Rucaparib plus enzalutamide in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Pharmacokinetics (PK) and safety data from the phase Ib RAMP study.

79 Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi), is approved in the US as monotherapy for BRCA1/2 mutated mCRPC that has been treated with androgen receptor (AR)-directed therapy and a taxane. In previous studies, synthetic lethality was observed with a combination of AR-directed therapy (eg, enzalutamide) and a PARPi, independent of DNA-damage repair gene defects. The potential for drug-drug interaction between rucaparib and enzalutamide was recognized as enzalutamide is a strong clinical inducer of CYP3A4, a mediator of the formation of rucaparib metabolite M324. RAMP (NCT04179396) is investigating the combination of rucaparib and enzalutamide in unselected pts with mCRPC to assess PK and safety and inform subsequent studies. Methods: Eligible pts had 0–2 lines of AR-directed therapy and ≤2 lines of chemotherapy for mCRPC. Prior PARPi treatment was not allowed. A 1-week run-in of rucaparib monotherapy (600 mg BID) was followed by rucaparib (600 mg BID) + enzalutamide (160 mg QD) in continuous 28-day cycles. Trough PK was evaluated for rucaparib and enzalutamide and their metabolites (M324 and N-desmethyl enzalutamide). Dose-limiting toxicities (DLTs) were assessed during the first 2 cycles. Primary endpoints were PK and safety for the combination. Secondary endpoints were change from baseline in prostate-specific antigen (PSA) levels and objective response rate (per modified RECIST/PCWG3). Results: As of Oct 1, 2020, 8 pts had received treatment; 7 were evaluable for PK and 6 for DLTs. The median age was 68.5 years, and 6/8 (75%) pts had ≥2 prior mCRPC therapies. Rucaparib and M324 reached apparent steady-state PK at the end of the run-in period. Concomitant treatment with enzalutamide had no significant effect on the PK of either rucaparib or M324. The PK of enzalutamide and N-desmethyl enzalutamide in the combination were also consistent with monotherapy enzalutamide PK data. No DLTs were reported. The most common grade ≥3 TEAEs among all 8 pts were anemia (n = 5) and fatigue (n = 4). Seven of 8 (87.5%) pts required a dose modification (treatment interruption or dose reduction). Four of 8 (50%) pts had a confirmed PSA response (reduction ≥50% from baseline); 1/1 (100%) pt with measurable disease achieved a confirmed complete radiographic response. At the time of data cutoff, 1/8 (12.5%) pts was on study for &gt; 6 cycles. Conclusions: A combination of enzalutamide and rucaparib was not associated with a clinically significant effect on PK profiles of either drug. No DLTs were observed. The overall safety profile of rucaparib 600 mg BID + enzalutamide 160 mg QD was consistent with that observed in monotherapy. These PK, safety, and early efficacy data support further studies of rucaparib and enzalutamide at the recommended combination dose, including in the phase 3 CASPAR study in pts with mCRPC (NCT04455750). Clinical trial information: NCT04179396. </jats:p

Tasquinimod and survival in men with metastatic castration-resistant prostate cancer: Results of long-term follow-up of a randomized phase II placebo-controlled trial.

4550 Background: Tasquinimod (T) is an oral quinoline-3-carboxamide derivative that binds S100A9 protein and has preclinical anti-angiogenic and anti-tumor activity. Between 12/07-6/09, 201 (134 T, 67 Placebo (P)) men with metastatic CRPC were randomized and received treatment once-daily at an initial dose of 0.25 mg/day escalated to 1.0 mg/day over 4 weeks. Placebo patients could cross over to T after 6 months or at disease progression. The primary endpoint of improved PCWG2 criteria-defined progression at 6 months was met (69 vs. 37% of patients (T/P) were progression free) with PFS of 7.6 vs. 3.3 months for pts on T vs. P1 with acceptable toxicity. This abstract provides the first analysis on symptomatic progression, overall survival (OS) as well as a multivariate analysis for PFS and OS. Methods: Survival data were collected between June 2011 and January 2012 with a median time to censoring of 32 months. Survival data was also evaluated in an exploratory multivariate model of known prognostic factors in CRPC. Results: An imbalance of several baseline prognostic criteria favored placebo (e.g. baseline PSA of 29 vs. 19 (T/P)) (JCO 2011;20:4022). Time to symptomatic progression was longer in T treated patients (p=0.039, HR=0.42). Record of death (97 events) or survival &gt;13 months was documented in 182 patients. Median time to death was 34.2 vs. 30.2 months (T/P). Median time to death in the PCWG2 bone-metastatic subgroup (N=92/44) was 34.2 vs. 25.6 months. A multivariate analysis of known prognostic factors including PSA, LDH, PSA kinetics, and hemoglobin demonstrated an adjusted HR for PFS of 0.54 (95% CI 0.37,0.81) and OS of 0.72 (95% CI 0.46,1.12) in the total population and 0.63 (95% CI 0.37,1.07, n=136) in the bone-metastatic group. Conclusions: OS observed after tasquinimod treatment is longer than previously reported in this patient population. The current exploratory data indicates that the prolongation in PFS observed with tasquinimod treatment may lead to a survival advantage in men with metastatic CRPC. A phase III placebo-controlled study (NCT01234311) is ongoing in men with bone-metastatic CRPC powered to detect an OS improvement. </jats:p

TRANSFORMER: Bipolar androgen therapy (BAT) versus enzalutamide (E) for castration-resistant metastatic prostate cancer (mCRPC).

5517 Background: Rapid cycling between high and low testosterone (T) (i.e BAT) produces tumor response in mCRPC, and may overcome resistance to newer AR therapies. Here we report a randomized study comparing BAT to E in men with mCRPC progressing on abiraterone (A). Methods: In this phase 2 trial, men received either T cypionate 400mg IM (BAT) once every 28 days or daily oral E 160mg. Primary endpoint was clinical/radiographic PFS; crossover was permitted at progression. Secondary endpoints were OS, PSA progression to primary and crossover therapy, PSA and objective responses (OR), time to PSA progression from randomization through crossover (PFS2), quality of life (QoL), and AEs. Results: 195 men were randomized (94 to BAT, 101 to E). Results are presented in table. Although diametrically opposed therapies, median PFS and PSA response in the intent-to-treat (ITT) population was not significantly different between BAT and E. OR and OS favored BAT. For those who received BAT and then crossed over to E the PSA50 response was 77.8% and time to PSA progression was 10.9 mo compared to 25.3% and 3.8 mo for those receiving E immediately after A. The sequence of treatment had a significant effect on median PSF2 which was 28.2 mo for men receiving BAT→E vs. 19.6 m for E→BAT. For men who crossed over from BAT to E, OS was 37.3 mo vs. 28.6 months for those receiving E without crossover. AEs were primarily grade 1-2 in the BAT arm and included fatigue, generalized pain, and lower extremity edema. BAT improved QoL (fatigue, physical functioning, sexual function) vs. E. Conclusions: BAT could be safely administered to asymptomatic men with mCRPC. BAT produced a comparable PFS to E in A-refractory mCRPC pts. However, PSA50 and OR after crossover, as well as PFS2, were significantly improved in men who received BAT→E versus E→BAT. OS in men receiving BAT→E was 37.3 mo, exceeding historical expectations. These results support the hypothesis that treatment with BAT is safe, has efficacy and can restore sensitivity to antiandrogens. Clinical trial information: NCT02286921 . [Table: see text] </jats:p