZ+ADT, AAP+ADT, or ADT alone in mHSPC.
• Continuous vs. Intermittent ADT: A study from the S9346 Phase 3 trial reaffirms that continuous ADT outperforms intermittent ADT in mHSPC, even for patients with strong PSA responses.
• Bone-Modifying Agents: An observational study found that bone-modifying agents (bisphosphonates like zoledronic acid and denosumab) were associated with improved overall survival (58 months vs. 45 months) in mCRPC patients with bone metastases.
• Fracture Risk in STAMPEDE: A secondary analysis of the STAMPEDE trial highlighted the significant risk of fractures in men with high-risk localized or mHSPC undergoing ADT.
• Lu-PSMA vs. Cabazitaxel: A real-world study from the FRAMCAP database confirmed that 177-Lutetium Prostate-Specific Membrane Antigen (Lu-PSMA) therapy offers significantly better outcomes (median PFS 13.4 months vs. 7.1 months) than cabazitaxel chemotherapy in mCRPC patients.
• PSA Nadir as Predictor: Real-world analysis from the IRONMAN registry confirms that achieving an undetectable PSA nadir (<0.2 ng/mL) within the first year of treatment is strongly associated with improved outcomes for mHSPC patients, especially with ADT + ARPI. An analysis of the EMBARK trial also showed enzalutamide significantly boosted undetectable PSA levels in high-risk biochemically recurrent prostate cancer.
• Early PSA Response (TITAN trial): An analysis of the TITAN trial found that achieving PSA ≤ 0.2 ng/mL by 6 months (early PSA response) predicted and mediated the treatment effect of ADT plus apalutamide on overall survival in mHSPC, guiding treatment intensification.

VIII. AI in Research & Development

Artificial intelligence is rapidly accelerating drug discovery and enabling more personalized treatment approaches.

• AlphaGenome: Google-owned AI lab DeepMind launched AlphaGenome, a new model to predict DNA encoding gene regulation, following AlphaFold 2 and 3 for protein structure prediction. This could aid in understanding cancer genetics.
• AI-designed drugs: The first patient was dosed with pocenbrodib (formerly CTT2274), an experimental therapy designed entirely with AI in few weeks, targeting p300/CBP epigenetic regulators in mCRPC. This dramatically speeds up drug development timelines. Insilico Medicine also received FDA clearance for its 10th AI-driven molecule, ISM5939, for solid tumors.
• Genomenon Genomic Graph (G3) knowledgebase: A comprehensive, searchable database of clinically relevant genomic evidence, built with AI, to accelerate discoveries and patient care.
• AI for predicting outcomes: A study shows an AI tool (multimodal artificial intelligence – MMAI biomarker) can analyze prostate cancer tissue samples and other clinical data to predict overall survival, disease progression, and castration-resistant prostate cancer development in mHSPC patients, allowing for more personalized treatment choices.
• FDA-cleared AI for pathology: Ibex Prostate Detect, an AI tool, demonstrated 99.6% accuracy in identifying prostate cancer, and even identified 13% of cases initially missed by human pathologists, enhancing diagnostic accuracy.
• AI-generated ATR Inhibitors: A new wave of AI-generated cancer therapies targeting the ATR protein has reached preclinical testing, aiming to exploit synthetic lethality in tumors with ATM gene deficiencies (including prostate cancer).
• AI for antibody discovery: New evolutions of AlphaFold are being used to identify better antibody therapies by predicting protein-antibody interactions.
• Predictive Oncology’s AI platform: Successfully analyzed nearly 1,000 drug-tumor interactions, identifying multiple candidates for treating various cancers, including two repurposed drugs that outperformed a standard colon cancer treatment.
• New pipeline for personalized cancer treatments: The University of Oulu created a new method to analyze how individual patient tumor samples respond to drugs, a major step toward personalized medicine.

The progress in the last year is not just incremental; it represents significant leaps in our understanding and ability to tackle advanced prostate cancer. While many promising treatments are still in clinical trials, the sheer volume and diversity of approaches offer real hope for us patients. The focus on precision, overcoming resistance, and leveraging advanced technologies like AI means that the future of prostate cancer treatment is rapidly improving!