A Phase 1b Adaptive Androgen Deprivation Therapy Trial in Metastatic Castration Sensitive Prostate Cancer

Jingsong Zhang, Jill Gallaher, Jessica J Cunningham, Jung W Choi, Filip Ionescu, Monica S Chatwal, Rohit Jain, Youngchul Kim, Liang Wang, Joel S Brown, Alexander R Anderson, Robert A Gatenby, Jingsong Zhang, Jill Gallaher, Jessica J Cunningham, Jung W Choi, Filip Ionescu, Monica S Chatwal, Rohit Jain, Youngchul Kim, Liang Wang, Joel S Brown, Alexander R Anderson, Robert A Gatenby

Abstract

Background: We hypothesize that cancer survival can be improved through adapting treatment strategies to cancer evolutionary dynamics and conducted a phase 1b study in metastatic castration sensitive prostate cancer (mCSPC). Methods: Men with asymptomatic mCSPC were enrolled and proceeded with a treatment break after achieving > 75% PSA decline with LHRH analog plus an NHA. ADT was restarted at the time of PSA or radiographic progression and held again after achieving >50% PSA decline. This on-off cycling of ADT continued until on treatment imaging progression. Results: At data cut off in August 2022, only 2 of the 16 evaluable patients were off study due to imaging progression at 28 months from first dose of LHRH analog for mCSPC. Two additional patients showed PSA progression at 12.4 and 20.5 months and remain on trial. Since none of the 16 patients developed imaging progression at 12 months, the study succeeded in its primary objective of feasibility. The secondary endpoints of median time to PSA progression and median time to radiographic progression have not been reached at a median follow up of 26 months. Conclusions: It is feasible to use an individual’s PSA response and testosterone levels to guide intermittent ADT in mCSPC.

Keywords: abiraterone; adaptive therapy; androgen deprivation therapy; apalutamide; enzalutamide; prostate cancer.

Conflict of interest statement

J.Z. has received speaker and or consulting fees from AstraZeneca, Astellas, Bayer, Dendreon, Sanofi and Pfizer. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Schema for this mCSPC adaptive therapy trial showing selection of Luteinizing hormone-releasing hormone analog (LHRH) and or a new hormonal agents (NHA) based on PSA, total testosterone (T) and imaging.
Figure 2
Figure 2
CT images of a retroperitoneal lymph node (white arrow) that has reduced from 1.53 × 1.62 cm (left) to 0.40 × 0.60 cm (right) after induction ADT in subject 103.
Figure 3
Figure 3
Swimmer Plots for 16 evaluable patients. Safety analysis included one additional patient (101) who withdrew from study treatment after refusing to restart LHRH analog at the time of his first off ADT PSA progression. Adaptive therapy was well tolerated with low frequency of all grades adverse events (AEs) regardless of the attribution. The most common Grade 1–2 treatment-related AEs were arthralgia, hot flashes, back pain and fatigue. One incidence of grade 3 hypertension was reported, which was attributed to abiraterone. All AEs were improved to baseline or resolved with recovery of testosterone while on the treatment break. There were no grade 4 AEs (Table 3).

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