Findings from a phase II trial demonstrate the potential of transdermal oestradiol (tE2) patches as androgen deprivation therapy (ADT) for men with metastatic (M1) prostate cancer who are on androgen receptor pathway inhibitors (ARPI).

“[We sought to evaluate tE2 because] by switching from oral to patches, you abrogate the cardiovascular thromboembolic problems seen with oral therapies … Two to three patches [may] suppress testosterone down to castrate levels,” said lead study author Dr Nicholas James from the Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, London, UK, at ASCO GU 2025.

“We were very interested to see what happens if you combined tE2 with ARPI. [We found that] tE2 plus ARPI is effective,” he said. “The prostate-specific antigen (PSA) response was identical between men with M1 prostate cancer treated with tE2 plus ARPI and those receiving luteinizing hormone-releasing hormone analogue (LHRHa) plus ARPI.”

In the first 24 weeks, 61 percent of men in both tE2 and LHRHa arms had achieved the primary outcome of a PSA nadir of ≤0.2 ng/mL. [ASCO GU 2025, abstract 21]

Safety profile

LHRHas ? the current standard form of ADT for prostate cancer ? are tied to adverse effects such as hot flashes, fatigue, and bone density loss. According to James, patients consider hot flashes and fatigue as the most troublesome side effects.

In the study, the incidence of any-grade hot flashes was markedly lower among men on the tE2 patches as opposed to those on LHRHa during the first 12 months (18 percent vs 54 percent), as was the rate of any-grade hypertension (5 percent vs 20 percent). Conversely, use of the tE2 patches led to higher rates of any-grade gynecomastia (45 percent vs 10 percent) and pruritus (21 percent vs 5 percent).

Nonetheless, tE2 plus ARPI is deemed safe, with no new safety signals emerging among recipients.

ASCO expert Dr Bradley McGregor from the Dana-Farber Cancer Institute, Boston, Massachusetts, US, shared his insight in a separate ASCO news release. “ADT remains the cornerstone of treatment for M1 prostate cancer. While traditionally pursued with LHRH agonists or antagonists, tE2 offers similar results with a different toxicity profile … As therapy has moved to incorporate ARPI earlier in the treatment, this study shows tE2 can be safely given with ARPI.”

Repurposing an old drug

The study comprised 79 men with M1 hormone-sensitive prostate cancer (median age at randomization 69 years, 62 percent T3) from the STAMPEDE trial who were scheduled to begin ARPI therapy. They were randomized to receive either tE2 (n=38) or LHRHa (n=41). The median PSA at randomization was 39 in the tE2 arm and 47 in the LHRHa arm.

A majority of participants in the tE2 and LHRHa arms used enzalutamide as ARPI (82 percent and 61 percent, respectively), followed by abiraterone (16 percent and 29 percent) and apalutamide (3 percent and 10 percent).

In summary, the pros of tE2 patches appear to outweigh their cons: they suppress testosterone without oestrogen depletion, increase bone density, are inexpensive, with no excess of thromboembolic events associated with oral oestrogen.

Compared with conventional ADT, other advantages of tE2 documented in previous reports are improved quality of life and cardiovascular risk markers such as blood pressure, cholesterol and glucose, and reductions in fatigue and sexual impact, James noted.

Despite the relatively small sample size and short follow-up, the findings imply that tE2 patches may be a viable alternative strategy for ADT, providing M1 prostate cancer patients with another therapeutic option.

“The findings are of global relevance, as [many] people across the world are paying for their own treatment. This is a really cheap treatment,” said James. “This sort of repurposing of an older, cheap drug is an important way to improve outcomes, separate from developing new drugs.”