A Phase Ib, Open-label Study Evaluating the Safety and Efficacy of Ipatasertib plus Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer

Prostate cancer is the second most common type of cancer in men and is the fifth leading cause of cancer mortality globally (1, 2). In 2020, over 1.4 million new cases and approximately 375,000 deaths globally were attributed to the disease (2). While localized disease is largely curable, cases (nonmetastatic or metastatic disease) that progress to metastatic castration-resistant prostate cancer (mCRPC) remain incurable, highlighting the need for improved therapies (3, 4).

Both AKT and PARP inhibition have demonstrated antitumor activity in patients with mCRPC (5–8). In the phase III IPATential150 trial, the addition of ipatasertib (AKT inhibitor) to abiraterone resulted in a significant risk reduction for radiologic disease progression or death vs. placebo plus abiraterone among patients with tumors that had lost or had low expression of the PTEN tumor suppressor (as assessed by IHC assay; ref. 6). Of note, a statistically significant risk reduction for radiologic disease progression or death was not observed in the intention-to-treat population (6). In follow-up analyses, a greater benefit from ipatasertib in progression-free survival and overall survival was observed in patients with PTEN loss assessed by next-generation sequencing (NGS) versus those assessed by IHC (9, 10). In the phase II TRITON2 trial, rucaparib (PARP inhibitor) demonstrated significant clinical activity with meaningful radiographic and prostate-specific antigen responses in men with BRCA1 or BRCA2 gene alterations (8). The single-agent rucaparib indication for the treatment of BRCA-mutated prostate cancer is currently under accelerated approval (11).

Tumors with mutations leading to homologous recombination (HR) deficiency, including BRCA1 and BRCA2 alterations, are dependent on PARP-mediated DNA repair and have increased sensitivity to PARP inhibitors (12, 13). However, the clinical activity of PARP inhibitors alone in HR-proficient tumors has been found to be limited (14–16). Preclinical studies have demonstrated synergy between PARP and PI3K/AKT inhibition, based on the evidence that PI3K/AKT inhibition can induce an HR deficiency phenotype in HR-proficient tumors, thereby inducing sensitivity to PARP inhibition in HR-proficient tumors in addition to the potential improvement of the response to PARP inhibition in HR-deficient tumors (17–19). In phase I studies, the combination of PARP inhibitors and PI3K or AKT inhibitors has demonstrated evidence of clinical activity, predominantly in breast, ovarian, or fallopian tube cancers (20–22). In addition, in a phase I study, the combination of olaparib and capivasertib was assessed in a range of tumor types, and 3 of 4 patients with prostate cancer achieved radiologic response (partial or complete) or stable disease after 4 or more months per Response Criteria in Solid Tumors (RECIST) 1.1 (23). Cumulatively, these data suggest that a PARP inhibitor and AKT inhibitor combination regimen may have enhanced antitumor activity in patients with mCRPC with an acceptable safety profile.

This phase Ib trial (NCT03840200) sought to determine the maximum tolerated dose (MTD) PARP inhibitor rucaparib combined with AKT inhibitor ipatasertib and explore early safety and clinical activity in patients with mCRPC unselected for tumor mutations.

This phase Ib, open-label, nonrandomized study was conducted in 14 centers internationally, (ClinicalTrials.gov identifier: NCT03840200) and comprised two parts. Part 1 was a dose-escalation phase in patients with advanced prostate, breast, or ovarian cancer, aiming to identify the recommended phase II dose (RP2D). Part 2 was a dose-expansion phase in which patients with advanced prostate cancer received the identified RP2D. The study was approved by the relevant institutional review board. Written informed consent was obtained from all enrolled patients. The clinical trial was performed in accordance with the Declaration of Helsinki.

In the part 1 dose-escalation phase, patients with advanced or metastatic castration-resistant prostate cancer treated with ≥1 prior line of second-generation androgen receptor inhibition therapy; advanced or metastatic ovarian cancer treated with ≥1 prior platinum-based therapy; or advanced or metastatic HER2-negative breast cancer who received and progressed on ≥1 prior endocrine therapy (estrogen receptor/progesterone positive) or were treated with one or two prior lines of chemotherapy (estrogen receptor/progesterone negative) were eligible. Prior taxane therapy, including docetaxel, was allowed. All patients were ≥18 years of age and had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, had fasting glucose of ≤150 mg/dL, and hemoglobin A1c ≤7.5%. Formalin-fixed, paraffin-embedded tumor tissue block or freshly cut tumor slides were required, and patients should have had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (and/or bone lesions by bone scan for mCRPC). Patients with prior treatment with a PARP inhibitor, AKT inhibitor, or PI3K inhibitor were excluded. The part 2 dose-expansion phase had the same eligibility criteria as part 1, but it was limited to patients with mCRPC. Patients were not selected on the basis of their biomarker profile, including HR status.

Part 1 consisted of multiple cohorts (Supplementary Fig. S1). The highest possible dose in the study for ipatasertib (400 mg daily) was chosen, as it was the current dose being evaluated in combination treatments in phase III studies (6, 24). The highest possible dose in the study for rucaparib (600 mg twice daily) was chosen, as it is the current approved dose for monotherapy (11). As the combination of ipatasertib plus rucaparib has not been previously assessed, a dose-escalation design was used. Patients in cohort 1 received reduced doses of ipatasertib (300 mg daily) plus rucaparib (400 mg twice daily). Patients in cohort 2a received the reduced dose of ipatasertib (300 mg daily) plus the highest study dose of rucaparib (600 mg twice daily) and patients in cohort 2b received the highest study dose of ipatasertib (400 mg daily) plus the reduced dose of rucaparib (400 mg twice daily). Patients in cohort 3 received the highest study doses of both agents, ipatasertib (400 mg daily) plus rucaparib (600 mg twice daily). All patients in part 1 underwent a 7-day run-in period of ipatasertib monotherapy prior to cycle 1 day 1. Patients continued to receive study treatment until disease progression (per RECIST 1.1 for breast or ovarian cancer or per Prostate Cancer Working Group 3 criteria for prostate cancer), unacceptable toxicity, death, or patient or investigator decision to withdraw. The RP2D was the highest dose level of each agent with an acceptable safety profile at which less than one-third of patients in a cohort experienced a dose-limiting toxicity. In the part 2 dose-expansion phase, all patients with mCRPC received the RP2D identified in part 1, but without the ipatasertib monotherapy run-in phase (Supplementary Fig. S1).

The primary safety objective was to evaluate the combination of ipatasertib plus rucaparib for (i) identification of the RP2D and schedule; (ii) the incidence, nature, and severity of adverse events (AE); and (iii) the incidence and nature of protocol predefined dose-limiting toxicities determining the MTD (defined as the highest dose level of each agent with an acceptable safety profile and where less than one-third of patients experience a dose-limiting toxicity). The primary efficacy objective was to evaluate the antitumor activity of ipatasertib plus rucaparib in patients with mCRPC based on confirmed PSA response, defined as the proportion of patients with ≥50% reduction in PSA level from baseline. PSA samples were collected on day 1 of each cycle. Secondary efficacy endpoints were objective response rate (ORR) per RECIST 1.1 (confirmed complete response or partial response on two consecutive occasions ≥4 weeks apart), duration of response, radiographic progression-free survival (rPFS) per Prostate Cancer Working Group 3 criteria, and overall survival (OS). The frequency of tumor assessments was approximately every 8 weeks (±2 weeks) for the first 6 months and every 12 weeks thereafter, as clinically indicated. Exploratory endpoints included evaluating the relationship between the presence of HR pathway alterations and efficacy outcomes. HR pathway genes included ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, and RAD54L. Pathway alterations were assessed using the FoundationOne NGS assay (Foundation Medicine). Tumors were considered HR deficient if at least one pathway gene had a functional alteration. Evidence of biallelic functional loss was not required to determine HR deficiency status. PTEN-inactivating alterations could be a homozygous deletion, a heterozygous deletion, dominant negative mutation, or biallelic inactivation (one protein-truncating mutation, splice-site mutation or confirmed somatic missense or non-frameshift mutation in PTEN that is under loss of heterozygosity). AKT1 alteration as determined by NGS included mutations that resulted in an amino acid substitution at E17, L52 or Q79. PIK3CA alterations as determined by NGS included mutations that resulted in an amino acid substitution at R88, G106, K111, G118, N345, C420, E453, E542, E545, Q546, M1043, H1047 or G1049.

The incidence, duration, nature, severity, seriousness, and causality of AEs were evaluated by investigators according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0. AE terms reported were coded using the standard Medical Dictionary for Regulatory Activities preferred terms.

During part 1, a dose-limiting toxicity was defined as any of (i) a death related to study treatment, (ii) grade 4 neutropenia for ≥7 days, (iii) grade ≥3 neutropenia complicated by fever ≥38°C or infection, (iv) grade 4 thrombocytopenia for ≥7 days, (v) grade ≥3 thrombocytopenia complicated by hemorrhage or that requires transfusion, or (vi) grade ≥3 nonhematologic toxicity related to study treatment [excluding grade 3 fatigue, asthenia, fever, anorexia, or constipation; grade 3 nausea, vomiting, or diarrhea that responds to treatment within 72 hours; grade 3 rash that resolves to grade 1 within 7 days with treatment; grade 3 hyperglycemia that is controlled with subcutaneous insulin; grade 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation not accompanied by concurrent increase in bilirubin; and any other grade 3 laboratory abnormality that is asymptomatic and deemed not clinically significant]. The dose-limiting toxicity reporting period corresponded to the first cycle of study treatment [i.e., from cycle 1, day −7 to day 28 (35 days)].

Plasma concentrations for both ipatasertib and its M1 metabolite (G-037720) were collected across the dose-escalation and dose-expansion phases of the study. Within the dose-escalation study, plasma samples for pharmacokinetic characterization of ipatasertib and G-037720 were collected on days 1 and 15 of cycle 1 and days 1 and 15 of cycle 2. Plasma samples on day 1 of cycle 1 (7 days post-ipatasertib monotherapy) were collected at 1, 2, 3, and 5 hours to evaluate ipatasertib pharmacokinetics at steady state when administered alone. Plasma samples on day 15 of cycle 1 onwards were collected pre-dose and at 1, 2, 3, and 5 hours to evaluate ipatasertib pharmacokinetics at steady state when administered in combination with rucaparib. Within the dose-expansion phase, plasma samples for pharmacokinetic characterization of ipatasertib and G-037720 were collected on day 15 of cycle 1, and days 1 and 15 of cycle 2. Plasma samples for pharmacokinetic characterization of rucaparib for both the dose-escalation and dose-expansion cohorts were collected on day 15 of cycle 1, and days 1 and 15 of cycle 2.

Population pharmacokinetic (popPK) analysis was conducted using NONMEM version 7.4.3 to evaluate the drug–drug interaction between ipatasertib and rucaparib. Using a previously developed ipatasertib popPK model (25), study-specific bioavailability parameters were estimated to adjust for observed changes in drug absorption. After the addition to the study specific bioavailability parameter, an additional categorical bioavailability parameter was estimated to explore changes in drug absorption upon the co-administration of ipatasertib and rucaparib. The significance of the rucaparib effect was assessed based on the parameter estimate as well as the change in objective function value after adding in the rucaparib parameter. The popPK model was run using the combination of both dose-escalation and dose-expansion cohorts.

Descriptive statistics were used to summarize the safety and clinical activity of treatment regimens. The 95% confidence interval (CI) for PSA response and ORR was estimated using the Clopper–Pearson method. The Kaplan–Meier method was used to estimate median rPFS, duration of response, and OS, and the Brookmeyer–Crowley method was used to determine the 95% CI.

For eligible studies, qualified researchers may request access to individual patient-level clinical data through a data request platform. At the time of writing, this request platform is Vivli (https://vivli.org/ourmember/roche/). For up-to-date details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see https://go.roche.com/data_sharing. Anonymized records for individual patients across more than one data source external to Roche cannot, and should not, be linked due to a potential increase in risk of patient reidentification.

Overall, 51 patients entered the study, including 47 with mCRPC, 1 with breast cancer, and 3 with ovarian cancer. There were 21 patients in part 1 (8 in cohort 1, 6 in cohort 2a, and 7 in cohort 2b) and 30 patients in part 2. The clinical cutoff date was March 17, 2020 for part 1 and February 2, 2022 for part 2. The representativeness of study participants is assessed in Supplementary Table S1.

The dose-limiting toxicity threshold was exceeded in cohort 2a (ipatasertib 300 mg daily plus rucaparib 600 mg twice daily), which prevented the opening of enrollment in cohort 3. During part 1, three patients experienced dose-limiting toxicities. In cohort 1, one patient experienced grade 3 mucositis; in cohort 2a, one patient had a grade 3 ALT elevation and grade 2 hyperbilirubinemia, and one patient had ALT/AST elevation and grade 3 acute renal failure. With the absence of DLTs in cohort 2b, ipatasertib 400 mg daily plus rucaparib 400 mg twice daily was the selected RP2D and was used in the part 2 dose expansion. As a result, 37 patients received the RP2D [cohort 2b from part 1 (n = 7) plus the part 2 dose expansion (n = 30)]. Patient demographics and disease characteristics of the 37 patients are shown in Table 1. All 37 patients had mCRPC, among whom 41% (15/37) had baseline ECOG PS of 1 and 41% (15/37) were Gleason grade group 5 at diagnosis.

The treatment exposure and safety summary by study cohorts and in all patients who received the RP2D is shown in Table 2. In cohort 1, 50% (4/8) of patients experienced a grade 3 AE, 25% (2/8) a serious AE, and 75% (6/8) an AE leading to treatment modification. In cohort 2a, 83% (5/6) of patients experienced a grade 3 AE, 17% (1/6) a serious AE, and 83% (5/6) an AE leading to treatment modification. There were no grade 4 or 5 AEs in Part 1.

In the 37 patients who received the RP2D, ipatasertib and rucaparib exposures were similar, with a median exposure of 4.9 months for each agent. Overall, 100% (37/37) of patients experienced any-grade AE. AEs occurring in >50% of patients were diarrhea, nausea, weight decrease, and fatigue (Table 3). Grade 3 or 4 AEs occurred in 46% (17/37) of patients. Grade 3 AEs occurring in ≥5% of patients were fatigue, anemia, and acute kidney injury in 8% each (3/37), and diarrhea, nausea, or pulmonary embolism in 5% each (2/37). One grade 4 AE (anemia, deemed by investigators to be related to rucaparib) and no grade 5 AEs were reported. Grade 3 AEs related to ipatasertib occurred in 30% (11/37) of patients and grade 3 AEs related to rucaparib in 30% (11/37); serious AEs occurred in 22% (8/37) of patients. AEs leading to discontinuation of any treatment occurred in 7% (2/37) of patients [fatigue (n = 1) and acute kidney injury (n = 1)]. Of note, a patient in cohort 1 discontinued treatment due to anemia (n = 1). AEs leading to dose reduction occurred in 46% (17/37) of patients and AEs leading to dose interruption in 62% (23/37).

Among the 37 patients with mCRPC exposed to the RP2D, two were excluded from the efficacy analysis, one due to the absence of lesions at baseline and one due to 6 months of underexposure to study drug (patient received a 50% reduced dose in error). The PSA response rate was 26% (9/35; Table 4). Among patients in the overall efficacy-evaluable population with measurable disease at baseline, objective response per RECIST 1.1 was achieved in 10% (2/21) with a duration of response ranging from 5 to 6 months. The median rPFS was 5.8 months (95% CI, 4.0–8.1), and the rPFS event-free rate at 6 months was 50.0% with 15 patients remaining at risk. Similarly, the median OS was 13.3 months (95% CI, 10.9–not evaluable), and the OS event-free rate at 6 months was 97.1% (33 patients at risk).

The efficacy of the combination treatment was also assessed in biomarker-defined subpopulations of patients with mCRPC, specifically those with HRD and/or PIK3CA/AKT1/PTEN alterations (see Methods for definitions). For the 6 patients with HR-deficient tumors [mutations were in BRCA2 (n = 3; 2 frameshift (C1200fs*1 and L2092fs*7) and 1 homozygous deletion), ATM (n = 2; 1 homozygous deletion and 1 splice site mutation (2125–1G>A)), and FANCA (n = 1; 1 frameshift (E1255fs*12))], the PSA response rate was 50% (3/6), with response occurring in the 3 patients with BRCA2 mutations. In patients who were HR-proficient (n = 16), the rate was 25% (4/16; Table 5). Of the HR-proficient patients, 7 had PIK3CA/AKT1/PTEN alterations and 6 had PIK3CA/AKT1/PTEN wild-type tumors (3 were undetermined). Patients with PIK3CA/AKT1/PTEN alterations had a PSA response rate of 14% (1/7) versus 40% (6/15) in patients with PIK3CA/AKT1/PTEN wild-type tumors. There were no patients in the RP2D cohort with tumors with both PIK3CA/AKT1/PTEN alterations and HRD.

Overall, ipatasertib exposures were comparable when administered alone and in combination with rucaparib (Supplementary Table S2). M1 metabolite (G-037720) exposure showed a slight decrease, approximately 18%, when ipatasertib was administered in combination with rucaparib.

Predose rucaparib geometric mean concentrations in the dose expansion cohort were approximately 1,660 ng/mL (64.8%) at cycle 1 day 15 (Table 6). While increased concentrations were observed in the dose-expansion cohort, the effect of ipatasertib on rucaparib was not consistent across the different dose levels evaluated in the dose-escalation cohort. Dose levels 1a and 2b showed comparable exposures when rucaparib was administered in combination with ipatasertib, whereas dose level 2a showed slightly higher concentrations.

In this phase Ib combined dose-escalation and dose-expansion study evaluating the combination of ipatasertib plus rucaparib, the study combination treatment was manageable with dose modification, and no new safety signals were identified beyond the known safety profile of each compound. However, ipatasertib plus rucaparib did not suggest evidence of synergistic or additive antitumor activity in patients with mCRPC. Because of the low number of patients, no final conclusions could be made on the efficacy of the treatment combination in biomarker-defined subgroups.

Key AEs associated with ipatasertib, and PI3K/AKT inhibitors as a class, include diarrhea, rash, and hyperglycemia (26, 27). In this study, diarrhea was the most frequent AE reported, occurring in 97% of patients who received the RP2D, but most events were mild or moderate. Two grade 3 diarrhea events were reported, with a median duration of 5 days. Hyperglycemia occurred in 16% of patients in this study, although none were grades 3 to 5. No treatment discontinuations due to diarrhea, rash, or hyperglycemia were reported. Overall, 70% of patients required a treatment modification (dose reduction, treatment interruption, or discontinuation). Key AEs associated with rucaparib are nausea, fatigue, and blood disorder (28). In the TRITON2 study of single-agent rucaparib for mCRPC, the most common grade ≥3 AEs were anemia/decreased hemoglobin, which occurred in 25% of patients, and thrombocytopenia/decreased platelets, which occurred in 10% of patients (8). In addition, in the TRITON2 study, anemia of any grade occurred in 44% of patients, was the leading cause of treatment interruption (22%) and was the cause of one treatment discontinuation. In this study, anemia occurred in 27% of patients, and one treatment discontinuation due to anemia was reported.

The selected dosing for ipatasertib was 400 mg daily, which is consistent with the dosing of ipatasertib combined with abiraterone and prednisone/prednisolone in the mCRPC setting (5, 6). The selected dosing for rucaparib was 400 mg twice daily due to dose-limiting toxicities occurring in patients receiving 600 mg twice daily in combination with ipatasertib at 300 mg daily. The recommended dose for single-agent rucaparib is 600 mg twice daily, but a 400 mg twice daily regimen is consistent with dosing modification recommendations in case of AE (11). The three dose-limiting toxicities observed overall were grade 3 mucositis in 1 patient, grade 3 ALT elevation, grade 2 hyperbilirubinemia, and ALT/AST elevation in 1 patient, and acute renal failure in 1 patient (none related to blood disorders). Ipatasertib is also associated with increased risk of transaminase increase (27) and may have contributed to the ALT/AST elevations.

On the basis of preclinical studies, suggesting the potential for additive or synergistic activity (19, 29), and prior clinical trial data (6, 8), we theorized that the combination of ipatasertib and rucaparib may have enhanced antitumor activity in mCRPC. In our study, the PSA response rate was 26% in the 35 biomarker unselected patients who received the RP2D, and the ORR was 10% in the 21 patients with measurable disease at baseline who received the RP2D. Compared with other treatments available to this patient population, the PSA response rate and ORR were low (30–32). In patients with mCRPC treated with docetaxel, the PSA response rate was 73% (33); the PSA response rate was 50% and the ORR was 23% when retreated after docetaxel therapy (34). In molecularly defined subgroups, patients treated with prior antiandrogen therapy and who have an alteration in 1 of 15 HR genes may benefit from olaparib, with a PSA response rate of 30% and an ORR of 22% (35). In particular, more heavily pretreated patients with BRCA alterations were more likely to benefit from treatment with rucaparib, with a PSA response rate of 55% and an ORR of 44%, or from treatment with niraparib, with a PSA response rate of 50% and an ORR of 41% (8, 36). In our study, the PSA response rate was 25% (4/16) in the HR-proficient population; however, the small number of patients with HR deficiency limits our ability to draw any conclusions in biomarker-defined populations.

The addition of ipatasertib to abiraterone increased PSA response levels to 81% versus 72% with placebo plus abiraterone in all patients (rates were 83% and 72%, respectively, in patients with PTEN loss tumors by IHC). The ORR was 61% in patients who received ipatasertib versus 44% in those who received placebo (rates were 61% and 39%, respectively, in patients with PTEN loss tumors by IHC; ref. 6). However, the differences in study population, treatment regimen, and study population sizes limit eventual comparison between the IPATential150 trial and the present study, as patients in IPATential150 had not received a prior line of second-generation androgen receptor–targeted therapy and received abiraterone in combination with ipatasertib.

In this study of HR mutation unselected patients, the median rPFS was 5.8 months, whereas it was observed to be 9.0 months in cohort A of the TRITON2 study and 7.4 months in the PROfound study, both of which were conducted in HR-selected populations (BRCA1/2 for TRITON2, and BRCA1/2 and ATM for PROfound; refs. 8, 35). The median rPFS in the IPATential150 trial was 19.2 months overall in patients treated with ipatasertib plus abiraterone (18.5 months in patients with PTEN loss), but this increased duration is likely impacted by the earlier disease stage of these patients (6). In the IPATential150 trial, in addition to PTEN loss by IHC, alterations in PTEN as assessed by NGS were associated with improved rPFS in patients treated with ipatasertib, and a greater impact was observed when the population was expanded to patients with mutations in PIK3CA/AKT1/PTEN (6, 9). A similar trend was observed for OS data at further follow-up (10). In these analyses, assessing PTEN or PIK3CA/AKT1/PTEN alteration by NGS seemed to better identify patients who may benefit from ipatasertib plus abiraterone compared with the assessment of PTEN loss by IHC (9, 10). This is in contrast with the results from our study, where NGS did not identify a target population for this treatment combination, as patients with PIK3CA/AKT1/PTEN wild type status had better clinical outcomes compared with patients with PIK3CA/AKT1/PTEN-altered tumors, although the low patient number limits our ability to comment on the utility of NGS in this population.

The overall ipatasertib plasma concentrations were comparable between administration of ipatasertib alone compared with ipatasertib in combination with rucaparib. The M1 metabolite (G-037720) plasma concentrations were slightly lower, but this is not expected to be detrimental to efficacy as the M1 is 3–5 fold less effective at AKT inhibition than ipatasertib (37, 38). Rucaparib concentrations in the dose expansion cohort were higher when administered in combination with ipatasertib; however, from an efficacy perspective, the rucaparib effect would be expected to be similar because the rucaparib exposures within this study when rucaparib was administered at 400 mg twice daily in combination with ipatasertib were similar to that observed at 600 mg twice daily monotherapy (39).

Methodologic study strengths include a dose-ranging study design to identify the optimal dose for the combination as well as the combined analysis of patients in cohort 2b and the dose-expansion population to increase the size of the population who received the RP2D. Limitations include the small study populations as a whole and the very low number of patients in the biomarker-defined subgroups, limiting the ability to assess the impact of biomarkers on clinical outcomes. In addition, many of the analyses performed herein were descriptive.

In conclusion, the combination of ipatasertib and rucaparib was sufficiently manageable with dose modification but did not show evidence of synergistic or simply additive antitumor activity in previously treated patients with mCRPC. As this was a small study, these results do not definitively rule out a potential benefit from combined AKT and PARP inhibition. However, insufficient clinical efficacy was shown relative to the safety profile to warrant further investigation in this population. Future avenues of research could include assessing this combination in larger numbers of more targeted patient populations, such as patients assessed for PTEN status by NGS instead of IHC.

D. Pook reports nonfinancial support from F. Hoffmann-La Roche during the conduct of the study; personal fees from Bayer, Ispen, and Pfizer; and other support from Astellas, Cipla, MSD, and Pfizer outside the submitted work. D.M. Geynisman reports personal fees from Merck, Bristol Myers Squibb, Seagen, Astellas, Sanofi, and Exelixis outside the submitted work. F. de Braud reports personal fees from Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, MSD, Novartis, Incyte, BMS, Menarini, AstraZeneca, Pierre Fabre, Mattioli 1885, McCann Health, Taiho, Healthcare Research & Pharmacoepidemiology, Merck Group, Pfizer, Servier, Sanofi, Amgen, Dephaforum, Seagen, Ambrosetti, and Itanet as well as other support from Novartis, F. Hoffmann-La Roche, BMS, Ignyta Operating, Merck Sharp & Dohme Italia, Kymab, Pfizer, Tesaro, MSD, MedImmune, Exelixis, Loxo Oncology, Daiichi Sankyo, Basilea Pharmaceutica International, Janssen-Cilag International, Merck KGaA, and IQVIA outside the submitted work. A.M. Joshua reports research funding to the institution from AstraZeneca, Bayer, BMS, Corvus Pharmaceuticals, Janssen Oncology, Macrogenics, Mayne Pharma, MSD, Lilly, Pfizer, and F. Hoffmann-La Roche/Genentech as well as served as a consultant to AstraZeneca, BMS, Eisai, Ideaya, Ipsen, IQVIA, Janssen Oncology, Merck Serono, Neoleukin, Novartis, Noxopharm, Pfizer, and Sanofi; A.M. Joshua also owns stock in Pricilium Therapeutics. J.L. Pérez-Gracia reports grants, personal fees, and nonfinancial support from Roche, MSD, Seagen, and BMS during the conduct of the study as well as grants from Novartis and personal fees from Ipsen outside the submitted work. C. Llácer Pérez reports nonfinancial support from Hoffmann-La Roche and other support from Hoffmann-La Roche during the conduct of the study. B. Fang reports other support from Genentech during the conduct of the study. M. Kim reports personal fees from Merck Sharp & Dohme, Ipsen, Bristol Myers Squibb/Ono Pharmaceutical, Eisai, and Yuhan outside the submitted work. Y. Kerloeguen reports other support from Hoffmann-La Roche during the conduct of the study and other support from Hoffmann-La Roche outside the submitted work; in addition, Y. Kerloeguen is an employee of Hoffmann-La Roche. J.D. Gallo reports other support from Hoffmann-La Roche outside the submitted work and stock options. S.L. Maund reports other support from Health Interactions and Roche during the conduct of the study, and other support from Roche outside the submitted work. A. Harris reports other support from Genentech outside the submitted work; in addition, A. Harris is an employee of Genentech, the sponsor of this study. V. Poon owns Roche stock. D.S. Sutaria is an employee of Roche/Genentech and holds ownership interest in F. Hoffmann-La Roche/Genentech. H. Gurney reports other support from Roche during the conduct of the study as well as personal fees from BMS, Pfizer, Merck Serono, MSD, AstraZeneca, and Ipsen outside the submitted work. No disclosures were reported by the other authors.

D. Pook: Writing–review and editing. D.M. Geynisman: Writing–review and editing. J. Carles: Writing–review and editing. F. de Braud: Writing–review and editing. A.M. Joshua: Writing–review and editing. J.L. Pérez-Gracia: Writing–review and editing. C. Llácer Pérez: Writing–review and editing. S.J. Shin: Writing–review and editing. B. Fang: Writing–review and editing. M. Barve: Writing–review and editing. M. Maruzzo: Writing–review and editing. S. Bracarda: Writing–review and editing. M. Kim: Writing–review and editing. Y. Kerloeguen: Writing–review and editing. J.D. Gallo: Writing–review and editing. S.L. Maund: Writing–review and editing. A. Harris: Writing–review and editing. K. Huang: Writing–review and editing. V. Poon: Writing–review and editing. D.S. Sutaria: Writing–review and editing. H. Gurney: Writing–review and editing.

The study was funded by F. Hoffmann-La Roche and Genentech, a member of the Roche group. We thank the patients who participated in the trial and the clinical site investigators. We thank Andrea Loehr and Heidi Giordano of Clovis Oncology for their contributions to the study. We thank Kenta Yoshida and Rucha Sane for assistance with pharmacokinetic study design and analysis. Medical writing assistance for this manuscript was provided by Scott Battle, PhD (Health Interactions), funded by F. Hoffmann-La Roche.

The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.