A Phase I Study of Abiraterone Acetate Combined with BEZ235, a Dual PI3K/mTOR Inhibitor, in Metastatic Castration Resistant Prostate Cancer

Abstract

Lessons Learned.

• The combination of standard dose abiraterone acetate and BEZ235, a pan‐class I PI3K and mTORC1/2 inhibitor, was poorly tolerated in men with progressive mCRPC.

• Although the clinical development of BEZ235 has been discontinued in prostate cancer, agents that more selectively target PI3K‐AKT‐mTOR signaling may have a more favorable therapeutic index and should continue to be explored.

Background.

Androgen receptor (AR) and phosphatidylinositol‐3 kinase (PI3K) signaling are two commonly perturbed pathways in prostate cancer. Preclinical data have shown that the two pathways compensate for each other when one is inhibited, and combined inhibition of AR and PI3K signaling may be a viable strategy to prevent or overcome castration resistance.

Methods.

This phase I study evaluated the safety and tolerability of abiraterone acetate and prednisone combined with BEZ235, a dual PI3K and mTORC1/2 inhibitor, in men with progressive metastatic castration resistant prostate cancer (mCRPC) who have not received prior chemotherapy.

Results.

Six patients (n = 6) were treated at the starting dose level of abiraterone acetate 1,000 mg with prednisone 5 mg twice daily and BEZ235 200 mg twice daily in a 3 + 3 dose escalation design. The study was terminated early because three of the six patients (50%) experienced dose‐limiting toxicities: grade 3 mucositis, grade 3 hypotension, and grade 4 dyspnea and pneumonitis. All six patients had previously progressed on abiraterone/prednisone. The median treatment duration was 27 days (range: 3–130 days). No prostate‐specific antigen (PSA) decline or objective response were observed.

Conclusion.

The combination of standard‐dose abiraterone/prednisone with BEZ235 200 mg twice daily was poorly tolerated in patients with mCRPC. The on‐target and off‐target effects of dual PI3K and mTORC inhibition likely contributed to the unacceptable toxicity profile. The Oncologist 2017;22:503–e43

Discussion

AR signaling and PI3K‐AKT‐mTOR signaling are among the most common aberrant pathways found in advanced prostate cancer and are implicated in the development and maintenance of castration resistant disease. Preclinical prostate cancer models have shown crosstalk and cross‐regulation between the two pathways, and enhanced tumor control with combination strategies that co‐inhibit AR and PI3K‐AKT‐mTOR signaling.

We report results of a phase I study evaluating the safety and tolerability of standard dose abiraterone acetate (1,000 mg daily with prednisone 5 mg b.i.d.) combined with BEZ235, a potent dual pan‐class I PI3K and mTORC1/2 inhibitor, in patients with progressive mCRPC. The original study design planned to determine the maximum tolerated dose (MTD) of the combination during 3 + 3 dose escalation, followed by a dose expansion phase to assess efficacy. The study protocol specified that if >1 of 3 or >2 of 6 patients experience a dose‐limiting toxicity (DLT) at dose level 1, the study would be terminated. One of the first three patients accrued experienced a DLT at dose level 1 (abiraterone/prednisone plus BEZ235 200 mg b.i.d.), and three more patients were accrued at dose level 1 (Table 1). Two of the last three patients also experienced DLT, and the study was terminated due to lack of safety as specified by study protocol. The median age of the patients was 71 years (range: 59–75 years). The majority of patients (83.3%) had Gleason 8–10 disease. All patients had bone metastases with or without nodal metastasis; no patients had visceral metastases. All patients had previously progressed on abiraterone.

Table 1. Dose‐limiting toxicities.

The combination of standard dose abiraterone acetate and BEZ235 200 mg b.i.d. was poorly tolerated. The median treatment duration was 27 days (range: 3–130 days). The most common adverse events were oral mucositis (83.4%), diarrhea (66.7%), nausea (50.0%), anorexia (50.0%), weight loss (50.0%), and musculoskeletal pain (50.0%). The DLTs experienced by patients (n = 3, 50%) were grade 3 mucositis, grade 3 hypotension, and grade 4 dyspnea and pneumonitis. Five patients (83%) came off study because of study‐related adverse events, and one patient came off study due to disease progression. No patient achieved any level of PSA decline (Fig. 1). The best radiographic response in two patients was stable disease. The clinical development of BEZ235 as a potential therapy for prostate cancer has been discontinued.

Figure 1.

Study schema. †, Phase 1 abiraterone dose was 1,000 mg daily with prednisone 5 mg b.i.d. and BEZ235 at MTD. ‡, Phase 2 starting dose was abiraterone 1,000 mg daily with prednisone 5 mg b.i.d. and BEZ235 at MTD. §, If >1 of 3 or ≥2 of 6 patients experienced a dose‐limiting toxicity at dose level 1, the study would be terminated.

Abbreviations: BL, baseline; BID, twice daily; MTD, maximum tolerated dose; mTOR, mechanistic target of rapamycin; ORR, objective response rate; PFS, progression‐free survival; PI3K, phosphoinositide 3‐kinase; PSA, prostate‐specific antigen; W12, week 12.

Trial Information

Disease

Prostate Cancer

Stage of disease/treatment

Metastatic/Advanced

Prior Therapy

No designated number of regimens

Type of study

Phase I/II

Primary Endpoint

Safety and feasibility

Secondary Endpoint

Pharmacokinetics studies were not performed because the study was terminated early.

Additional Details of Endpoints or Study Design

 

The original study design planned to determine the MTD of the combination of abiraterone acetate and BEZ235 during 3 + 3 dose escalation (phase I), followed by a dose expansion phase to assess efficacy (phase II). The primary endpoint of the phase I study was to determine the safety and feasibility of combining BEZ235 and abiraterone acetate. The primary endpoint of the phase II study was PSA response rate, by >50%, at 12 weeks. The study protocol specified that if >1 of 3 patients or >2 of 6 patients experience a dose‐limiting toxicity (DLT) at dose level 1, the study would be terminated (Fig. 2).

 

Investigator's Analysis

Poorly tolerated/not feasible

Figure 2.

Percentage PSA change from baseline during study period for patients who received at least 1 month of study treatment. The longest treatment break was 12 days in patient 2.

Abbreviation: PSA, prostate‐specific antigen.

Drug Information

Drug 1

 

Generic/Working name

Abiraterone acetate

Trade name

Zytiga

Company name

Janssen Biotech

Drug type

Small molecule

Dose

milligrams (mg) per flat dose

Route

oral (p.o.)

Schedule of Administration

1,000 mg daily (given with prednisone 5 mg twice daily)

Drug 2

 

Generic/Working name

BEZ235

Trade name

N/A

Company name

Novartis

Drug type

Small molecule

Drug class

PI3 kinase

Dose

milligrams (mg) per flat dose

Route

oral (p.o.)

Schedule of Administration

200 mg twice daily

Patient Characteristics

Number of patients, male

6

Number of patients, female

0

Stage

Metastatic, castration resistant

Age

Median (range): 71 years (59–75 years)

Number of prior systemic therapies

Median (range): 2 (1–3)

Performance status: ECOG

0 — 4

1 — 2

2 —

3 —

unknown —

Cancer types or histologic subtypes

Prostate 6

Primary Assessment Method

Control Arm: Prostate

 

Number of patients screened

13

Number of patients enrolled

6

Number of patients evaluable for toxicity

6

Number of patients evaluated for efficacy

2

Evaluation method

RECIST v1.1 and PCWG2

Response assessment SD

n = 2 (100%)

(Median) duration assessments duration of treatment

27 days

Adverse Events

Adverse Events Legend

^aNo Change from Baseline/No Adverse Event

All adverse events that are at least probably related to study therapy, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

Serious Adverse Events

Serious Adverse Events Legend

Grade 4 dyspnea and pneumonitis occurred in the same patient.

Dose‐Limiting Toxicities

Assessment, Analysis, and Discussion

Completion

Study terminated before completion

Terminated reason

Toxicity

Pharmacokinetics/Pharmacodynamics

Not collected—pharmacokinetics studies were not performed because the study was terminated early.

Investigator's Assessment

Poorly tolerated/not feasible

In this phase I study of the combination of abiraterone/prednisone plus BEZ235, combination therapy was found to be intolerable. The PI3K (phosphoinositide 3‐kinase) pathway is a major driver of cancer progression in different malignancies. Genomic aberrancy in the PI3K pathway is present in approximately 60% of mCRPC, and PI3K signaling has been identified as a major mechanism of resistance in mCRPC [1], [2]. Preclinical work from different groups has shown cross‐regulation between AR signaling and PI3K‐AKT‐mTOR signaling [3], [4], [5]. Furthermore, combined inhibition of AR signaling and PI3K‐AKT‐mTOR signaling has been shown to augment anti‐cancer activity, particularly in models of prostate cancer with PTEN‐loss [3], [4], [5]. This led to the hypothesis that co‐inhibition of these two interconnected pathways may be a viable strategy to prevent or overcome resistance in patients with CRPC.

Clinical trials of allosteric mTOR inhibitors in men with advanced prostate cancer have demonstrated limited clinical activity [6], [7]. This was thought to be due in part to the activation of AKT and led to the development of strategies that target upstream of PI3K‐AKT‐mTOR signaling. Here, we report the first study designed specifically to target androgen synthesis inhibition in combination with targeting PI3K signaling in mCRPC. In this study, the combination of standard dose abiraterone acetate (1,000 mg daily with prednisone 5 mg b.i.d.) with BEZ235, a potent dual pan‐class I PI3K and mTORC1/2 inhibitor was evaluated (Figure 1). The combination was found to be poorly tolerated, and dose escalation and cohort expansion was not possible.

Six patients were accrued at dose level 1. The median age of the patients was 71 years. The majority of patients (83.3%) had Gleason 8–10 disease (Table 2). All patients had bone metastasis with or without nodal metastasis; no patients had visceral metastasis. The median number of prior therapy for mCRPC was 2 (range: 1–3). All patients had previously progressed on abiraterone and were abiraterone‐resistant. All patients were chemotherapy‐naive (Table 1).

Table 2. Baseline demographic and disease characteristics.

^aAbiraterone dose: 1,000 mg daily with prednisone 5 mg b.i.d.

Abbreviations: ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; mCRPC, metastatic castration resistant prostate cancer; PSA, prostate specific antigen.

The median treatment duration was 27 days (range: 3–130 days). The most common adverse events were grade 1–2 oral mucositis (66.7%), diarrhea (66.7%), nausea (50.0%), anorexia (50.0%), weight loss (50.0%), and musculoskeletal pain (50.0%). Three patients (50%) experienced DLT: grade 3 mucositis, grade 3 hypotension, and grade 4 dyspnea and pneumonitis (Table 3). Five patients (83%) came off study due to study‐related adverse events, and one patient came off study due to disease progression (Table 4). Of the three patients who received study therapy for at least 1 month (range: 38–130 days), none achieved any level of PSA decline (Figure 2). The best radiographic response in two patients was stable disease.

Table 3. Treatment‐related adverse events.

Adverse events were graded by CTCAE v4.0. Patients were classified according to the worst grade of adverse event(s) reported. Adverse events occurring in more than 1 patient (>16.7%) are shown. *Abiraterone dose: 1,000 mg daily with prednisone 5 mg b.i.d.

Table 4. Treatment duration and reason off study.

Abbreviation: AE, adverse event.

Mucositis, anorexia, and weight loss are adverse events previously observed with PI3K‐AKT‐mTOR pathway inhibition and may represent a class effect of targeting the PI3K pathway. These adverse events were observed to a greater extent than anticipated. BEZ235 was administered in suspension, after sachets of the drug were dissolved in approximately 200 mL of water; therefore, the increased rate of mucositis observed may be related to higher drug exposure and absorption in the oral mucosa. All patients enrolled received maximal supportive care; therefore, our findings demonstrate an extremely low likelihood that pan‐PI3K and mTORC1/2 inhibition can be achieved at the dose administered. It is likely that adverse events were contributed by off‐target effects as well as on‐target effects from inhibiting all class I PI3K isoforms in addition to mTORC1/2 inhibition, irrespective of their role in tumorigenesis. Based on these findings as well as findings from another study with this agent (NCT01634061, unpublished, but registered at ClinicalTrials.gov), clinical development of BEZ235 as a potential therapy for prostate cancer was discontinued. Of note, the development of BEZ235 has also been discontinued for renal cell carcinoma (RCC) due to high incidence of DLTs seen in a phase Ib study of BEZ235 monotherapy in advanced RCC patients [8].

Metastatic castration resistant prostate cancer that has progressed despite abiraterone therapy is a challenge for drug development as no agent other than docetaxel chemotherapy has shown consistent clinical activity in this setting [9]. The rationale for targeting the PI3K‐AKT‐mTOR pathway in mCRPC remains sound, however, and distinct agents that may have a more favorable therapeutic index should continue to be explored. Agents targeting specific PI3K isoforms may be better tolerated and achieve greater therapeutic efficacy [10], and several isoform‐specific PI3K inhibitors are currently under investigation as monotherapy or as combination therapy in advanced solid tumors in early phase clinical trials [11]. Furthermore, mTOR inhibitors that compete with the ATP‐binding site are currently under clinical development, including the combination of enzalutamide with a dual ATP‐competitive mTOR and DNA‐PK inhibitor, CC‐115 in men with abiraterone‐ and enzalutamide‐naive progressive mCRPC (NCT02833883) [12].

It remains to be determined what combination of AR and PI3K pathway inhibition will be both tolerable and clinically active. The combination of enzalutamide with BKM120, a pan‐class I PI3 kinase inhibitor, was investigated in a phase II nonrandomized study of BKM120 with or without enzalutamide in men with progressive mCRPC who failed or were not candidates for docetaxel chemotherapy [13]. Thirteen of 30 (43%) patients received BKM120 while continuing enzalutamide. Of all patients treated, treatment was not well tolerated (47% of patients experienced grade 3 adverse events), and no patient achieved >50% PSA response or objective response [13]. More recently, results of a randomized phase II study of ipatasertib (GDC‐0068), an AKT inhibitor, combined with abiraterone/prednisone in men with docetaxel‐pretreated mCRPC, were presented [14). In this study, 253 patients were randomized to ipatasertib 200 mg daily, ipatasertib 400 mg daily, or placebo in combination with standard dose abiraterone. A trend toward improved radiographic progression‐free survival (hazard ratio (HR) = 0.75, p = .17) and overall survival (HR = 0.72, p = .22) was observed with ipatasertib 400 mg daily plus abiraterone, but not ipatasertib 200 mg daily plus abiraterone, indicating a dose response. Importantly, adverse events were also dose dependent, and this combination was well tolerated with manageable side effects. AKT inhibitors lie at an important signaling junction—downstream of PI3K and upstream of mTOR—and may have a better therapeutic index compared with agents such as BEZ235.

Disclosures

Andrew C. Hsieh: Revolution Medicines (C/A); Won Kim: Genentech (C/A); Terence Friedlander: MedBioGene (E), Genentech, AstraZeneca, Clovis Oncology, Pfizer (C/A), Dendreon, Astellas, Sanofi‐Genzyme (H), Janssen, Novartis (RF). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board