Strategies to Resensitize CRPC to AR-Targeted Therapies
Castration-resistant prostate cancer (CRPC) often remains driven by the androgen receptor (AR) pathway despite resistance to standard AR-targeted treatments. Numerous strategies – from drugs and combinations to hormonal cycling and lifestyle changes – have been proposed to re-sensitize CRPC tumors to androgen receptor pathway inhibitors (ARPIs like abiraterone), AR signaling inhibitors (ARSIs like enzalutamide/darolutamide), or androgen deprivation therapy (ADT). Below is a comprehensive list of known and theoretical approaches, organized by category. Each strategy is described with its mechanism of action, evidence quality (A–F), estimated probability of success, and key references.
Pharmacological Interventions (Drugs & Combination Therapies)
These strategies use drugs (beyond standard ARPIs/ARSIs) to overcome resistance mechanisms or synergize with AR blockade:
Androgen Receptor Degraders (PROTACs) – Description: Novel bifunctional molecules that target AR for ubiquitin-proteasome degradation (e.g. ARV-110 and ARV-766). Mechanism: Bind AR and an E3 ligase to induce AR protein destruction, thereby removing both full-length and mutant AR that drive resistance. This can overcome AR mutations or amplifications that confer drug resistance. Evidence: C – Early-phase trials show some PSA responses in enzalutamide-resistant mCRPC, but data are preliminary. Prob. of Success: ~30% (estimated; some patients in Phase I had >50% PSA decline). Refs: ARV-110 Phase I results
AR N-terminal Domain Inhibitors (e.g. EPI-7386) – Description: Small molecules that block the N-terminal domain of AR, which is required for AR activity including splice variants. Mechanism: Inhibit AR’s NTD, shutting down AR-driven transcription even for variants lacking the ligand-binding domain (like AR-V7). This can reverse resistance due to AR splice variants. Evidence: C – Preclinical efficacy in enzalutamide-resistant models first-gen compound (EPI-506) showed minimal PSA declines in a Phase I/II. A more potent analog (EPI-7386) is in Phase I/II (combo with enzalutamide). Prob. of Success: ~20–30% (early clinical activity, but unproven in large trials).
Bromodomain (BET) Inhibitors – Description: Epigenetic drugs targeting BET family proteins (e.g. BRD4) that regulate AR transcription. Mechanism: Inhibit BET proteins, disrupting AR transcriptional activity and expression of AR target genes and variants. This can reduce AR signaling and overcome AR-V driven growth. Evidence: C – Preclinical studies (e.g. BRD4 inhibitor JQ1, or ZEN-3694) show restored anti-androgen sensitivity. A Phase I/II trial of ZEN-3694 + enzalutamide showed disease stabilization in some patients (early evidence). Prob. of Success: ~20% (modest activity observed; under investigation). Refs: Asangani et al. 2014 (Nature) preclinical proof-of-concept.
Histone Deacetylase Inhibitors (HDACi) (e.g. Panobinostat) – Description: Epigenetic modulators that alter chromatin structure and gene expression. Mechanism: Inhibit HDACs required for AR mRNA transcription and AR protein stability, downregulating AR and splice variants (AR-V7). Intermittent HDAC inhibition can “rewrite” the epigenetic code to restore sensitivity to antiandrogens. Evidence: C – Strong preclinical synergy: panobinostat repressed AR/AR-V7 and resensitized bicalutamide-resistant cells. Clinical monotherapy had little effect due to toxicity-limited dosing, but combination trials (HDACi + enzalutamide) are in development. Prob. of Success: ~20% (if dosing issues overcome; concept proven in vitro).
EZH2 Inhibitors (Epigenetic Reprogramming) – Description: Targeting EZH2 (a histone methyltransferase) via small molecules or antisense oligonucleotides (ASO). Mechanism: Inhibit EZH2 to reverse repressive chromatin marks. This can reactivate silenced AR expression/signaling in tumors that had shifted to an AR-independent (e.g. neuroendocrine-like) state. Reactivating AR can then resensitize cells to AR-targeted therapy. Evidence: C – Preclinical evidence in CRPC and neuroendocrine PC: EZH2 ASO caused AR pathway reactivation and restored antiandrogen sensitivity. A small-molecule EZH2 inhibitor (tazemetostat) is in early trials for CRPC. Prob. of Success: ~15% (theoretical in humans; proven in lab models).
Antiandrogen Combinations & Sequencing – Description: Using multiple AR-pathway agents in sequence or combination to overcome cross-resistance. Examples: sequencing abiraterone then enzalutamide (or vice versa), or combining ARSIs (though not typically beneficial. Mechanism: Some patients progressing on one ARPI/ARSI still respond briefly to another, possibly due to non-overlapping resistance mechanisms (e.g. abiraterone lowering androgen levels vs. enzalutamide blocking AR). Evidence: D – Sequential therapy yields limited responses (~15–30% PSA response) due to cross-resistance. No survival benefit for combining ARSIs concurrently. Prob. of Success: ~20% (short-term PSA declines common, but usually not durable). Refs: Practical clinical experience and sequencing trials (e.g. abiraterone→enzalutamide).
CYP17 & Intracrine Androgen Blockade – Description: Further suppression of residual androgen synthesis (beyond standard ADT/abiraterone). E.g. novel CYP17 lyase inhibitors or AKR1C3 inhibitors. Mechanism: Block adrenal/intratumoral steroid production that fuels AR signaling. Indomethacin, an NSAID, inhibits AKR1C3, an enzyme that converts adrenal androgen precursors to testosterone. Indomethacin thus lowers intracrine androgens in CRPC cells. Evidence: B – Preclinical: indomethacin restored enzalutamide/abiraterone sensitivity in resistant cell lines. Clinically, a Phase II trial of indomethacin + enzalutamide showed tolerability and signs of efficacy in CRPC. Prob. of Success: ~30% (for combinations like NSAIDs + ARSI in appropriate patients).
AKT/PI3K Pathway Inhibitors (e.g. Ipatasertib, Capivasertib) – Description: Target the PI3K–AKT–mTOR signaling axis often upregulated in CRPC (especially with PTEN loss). Mechanism: Inhibition of AKT can induce apoptosis and block a key escape pathway that allows AR-independent survival. Combining an AKT inhibitor with AR therapy can drastically suppress tumor growth. Evidence: B – Preclinical synergy is strong. Clinically, a Phase III trial (IPATential150) showed improved radiographic PFS by adding ipatasertib to abiraterone in PTEN-null mCRPC (median PFS ~18 vs 14 months). Another AKT inhibitor (capivasertib) similarly showed benefit in PTEN-deficient tumors. Prob. of Success: ~40% in biomarker-selected patients (PTEN-mutated) but low in others.
Src Kinase Inhibitors (e.g. Dasatinib) – Description: Src family kinases crosstalk with AR and promote CRPC progression. Mechanism: Inhibiting Src (via dasatinib) can downregulate AR-related survival pathways and even reduce expression of AR-V7 splice variant. This may resensitize tumors to AR blockade. Evidence: C – Preclinical data: dasatinib lowered AR-V7 and overcame enzalutamide resistance in cell models. Clinical trials in unselected CRPC have been mostly negative (no OS benefit as monotherapy or with chemo), but ongoing studies target specific subsets. Prob. of Success: ~15% (likely needs combination with other therapies; modest single-agent activity).
HER2/EGFR Inhibitors (e.g. Lapatinib) – Description: Blockade of receptor tyrosine kinases HER2 and EGFR. Mechanism: In abiraterone-resistant prostate tumors, ErbB2 (HER2) signaling is upregulated as a bypass pathway. Lapatinib (dual EGFR/HER2 inhibitor) can block this axis, enhancing responses to AR-pathway inhibitors. Evidence: D – Xenograft models: lapatinib plus abiraterone slowed tumor growth vs abiraterone alone; lapatinib also improved enzalutamide response by inhibiting HER2 signaling. No significant clinical trial data yet in CRPC. Prob. of Success: ~10% (theoretical until clinical confirmation).
Notch Signaling Inhibitors (γ-secretase inhibitors) – Description: Small molecules blocking Notch receptor activation (via γ-secretase). Mechanism: Notch signaling contributes to treatment resistance and stem-like cells. γ-secretase inhibitors prevent Notch receptor cleavage/activation. In CRPC models, this combined with AR inhibition curbed growth and resensitized resistant cells. Evidence: D – Preclinical only: Notch inhibition + enzalutamide or abiraterone had synergistic anti-tumor effects in vitro and in enzalutamide-resistant xenografts. No clinical trials reported yet for CRPC. Prob. of Success: ~10% (preclinical proof-of-concept, but untested in patients).
Monoamine Oxidase-A Inhibitors (MAOIs) – Description: Antidepressants like phenelzine that inhibit MAO-A, an enzyme linked to polyamine metabolism in prostate cancer. Mechanism: MAO-A inhibition appears to slow CRPC growth and may sensitize cells to enzalutamide
(mechanism under study; possibly through reducing oncogenic signaling or altering androgen metabolism). Evidence: C – A small pilot trial of phenelzine in recurrent PCa showed PSA declines in some patients, and preclinical work indicated MAOAIs enhance enzalutamide efficacy. This is an emerging repurposed strategy. Prob. of Success: ~20% (anecdotal clinical activity; needs larger validation).
Autophagy Inhibitors (e.g. Hydroxychloroquine, Metformin, Clomipramine) – Description: Agents that block autophagy, a cell survival process upregulated by androgen deprivation. Mechanism: ADT-induced stress can trigger autophagy, helping CRPC cells survive nutrient/hormone starvation. Inhibiting autophagy forces these cells into apoptosis. Metformin and clomipramine both have autophagy-inhibitory effects, in addition to metabolic impacts. They have each reversed enzalutamide resistance in cell and animal models. Evidence: C – Preclinical: combination of autophagy inhibitors with enzalutamide significantly reduced growth of enza-resistant tumors
Clinically, metformin use in ADT-treated patients was associated with improved outcomes in some studies, but prospective trials are mixed. Prob. of Success: ~20% (metformin is low-risk and widely used; likely modest benefit.
PARP Inhibitors (e.g. olaparib) with AR therapy in DNA-repair deficient tumors.
Checkpoint Inhibitors with ARSI (discussed under Immunotherapy)..
Taxane chemotherapy plus ARSI (though concurrent docetaxel+ARSI in CRPC isn’t standard). These aim to either exploit non-AR vulnerabilities or induce additive tumor kill. Mechanism: Varies – PARPi exploit synthetic lethality in BRCA-mutated CRPC, potentially allowing continued ADT; chemo can kill AR-independent cells. Evidence: B (for PARPi in biomarker-selected cases) – e.g. olaparib + abiraterone improved PFS in BRCA-mutated mCRPC. Other combos (checkpoint or chemo with ARSIs) have mostly not improved survival in unselected patients. Prob. of Success: High (~50%+) in specific genomic subsets (e.g. BRCA2) for PARPi combos, but low in unselected populations. Refs: PROfound trial (olaparib) – improved outcomes in ARPI-resistant, BRCA-mutated CRPC; KEYNOTE-641 (pembro+enza) – no benefit in all-comers.
Metabolic Strategies (Targeting Steroidogenesis & Tumor Metabolism)
These approaches modify the hormonal and metabolic environment to slow CRPC and restore hormone sensitivity:
Enhanced Steroid Suppression – Description: Further reduction of androgen synthesis beyond standard therapy. Mechanism: Building on abiraterone’s blockade of CYP17, additional measures include ketoconazole (older adrenal inhibitor), or 5α-reductase inhibitors like dutasteride to block residual DHT conversion. These aim to deprive tumors of any androgen. Evidence: D – Abiraterone is standard; adding dutasteride did not significantly improve outcomes in trials (castration already minimizes 5α-reductase substrate). Ketoconazole (pre-abiraterone era) showed PSA responses but with toxicity. Prob. of Success: ~10% (limited incremental benefit beyond current ADT/abiraterone). Refs: Historic ketoconazole studies; DUTY trial of dutasteride with ADT (no major benefit).
Statins (Cholesterol Lowering) – Description: Use of statin drugs (e.g. atorvastatin) during ADT. Mechanism: Statins reduce circulating cholesterol, the precursor for androgen synthesis, potentially lowering intratumoral androgen levels. They also may inhibit cancer cell growth via the mevalonate pathway. Evidence: B – Clinical data show men on ADT plus a statin have longer time to progression: one study found median 27.5 vs 17.4 months before PSA progression for statin users vs non-users.
Statin use was associated with a 10-month delay in castration resistance.
Prob. of Success: ~30% (as an adjunct to ADT: high safety and low cost support its use).
Biguanides (Metformin) – Description: Anti-diabetic drug metformin, repurposed for its metabolic and anti-cancer effects. Mechanism: Metformin lowers insulin and IGF-1, which are growth factors for prostate cancer; it also activates AMPK, potentially inhibiting mTOR and reducing anabolic processes in tumor cells. By altering tumor metabolism, metformin can slow CRPC growth and has been shown to improve efficacy of ARSIs in lab models.
Evdence: C – Epidemiologic studies suggest improved outcomes in diabetic prostate cancer patients on metformin. Preclinical data: metformin enhanced enzalutamide/abiraterone effects in vitro
Ongoing trials are testing metformin in CRPC. Prob. of Success: ~20% (likely a modest slowing of progression rather than dramatic regression
Adrenal/Glucocorticoid Modulation (Steroid Switch) – Description: Tactic used in patients on abiraterone + prednisone who show progression – switch prednisone to a more potent glucocorticoid like dexamethasone. Mechanism: Abiraterone suppresses CYP17 and raises ACTH, which can drive upstream steroidogenesis. Low-dose prednisone mitigates side effects, but tumor can adapt. Dexamethasone more strongly suppresses ACTH and also has a longer half-life, further lowering adrenal androgens. In addition, some tumor cells upregulate steroid-activating enzymes (like AKR1C3) that prednisone (but not dexamethasone) feeds into; dexamethasone bypasses this pathway. Evidence: B – A Phase II pilot showed that in men progressing on abiraterone+prednisone, switching to abiraterone+dexamethasone led to renewed PSA declines and disease control in a subset. Median duration of benefit can be several months. Prob. of Success: ~30% (in “prednisone-resistant” patients, dexamethasone switch often induces a response.
Tumor Metabolic Reprogramming – Description: Emerging attempts to exploit CRPC’s altered metabolism (e.g. reliance on fatty acid oxidation or glutamine). Mechanism: For instance, inhibitors of lipid oxidation (CPT1A inhibitors) or glutaminase inhibitors might starve CRPC cells that have adapted to low-androgen conditions by using alternate fuels. Evidence: D – Preclinical only. Example: blockade of acetate metabolism or short-chain fatty acid supply inhibited CRPC growth in lab models. No clinical trials yet showing efficacy. Prob. of Success: ~10% (highly experimental).
Radiotherapy and Theranostics
These strategies use targeted radiation to kill resistant cells, potentially allowing AR-directed therapies to work on remaining disease:
Radium-223 Dichloride – Description: An alpha-particle emitting radiotherapeutic that targets bone metastases (calcium-mimetic). Mechanism: Radium-223 deposits in areas of active bone turnover (sites of bone metastasis) and emits high-energy alpha radiation causing double-strand DNA breaks in nearby cancer cells. By selectively killing tumor cells in bone, it can reduce total tumor burden and alleviate the “sanctuary” sites of ARI-resistant growth. Evidence: A – A phase III trial (ALSYMPCA) showed significantly improved overall survival with radium-223 in mCRPC metastatic to bone (median OS 14.9 vs 11.3 months).
along with delayed skeletal complications. It’s FDA-approved. Prob. of Success: ~50% (for prolonging survival in bone-predominant CRPC
though it does not directly resensitize AR signaling).
[^177Lu]PSMA-617 (Radioligand Therapy) – Description: A radiotheranostic agent (Lutetium-177 labeled PSMA ligand) that delivers beta radiation to PSMA-expressing prostate cancer cells. Mechanism: PSMA-617 ligand binds to the PSMA protein abundant on CRPC cells, and the attached Lu-177 emits beta radiation, killing the cell and nearby cells. This therapy can drastically reduce tumor burden, potentially allowing previously ineffective ADT/ARPI to regain some control over residual disease. Evidence: A – The VISION Phase III trial showed Lu-177–PSMA significantly improved survival in post-ARPI mCRPC: median OS 15.3 vs 11.3 months (HR 0.62) with 46% of patients achieving >50% PSA declines. Now FDA-approved (Pluvicto). Prob. of Success: ~50% (high efficacy in PSMA-positive mCRPC can be combined with ongoing ADT). Refs: Sartor et al., 2021 (NEJM); VISION trial summary. External Beam Radiotherapy (EBRT) to Oligoprogression – Description: Directed radiation to one or few progressing metastatic lesions while continuing systemic AR therapy. Mechanism: Eliminates ARI-resistant clones at isolated sites, allowing continued control of remaining disease with AR-targeted therapy. This “weeds the garden” approach can prolong the usefulness of a given systemic therapy. Evidence: B – In oligometastatic PCa, SBRT to lesions delayed progression. In CRPC, case series report prolonged stabilization when oligoprogressive sites are ablated. Ongoing trials (e.g. ORIOLE, TRAP) are evaluating this formally. Prob. of Success: ~30–40% in carefully selected patients (buying time before changing systemic therapy). Refs: Ost et al., 2018 (ORIOLE trial for oligomets); empirical clinical practice.
**Alpha-Emitter Theranostics (e.g. [^225Ac]PSMA-617) – Description: Experimental PSMA-targeted therapy using an alpha emitter (Actinium-225) instead of beta emitter. Mechanism: Alpha particles have higher energy and shorter range, potentially causing lethal damage even in ARI-resistant micro-metastases with minimal collateral damage. Evidence: C – Early reports in advanced CRPC show high PSA response rates even after failure of beta-emitting RLT, but significant toxicity (xerostomia). No randomized trials yet. Prob. of Success: ~25% (promising activity but needs refinement due to side effects). Refs: Kratochwil et al., 2018 (Lancet Oncol) – initial ^225Ac-PSMA study results.
Immunotherapy and Microenvironment Modulation
Immunotherapeutic approaches aim to harness the immune system or alter the tumor microenvironment (TME) to attack CRPC cells, potentially targeting AR-resistant cell populations and allowing AR therapies to work on the rest:
Checkpoint Inhibitors (PD-1/PD-L1 and CTLA-4) – Description: Immune checkpoint blockade with antibodies like pembrolizumab (anti–PD-1) or ipilimumab (anti–CTLA-4). Mechanism: Can unleash T-cells against prostate cancer cells. While prostate cancer is generally “cold” (low mutation burden), a subset (e.g. MSI-high or CDK12-mutated tumors) has neoantigens that elicit immune responses. In those cases, checkpoint inhibitors can cause tumor regression and may eliminate ARI-resistant clones. Evidence: C – Pembrolizumab is approved for MSI-high solid tumors including a small fraction of CRPC, with ~20% response rates in that group. In AR-V7-positive, ARPI-resistant mCRPC, pembrolizumab yielded PSA or radiographic responses in ~18% in a Phase II trial. However, in unselected mCRPC, PD-1 ± enzalutamide did not improve survival (KEYNOTE-641 was negative)
Ipilimumab monotherapy also failed to improve OS in post-docetaxel CRPC. Prob. of Success: ~5–10% overall (higher, ~20–40%, if proper biomarkers like MSI-H, high TMB, or CDK12 loss are present).
Cancer Vaccines (Cell-based or Viral) – Description: Therapeutic vaccines that prime the immune system against prostate tumor antigens. Sipuleucel-T ( Provenge) is an autologous dendritic cell vaccine loaded with a prostate antigen (PAP). Others include PROSTVAC (viral vector vaccine targeting PSA). Mechanism: Trains immune cells to recognize and attack prostate cancer, which could eliminate resistant cells and potentially restore equilibrium where ADT can control remaining tumor. Evidence: B – Sipuleucel-T showed a modest but significant survival benefit in asymptomatic mCRPC (median OS +4 months) in a Phase III trial, despite no PSA responses【no PSA drop reference】. PROSTVAC failed to improve survival in a Phase III trial (negative). Prob. of Success: ~10–20% (sipuleucel-T benefit is small but real【no citation】; other vaccines yet to show benefit). Refs: Kantoff et al., 2010 (NEJM) – Sipuleucel-T trial; Gulley et al., 2019 – PROSTVAC trial.
Tumor Microenvironment (TME) Modulation – Description: Targeting TME factors (cytokines, growth factors, stromal interactions) that contribute to AR therapy resistance. Mechanism: CRPC cells often thrive with help from the microenvironment – e.g. IL-6 and STAT3 signaling can promote AR-independent growth and neuroendocrine differentiation; TGF-β fosters an invasive, AR-low phenotype; tumor-associated macrophages provide survival signals. Strategies include IL-6 blockade (e.g. siltuximab), JAK/STAT inhibitors, TGF-β inhibitors (e.g. galunisertib), or CSF1R inhibitors (to deplete protumoral macrophages). By disrupting these, tumors may revert to a more AR-dependent state or become vulnerable overall. Evidence: D – Preclinical and early-phase evidence mainly. Example: IL-6 inhibition in CRPC showed some PSA declines but no proven long-term benefit. A trial of galunisertib + enzalutamide suggested potential benefit in patients with certain tumor markers, but data are preliminary. Prob. of Success: ~10% (likely needs combination with other treatments; patient selection critical). Refs: Lee et al., 2019 – IL-6 in NEPC; Zhang et al., 2020 – TGFβ and lineage plasticity in CRPC.
Bispecific T-cell Engagers and CAR-T cells – Description: Novel immunotherapies like PSMA-directed bispecific antibodies (e.g. AMG 160) or CAR-T cells engineered to target PSMA or other prostate antigens. Mechanism: These bring T-cells directly to tumor cells, causing immune killing independent of AR signaling status. Eradicating AR-inhibitor–resistant cells could allow ADT/ARPI to control any remaining AR-driven cells. Evidence: C – Early-phase trials of PSMA bispecifics have shown encouraging response rates in heavily pretreated CRPC (PSA declines and some tumor shrinkage). CAR-T for solid tumors are still experimental; some cases of partial responses with PSMA CAR-T have been reported, alongside toxicity. Prob. of Success: ~20% (if toxicity can be managed and in conjunction with other therapy). Refs: Ferdinandus et al., 2022 – AMG 160 results; Zhang et al., 2021 – PSMA CAR-T case studies.
Dietary and Supplement-Based Approaches
Nutritional strategies and supplements have been explored for their potential to slow CRPC progression or enhance hormone therapy efficacy. These are largely supportive or preventive in nature, with limited direct evidence of resensitizing tumors, thus considered theoretical or adjunct:
Low-Carbohydrate / Low-Insulin Diet – Description: Dietary approach to reduce insulin spikes and metabolic syndrome (e.g. ketogenic or low glycemic diet). Mechanism: High insulin and obesity can promote CRPC progression via increased IGF and inflammatory signaling. Calorie or carb restriction may create a less growth-permissive metabolic environment, potentially slowing CRPC and maintaining sensitivity to ADT. Evidence: D – Some mouse studies show slowing of CRPC on low-carb/low-fat diets. Clinically, correlation studies indicate obese men progress faster on ADT, but formal trials of diet in mCRPC are lacking. Prob. of Success: ~10% (likely modest effect on tumor dynamics, but positive impact on patient health).
Omega-3 Fatty Acids and Dietary Fats – Description: Adjusting fatty acid intake (e.g. increasing fish oil omega-3, reducing saturated and omega-6 fats). Mechanism: Omega-3 fatty acids have anti-inflammatory effects and may reduce prostaglandin and androgen synthesis precursors, theoretically slowing CRPC growth. Evidence: E – Epidemiologic data on fish oil and prostate cancer are mixed; no clear evidence that omega-3 supplements reverse resistance. One hypothesis is that a high omega-3/omega-6 ratio could reduce AR activation via less inflammation. Prob. of Success: ~5% (unproven in CRPC; possibly beneficial for general health). Refs: (Nutrition and prostate cancer reviews, mixed results).
Phytonutrient Supplements – Description: Natural compounds with purported anti-cancer effects, often taken as supplements. Examples: Curcumin (from turmeric), Resveratrol, Green tea catechins (EGCG), Lycopene (tomato extract), Sulforaphane (broccoli sprout extract). Mechanism: Many of these have anti-androgen or anti-proliferative activity in preclinical models. For instance, lycopene and curcumin can downregulate AR or AR target genes in cell studies; green tea polyphenols showed preventive effects. They may also act as antioxidants or epigenetic modulators. Evidence: D/F – Largely preclinical and anecdotal. A mouse model showed tomato-rich diet slowed CRPC progression. Small human studies (non-randomized) suggest PSA stabilization in some patients taking these supplements, but no high-level evidence of tumor resensitization. Prob. of Success: <10% (mainly supportive care, unlikely to overcome established resistance on their own).
Vitamin D Optimization – Description: Ensuring adequate Vitamin D levels or high-dose calcitriol in prostate cancer patients. Mechanism: Vitamin D has differentiating and mild anti-proliferative effects in prostate cells. Vitamin D receptor activation might synergize with AR pathway blockade (since both receptors can interact). Evidence: D – Observational studies link low Vitamin D with aggressive PCa. A randomized trial of calcitriol plus docetaxel (ASCENT) showed improved PSA responses but not survival. No clear evidence that Vitamin D reverses ARI resistance, but it supports bone health during ADT. Prob. of Success: ~10% (for cancer control; important for bone/supportive care). Refs: Beer et al., 2007 (JCO) – calcitriol + chemo trial.
Note: While dietary and supplement approaches have low evidence for resensitizing CRPC, they are generally low-risk and may be combined with standard treatments to support overall health. They should not replace proven therapies, but rather complement them (with physician guidance).
Hormonal Cycling Strategies
Unlike continuous suppression, these approaches deliberately alternate hormonal conditions to exploit tumor adaptive dynamics:
Bipolar Androgen Therapy (BAT) – Description: An intermittent strategy cycling between supraphysiologic testosterone and rapid androgen deprivation. Patients receive high-dose testosterone injections followed by resumed ADT, in a monthly cycle. Mechanism: Several effects are proposed: high androgen causes DNA double-strand breaks in prostate cancer cells and can induce cell death
; it “shocks” cells adapted to low-androgen conditions, leading to lethal genomic instability. BAT also downregulates AR variants like AR-V7 and represses oncogenes (MYC, SKP2) associated with resistance. After high-T exposure, tumor AR levels often drop and cells become re-sensitized to the next androgen-deprivation phase. In essence, BAT exploits the tumor’s AR addiction by oscillating the ligand supply. Evidence: A− – Multiple Phase II trials have shown BAT is safe and can induce responses even in ARPI-resistant mCRPC. Notably, ~30% of men had ≥50% PSA declines on BAT, and importantly, when subsequently re-challenged with enzalutamide or abiraterone after BAT, the majority (12 of 13 in one study) regained sensitivity, achieving PSA reductions. This resensitization effect has been reproduced in trials (e.g. RESTORE, TRANSFORMER). Ongoing Phase III research is evaluating BAT in larger cohorts. Prob. of Success: ~70% (about two thirds of patients derive clinical benefit from BAT and/or subsequent ARSI re-challenge.
Intermittent Androgen Deprivation Therapy (IADT) – Description: Cycling ADT on and off, typically in men responding to initial ADT, to allow intermittent recovery of testosterone before reintroducing ADT. Mechanism: By periodically re-exposing the tumor to androgens, IADT may prevent or delay permanent adaptations to low-androgen environment. During the “on” phase, ADT still kills AR-dependent cells; during the “off” phase, normal androgen levels may cause differentiated (AR-dependent) tumor cells to outgrow any androgen-independent subclones, thus restoring the pool of hormone-sensitive cells. This aims to prolong the overall sensitivity of the cancer to androgen withdrawal. Evidence: B – Large trials in hormone-sensitive prostate cancer have shown intermittent ADT yields similar overall survival to continuous ADT, with improved quality of life.
Some analyses suggest intermittent therapy might slightly extend time to castration resistance in non-metastatic disease though results vary. In mCRPC, IADT is less studied, but clinical practice uses IADT in earlier disease stages to delay resistance and side effects. Prob. of Success: ~20–30% (in delaying resistance – IADT is effective for palliation/QOL, with oncologic outcomes comparable to continuous therapy in many cases
Sequential Anti-androgen Withdrawal and Re-challenge – Description: Observing the anti-androgen withdrawal phenomenon and then re-administering AR pathway blockers. Mechanism: Long-term use of first-generation anti-androgens (bicalutamide, flutamide) can select for AR mutations that paradoxically convert these drugs into agonists. Stopping the drug (withdrawal) leads to tumor regressions in ~15–30% of cases (temporary PSA drop) as the mutant AR is no longer activated by the drug. While this classic withdrawal effect is short-lived, subsequent switch to a different ARSI may then be effective. Even with modern ARSIs, if resistance involves an antagonist-to-agonist mutation (e.g. enzalutamide resistance via AR F877L), stopping the drug might help, then a different ARSI (like darolutamide which maintains activity despite certain mutations) can be introduced. Evidence: C – Anti-androgen withdrawal is an established clinical observation for first-gen agents【no specific citation】. For second-gen ARSIs, case reports suggest withdrawal or switching to an alternate ARSI (with a different profile) can produce responses in a minority of patients. Prob. of Success: ~15% (withdrawal responses are usually transient). Refs: Scher et al., 2004 – bicalutamide withdrawal syndrome; recent case studies in AR mutation-driven resistance.
Estrogenic Therapy (High-Dose Estrogens) – Description: An old hormonal therapy being reconsidered (e.g. diethylstilbestrol or transdermal estrogen in CRPC). Mechanism: Estrogens suppress LH production (alternative way to lower androgens) and also directly induce apoptosis in prostate cancer cells via estrogen receptor-beta. They can modulate AR co-regulators and reduce AR protein levels. Intermittent estrogen therapy might therefore resensitize cells to ADT by providing a different hormonal milieu. Evidence: C – DES was used before modern ARPIs; it can produce PSA responses in CRPC but with cardiovascular risk. Modern transdermal estradiol is safer on clots and has shown PSA declines in some CRPC patients even post-enzalutamide. No definitive trials against newer agents, but there is renewed interest in combination with AR blockers (to exploit a double-hit on the AR axis). Prob. of Success: ~20% (PSA response rate in CRPC with estrogen therapy historically ~20%, but survival impact unclear). Refs: Fowler & Whitmore, 1981 – DES in CRPC; PEACE-1 trial arm exploring estradiol patches.
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Each strategy above has a distinct rationale and varying levels of support. In summary, the most evidence-backed approaches (Grade A/B) include BAT (demonstrated clinical resensitization to AR therapy) and certain combination therapies in molecularly defined groups (e.g. adding AKT inhibitors in PTEN-loss, PARP inhibitors in BRCA-mutated cases, or using radium-223 and Lu-PSMA radioligands to extend survival). Many other interventions (Grades C–E) are in experimental or early phases – they offer promising paths to overcome resistance but require further clinical validation. Given the heterogeneity of CRPC, a combination of these strategies, tailored to an individual’s tumor biology (AR mutations, splice variants, metabolic profile, etc.), will likely be necessary to re-sensitize resistant disease to AR-targeted therapies
ADT vacation versus Continuous
2nd pBAT cycle results: AR upregulation? Double strand breaks? Darolutamide?
