Beyond the Ligand-Binding Domain: jamming the "docking site"
Promising Treatments for Refractory and Resistant Prostate Cancer - Ramesh Narayanan, PhD, MBA - YouTube
A Closer Look at the Next Generation of Androgen-Receptor Drugs
BLUF (Bottom Line Up Front):
Why This Topic Matters
Almost every IPCSG member has taken, or will take, a drug that blocks the androgen receptor — enzalutamide, abiraterone, apalutamide, or darolutamide. These drugs are the backbone of modern prostate cancer treatment, and they work by either shutting off testosterone production or by jamming the "docking site" on the AR protein where testosterone normally binds (called the ligand-binding domain, or LBD). The problem, as cancer patients know all too well, is that the disease eventually finds a way around these drugs. Understanding how it does that — and what researchers are doing to stay a step ahead — helps explain why so many new drug names keep appearing in your oncologist's vocabulary.
The Huggins-and-Hodges Story: Where It All Began
Dr. Narayanan opened his talk with a bit of history that's worth repeating for patients. In the 1940s, Drs. Charles Huggins and Clarence Hodges showed — using nothing more sophisticated than a blood test for an enzyme called acid phosphatase — that surgically removing the testicles (the body's main androgen factory) caused prostate tumors to shrink. They also showed that giving estrogen had the same effect, because it tricks the brain's hormonal control center (the hypothalamus-pituitary-gonadal axis) into shutting down testosterone production. This work won Huggins the Nobel Prize and set the template that every AR-targeted drug since then has followed: cut off the hormone supply, or block the receptor that hormone needs to dock with.
The Escape Route: AR Splice Variants
The androgen receptor is built like a chain with several functional links: an N-terminus domain, a DNA-binding domain, a hinge region, and the ligand-binding domain. Every FDA-approved AR drug on the market today — enzalutamide, apalutamide, darolutamide, and abiraterone (which blocks androgen production rather than the receptor itself) — works on or through that ligand-binding domain.
The cancer's escape route, Dr. Narayanan explained, is to simply stop making that part of the receptor. The result is a shortened, "constitutively active" version of the AR called a splice variant, most commonly AR-V7. This truncated receptor keeps roughly 75-80% of its normal activity — including its ability to drive cancer growth — but has no ligand-binding domain left for drugs to grab onto. Patients whose tumors express high levels of AR splice variants tend to have a faster, more treatment-resistant course of disease. This is the central problem the next generation of AR drugs is trying to solve.
The Featured Drug: ONCT-534 / RAMiller's AR Degrader
The drug Dr. Narayanan discussed binds to a different part of the receptor — the N-terminus domain, sometimes called a "non-canonical" site because it's not where traditional drugs bind. By attaching there, the molecule does two things at once: it blocks the receptor's function, and it recruits the cell's own protein-disposal machinery (an E3 ubiquitin ligase) to tag and destroy the entire AR protein, including the splice variants. Because it targets a domain shared by both the full-length receptor and the splice variants, it's designed to work even after standard AR drugs have failed.
What the early data actually showed
This compound has gone by several names over its development history: UT-34, GTx-534, and ONCT-534, after it was licensed to the publicly traded company Oncternal Therapeutics, where Dr. Narayanan served as a consultant.1,2 A first-in-human Phase 1/2 trial (NCT05917470) enrolled patients with metastatic castration-resistant prostate cancer who had already progressed on at least one AR pathway inhibitor, testing doses from 40 mg to 1,200 mg daily.3
A subsequent published analysis (after the trial closed) reported that some patients did show PSA declines and reductions in target lesions, and that the drug was reasonably well tolerated — but the company maintained that discontinuation was the correct call given the overall results.7,8
The drug's second act
As Dr. Narayanan described in the webinar, rights to the compound have returned to the University of Tennessee Research Foundation, and he has formed a new company — RAMiller Biotechnologies (the name blends "Ramesh" and "Miller," after his longtime chemistry collaborator, Professor Emeritus Duane Miller) — with the goal of restarting clinical development.9 RAMiller's public materials describe the same N-terminus-domain "dual mechanism" androgen-receptor degrader approach, now also being explored for triple-negative breast cancer and for Kennedy's disease (spinal and bulbar muscular atrophy), a separate condition driven by the same receptor.10 In the webinar, Dr. Narayanan said the company is raising roughly $25 million to fund a refined Phase 1B/2 trial focused on twice-daily 300 mg and 450 mg dosing (a schedule not yet tested in the terminated trial, which was largely once-daily), with a goal of beginning that trial in the second half of 2026. As of this writing, IPCSG could not independently verify a new FDA filing, an active new trial registration, or completed financing for this restarted program; readers should treat the company's funding and timeline statements as forward-looking, not yet confirmed milestones.
How This Fits the Broader AR-Degrader Landscape
RAMiller's compound is not alone in trying to directly destroy the androgen receptor rather than merely block it. Other AR-targeting degraders and PROTACs (proteolysis-targeting chimeras) in clinical development include bavdegalutamide (ARV-110) and ARV-766, both of which have shown PSA50 responses in subsets of patients with ligand-binding-domain mutations.11 Dr. Narayanan noted that, to his knowledge, no other compound currently in development binds to the same N-terminus site his team targets — though the broader degrader field, including BRD4-AR "molecular glue" approaches recently presented at ASCO, is moving quickly.
The PARP Inhibitor Discussion: A Newer, More Selective Option
A meaningful part of the Q&A focused on PARP inhibitors, which are currently approved for metastatic castration-resistant prostate cancer patients with BRCA or other homologous-recombination-repair (HRR) gene mutations. Three PARP inhibitors are FDA-approved today: olaparib, rucaparib, and talazoparib. A participant asked about a newer drug, saruparib (AZD5305) — and the questioner had the details right.
Saruparib is a "PARP1-selective" inhibitor, meaning it targets PARP1 while largely sparing PARP2, the enzyme thought to be responsible for much of the blood-cell toxicity (anemia, low platelets) seen with older, dual PARP1/2 inhibitors.12 In the Phase 1/2a PETRA trial, saruparib monotherapy produced an objective response rate of 48.4% in heavily mutated, HRR-positive advanced prostate cancer patients at the 60 mg daily dose.13 It is now being tested in two large Phase 3 trials:
- EvoPAR-Prostate01 (NCT06120491) — saruparib combined with standard hormonal therapy in metastatic hormone-sensitive prostate cancer, both with and without HRR mutations.14
- EvoPAR-Prostate02 (NCT06952803) — saruparib as an "adjuvant" treatment after radiation in BRCA-mutated, high-risk localized prostate cancer; recruitment began in July 2025 and roughly 700 patients are planned.15
Saruparib is not yet FDA approved; it remains investigational. Patients curious about PARP inhibitor eligibility should ask their oncologist about germline and tumor genetic testing for BRCA1/2 and other HRR genes — testing that IPCSG has long advocated for as part of standard care.
On Immunotherapy and "Cold Tumors"
A separate exchange addressed why immunotherapy (checkpoint inhibitors like pembrolizumab) has largely disappointed in prostate cancer, unlike in melanoma or lung cancer. Dr. Narayanan and a second panelist, a pathologist specializing in functional tumor profiling, explained that most prostate tumors are "immunologically cold" — they lack the immune-cell infiltration that checkpoint drugs need to work. The one FDA-approved prostate cancer immunotherapy, sipuleucel-T (Provenge), was approved in 2010 and showed a real, if modest, survival benefit, but struggled commercially in part because it requires an individualized cell-collection and infusion process rather than a pill. Researchers continue to look for ways to make cold prostate tumors "hot" enough for immunotherapy to help, but as of this writing no such combination has reached approval.
Quick Glossary
- Androgen receptor (AR)
- The protein inside prostate cells that testosterone and other androgens attach to, switching on genes that drive cell growth — including PSA production.
- Ligand-binding domain (LBD)
- The "docking site" on the AR where testosterone (and most current AR drugs) attach.
- N-terminus domain
- A different part of the AR, not targeted by standard drugs, now being explored by next-generation degraders.
- AR splice variant (e.g., AR-V7)
- A shortened, always-on version of the AR that lacks the ligand-binding domain and is resistant to standard AR drugs.
- PROTAC / molecular glue degrader
- A drug designed to mark a target protein for destruction by the cell's own disposal system, rather than simply blocking it.
- PARP1-selective inhibitor
- A newer class of PARP inhibitor designed to spare PARP2, potentially reducing blood-related side effects.
Patient Takeaways
| Point | What It Means for You |
|---|---|
| AR splice variants drive resistance | If your cancer has progressed on multiple AR drugs, ask your care team whether AR-V7 or other resistance testing is relevant to your case. |
| ONCT-534's first trial was terminated for lack of efficacy | Encouraging early mechanism data does not guarantee a working drug — wait for confirmatory results before counting on any specific investigational therapy. |
| A relaunch under RAMiller Biotechnologies is planned but not yet confirmed as funded or active | Ask your oncologist or check ClinicalTrials.gov directly before assuming a new trial is enrolling. |
| Saruparib (PARP1-selective) is in Phase 3 testing | Genetic testing (BRCA/HRR) remains the gateway to PARP inhibitor eligibility, current or future. |
| Immunotherapy remains limited in prostate cancer | Sipuleucel-T (Provenge) is the one approved option; broader checkpoint-inhibitor use is still investigational outside of select biomarker-defined cases. |
Verified Sources
- Inventor Spotlight: Ramesh Narayanan. University of Tennessee Research Foundation. https://utrf.tennessee.edu/inventor-spotlight-ramesh-narayanan/
- ONCT-534. Oncternal Therapeutics pipeline page. https://www.oncternal.com/pipeline/onct-534/
- A Phase 1/2 Study of ONCT-534 in Subjects with Metastatic Castration-Resistant Prostate Cancer (NCT05917470). ClinicalTrials.gov protocol document. https://cdn.clinicaltrials.gov/large-docs/70/NCT05917470/Prot_SAP_003.pdf
- Oncternal Therapeutics Announces Termination of its Clinical Studies and Exploration of Strategic Alternatives. GlobeNewswire, September 12, 2024. globenewswire.com
- Phase 1/2 trial of ONCT-534 in mCRPC has been terminated. Urology Times. urologytimes.com
- Oncternal stock sinks 60% amid layoffs, trial terminations. Fierce Biotech, September 2024. fiercebiotech.com
- ONCT-534 Reduces PSA Levels, Is Tolerable in Relapsed/Refractory mCRPC. OncLive. onclive.com
- Phase I multi-center clinical and biomarker study of the dual-action androgen receptor inhibitor ONCT-534. Investigational New Drugs (Springer Nature), 2026. link.springer.com
- RAMiller Biotechnologies — company website. ramillerllc.com
- RAMiller Biotechnologies — mechanism of action description (molecular glue / N-terminus domain degraders). ramillerllc.com
- PROTACs as Therapeutic Modalities for Drug Discovery in Castration-Resistant Prostate Cancer. Annual Reviews of Pharmacology and Toxicology. annualreviews.org
- First-in-Class PARP1 Selective Inhibitor Saruparib Shines in Phase 1 Trial of Advanced Solid Tumors. OncLive. onclive.com
- PETRA trial (NCT04644068) results, as cited in OncLive coverage above (AACR 2024 presentation by Timothy Yap).
- Azad AA, et al. Saruparib in combination with androgen receptor pathway inhibitors in metastatic hormone-sensitive prostate cancer: EvoPAR-Prostate01. Future Oncology, 2026. PMID: 41979035. pmc.ncbi.nlm.nih.gov
- McKay RR, et al. Phase III, randomized, double-blind, placebo-controlled study of adjuvant saruparib (AZD5305) in patients with BRCAm localized high-risk prostate cancer (EvoPAR-Prostate02). J Clin Oncol 44, TPS412, ASCO GU 2026. ascopubs.org
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